establishment-dual-humanized-tk-nog-mouse-model-for-hiv-associated

Establishment of the Dual Humanized TK-NOG Mouse Model for HIV-associated Liver Pathogenesis

Despite the increased life expectancy of patients infected with human immunodeficiency virus-1 (HIV-1), liver disease has emerged as a common cause of ...

University of Nebraska Medical Center

Stable engraftment of human lymphoid tissue in NOD/scid-IL-2Rgammacnull mice after CD34+ hematopoietic stem cell reconstitution permits the evaluation of ongoing HIV-1 infection for weeks to months. We demonstrate that HIV-1-infected rodents develop virus-specific cellular immune responses. CD8+ cell depletion, 2 or 5-7 wk after viral infection, resulted in a significant increase of HIV-1 load, robust immune cell activation, and cytopathology in lymphoid tissues but preserved CD4/CD8 double-positive thymic T cell pools. Human CD8+ cells reappeared in circulation as early as 2-3 wk. These data support a role of CD8+ cells in viral surveillance and the relevance of this humanized mouse model for the studies of HIV-1 pathobiology and virus-specific immunity.

CD8+ cell depletion accelerates HIV-1 immunopathology in humanized mice.

Stabile Verteilung von menschlichem lymphatischen Gewebe NOD/scid-IL-2Rgammacnull M&auml;usen nach CD34 + h&auml;matopoetischen Stammzellen Rekonstitution die Bewertung der laufenden HIV-1-Infektion f&uuml;r Wochen bis Monate erm&ouml;glicht. Wir zeigen, dass HIV-1-infizierten Nagetiere Virus-spezifische zellul&auml;re Immunantworten zu entwickeln. CD8 + Zellen Ersch&ouml;pfung, 2 oder 5-7 wk nach Virusinfektion, f&uuml;hrte zu einem deutlichen Plus von HIV-1 laden, robuste Immunzellen Aktivierung und Inneres in lymphatischen Geweben aber bewahrt CD4/CD8-doppelt-positiven Tumor T-Zell-Becken. Menschliche CD8 +-Zellen tauchte im Umlauf bereits 2-3 Wch. Diese Daten unterst&uuml;tzen eine Rolle von CD8 +-Zellen in virale &Uuml;berwachung und die Relevanz dieser humanisierten Mausmodell f&uuml;r die Studien von HIV-1 Pathobiologie und Virus-spezifischer Immunit&auml;t.

CD8 + Zellen Ersch&ouml;pfung beschleunigt HIV-1 Immunpathologie humanisierte M&auml;usen.

Attecchimento stabile dei tessuti linfoidi umani in topi NOD/scid-IL-2Rgammacnull dopo ricostituzione di cellule staminali emopoietiche CD34 + permette la valutazione dell&#39;infezione da HIV-1 in corso per settimane o mesi. Dimostriamo che HIV-1-infected roditori sviluppano specifici per il virus cellulare risposte immunitarie. CD8 + deplezione delle cellule, 2 o 5-7 settimana dopo l&#39;infezione virale, ha provocato un aumento significativo del carico dell&#39;HIV-1, attivazione delle cellule immunitarie robusto e citopatologia nei tessuti linfoidi, ma conservato piscine double positivo del timo T cell CD4/CD8. CD8 + cellule umane riapparve in circolazione fin dal 2-3 sett. Questi dati supportano un ruolo delle cellule CD8 + in sorveglianza virale e la rilevanza di questo modello di topo umanizzato per gli studi di HIV-1 pathobiology e immunit&agrave; virus-specifici.

Deplezione di cellule CD8 + accelera Immunopatologia di HIV-1 nei topi umanizzati.

La prise de greffe stable du tissu lympho&#xEF;de humain chez la souris apr&#xE8;s NOD/scid-IL-2Rgammacnull h&#xE9;matopo&#xEF;&#xE9;tiques CD34 + de reconstitution sur les cellules souches permet l&#x26;#39;&#xE9;valuation des cours sur le VIH-1 infection pour quelques semaines ou mois. Nous d&#xE9;montrons que le VIH-1-rongeurs infect&#xE9;s de d&#xE9;velopper des virus sp&#xE9;cifiques des r&#xE9;ponses immunitaires cellulaires. CD8 + d&#xE9;pl&#xE9;tion des cellules, 2 ou 5-7 semaines apr&#xE8;s l&#x26;#39;infection virale, a entra&#xEE;n&#xE9; une augmentation significative de la charge du VIH-1, robuste activation des cellules immunitaires, et la cytopathologie dans les tissus lympho&#xEF;des, mais pr&#xE9;serv&#xE9; CD4/CD8 double-positifs thymiques piscines lymphocytes T. L&#x26;#39;homme CD8 + r&#xE9;apparu en circulation d&#xE8;s 2-3 sem. Ces donn&#xE9;es confirment le r&#xF4;le des cellules CD8 + dans la surveillance virale et la pertinence de ce mod&#xE8;le de souris humanis&#xE9;es pour les &#xE9;tudes de VIH-1 et le virus de pathobiologie l&#x26;#39;immunit&#xE9; sp&#xE9;cifique.

CD8 + acc&#xE9;l&#xE8;re la d&#xE9;pl&#xE9;tion des cellules VIH-1 chez la souris humanis&#xE9;es Immunopathologie

&#x690D;&#x5165;&#x7A33;&#x5B9A;&#x72B6;&#x6001;&#x7684; NOD/scid-IL-2Rgammacnull &#x5C0F;&#x9F20;&#x540E; /cd34 + &#x9020;&#x8840;&#x5E72;&#x7EC6;&#x80DE;&#x91CD;&#x5EFA;&#x8BB8;&#x53EF;&#x8BC4;&#x4EF7;&#x7684;&#x51E0;&#x4E2A;&#x661F;&#x671F;&#x5230;&#x51E0;&#x4E2A;&#x6708;&#x6B63;&#x5728;&#x8FDB;&#x884C;&#x827E;&#x6ECB;&#x75C5;&#x6BD2;-1 &#x611F;&#x67D3;&#x4EBA;&#x7C7B;&#x6DCB;&#x5DF4;&#x7EC4;&#x7EC7;&#x3002;&#x6211;&#x4EEC;&#x8BC1;&#x660E;&#x611F;&#x67D3;&#x827E;&#x6ECB;&#x75C5;&#x6BD2; 1 &#x556E;&#x9F7F;&#x52A8;&#x7269;&#x5F00;&#x53D1;&#x75C5;&#x6BD2;&#x7279;&#x5F02;&#x6027;&#x7EC6;&#x80DE;&#x514D;&#x75AB;&#x5E94;&#x7B54;&#x3002;CD8 + &#x7EC6;&#x80DE;&#x8017;&#x7AED;&#xFF0C;2 &#x6216; 5-7 wk &#x540E;&#x75C5;&#x6BD2;&#x6027;&#x611F;&#x67D3;&#xFF0C;&#x5BFC;&#x81F4;&#x827E;&#x6ECB;&#x75C5;&#x6BD2; 1 &#x8D1F;&#x8F7D;&#x3001; &#x5F3A;&#x5065;&#x7684;&#x514D;&#x75AB;&#x7EC6;&#x80DE;&#x6FC0;&#x6D3B;&#x548C;&#x7EC6;&#x80DE;&#x75C5;&#x7406;&#x5B66;&#x5728;&#x6DCB;&#x5DF4;&#x7EC4;&#x7EC7;&#x4E2D;&#x7684;&#x663E;&#x8457;&#x589E;&#x52A0;&#xFF0C;&#x4F46;&#x4FDD;&#x7559; CD4/CD8 &#x53CC;&#x9633;&#x6027;&#x80F8;&#x817A; T &#x7EC6;&#x80DE;&#x6C60;&#x3002;CD8 + &#x7EC6;&#x80DE;&#x91CD;&#x65B0;&#x6D6E;&#x73B0;&#x5728;&#x65E9;&#x5728; 2-3 wk &#x6D41;&#x901A;&#x3002;&#x8FD9;&#x4E9B;&#x6570;&#x636E;&#x652F;&#x6301;&#x75C5;&#x6BD2;&#x76D1;&#x6D4B;&#x548C;&#x827E;&#x6ECB;&#x75C5;&#x6BD2; 1 &#x75C5;&#x539F;&#x751F;&#x7269;&#x5B66;&#x4E0E;&#x75C5;&#x6BD2;&#x7279;&#x5F02;&#x6027;&#x514D;&#x75AB;&#x7684;&#x7814;&#x7A76;&#x8FD9;&#x4E2A;&#x4EBA;&#x6027;&#x5316;&#x7684;&#x5C0F;&#x9F20;&#x6A21;&#x578B;&#x7684;&#x76F8;&#x5173;&#x6027;&#x7684; CD8 + &#x7EC6;&#x80DE;&#x7684;&#x4F5C;&#x7528;&#x3002;

CD8 + &#x7EC6;&#x80DE;&#x6D88;&#x8017;&#x52A0;&#x5FEB;&#x827E;&#x6ECB;&#x75C5;&#x6BD2; 1 &#x4EBA;&#x6027;&#x5316;&#x5C0F;&#x9F20;&#x7684;&#x514D;&#x75AB;&#x75C5;&#x7406;&#x5B66;&#x3002;

CD34&#x5F8C;NOD/scid-IL-2Rgammacnull&#x30DE;&#x30A6;&#x30B9;&#x306B;&#x304A;&#x3051;&#x308B;&#x30D2;&#x30C8;&#x30EA;&#x30F3;&#x30D1;&#x7CFB;&#x7D44;&#x7E54;&#x306E;&#x5B89;&#x5B9A;&#x3057;&#x305F;&#x79FB;&#x690D;&#x306F;&#x3001;+&#x9020;&#x8840;&#x5E79;&#x7D30;&#x80DE;&#x306E;&#x518D;&#x69CB;&#x6210;&#x306F;&#x3001;&#x6570;&#x9031;&#x9593;&#x304B;&#x3089;&#x6570;&#x30AB;&#x6708;&#x306E;&#x7D99;&#x7D9A;&#x7684;&#x306A;HIV-1&#x611F;&#x67D3;&#x75C7;&#x306E;&#x8A55;&#x4FA1;&#x3092;&#x53EF;&#x80FD;&#x306B;&#x3057;&#x307E;&#x3059;&#x3002;&#x6211;&#x3005;&#x306F;HIV-1&#x611F;&#x67D3;&#x3052;&#x3063;&#x6B6F;&#x985E;&#x306F;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x7279;&#x7570;&#x7684;&#x7D30;&#x80DE;&#x6027;&#x514D;&#x75AB;&#x5FDC;&#x7B54;&#x3092;&#x958B;&#x767A;&#x3059;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002; CD8 +&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x611F;&#x67D3;&#x5F8C;&#x306E;&#x7D30;&#x80DE;&#x306E;&#x67AF;&#x6E07;&#x3001;2&#x307E;&#x305F;&#x306F;5&#x304B;&#x3089;7&#x9031;&#x9593;&#x3001;&#x30EA;&#x30F3;&#x30D1;&#x7D44;&#x7E54;&#x306B;&#x304A;&#x3051;&#x308B;HIV-1&#x306E;&#x8CA0;&#x8377;&#x3001;&#x5F37;&#x529B;&#x306A;&#x514D;&#x75AB;&#x7D30;&#x80DE;&#x306E;&#x6D3B;&#x6027;&#x5316;&#x3001;&#x7D30;&#x80DE;&#x75C5;&#x7406;&#x306E;&#x8457;&#x3057;&#x3044;&#x5897;&#x52A0;&#x3092;&#x3082;&#x305F;&#x3089;&#x3057;&#x307E;&#x3059;&#x304C;&#x3001;CD4/CD8&#x30C0;&#x30D6;&#x30EB;&#x30DD;&#x30B8;&#x30C6;&#x30A3;&#x30D6;&#x80F8;&#x817A;T&#x7D30;&#x80DE;&#x30D7;&#x30FC;&#x30EB;&#x3092;&#x7DAD;&#x6301;&#x3057;&#x305F;&#x3002;&#x30D2;&#x30C8;CD8 +&#x7D30;&#x80DE;&#x306F;2-3&#x9031;&#x306B;&#x306F;&#x65E9;&#x304F;&#x3082;&#x6D41;&#x901A;&#x3057;&#x3066;&#x518D;&#x3073;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x30C7;&#x30FC;&#x30BF;&#x306F;&#x3001;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x306E;&#x30B5;&#x30FC;&#x30D9;&#x30A4;&#x30E9;&#x30F3;&#x30B9;&#x3068;HIV-1&#x75C5;&#x7406;&#x3068;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x7279;&#x7570;&#x7684;&#x514D;&#x75AB;&#x306E;&#x7814;&#x7A76;&#x306F;&#x3001;&#x3053;&#x306E;&#x30D2;&#x30C8;&#x5316;&#x30DE;&#x30A6;&#x30B9;&#x30E2;&#x30C7;&#x30EB;&#x306E;&#x59A5;&#x5F53;&#x6027;&#x306E;CD8 +&#x7D30;&#x80DE;&#x306E;&#x5F79;&#x5272;&#x3092;&#x30B5;&#x30DD;&#x30FC;&#x30C8;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;

CD8 +&#x7D30;&#x80DE;&#x306E;&#x67AF;&#x6E07;&#x306F;&#x30D2;&#x30C8;&#x5316;&#x30DE;&#x30A6;&#x30B9;&#x306B;&#x304A;&#x3051;&#x308B;HIV-1&#x514D;&#x75AB;&#x75C5;&#x7406;&#x3092;&#x52A0;&#x901F;

CD34 + &#xC870; &#xD608; &#xC904;&#xAE30; &#xC138;&#xD3EC; &#xC7AC;&#xAD6C;&#xC131;&#xD560; &#xC218; &#xC8FC; &#xB2EC;&#xC5D0; &#xB300; &#xD55C; &#xC9C0;&#xC18D;&#xC801;&#xC778; &#xC5D0;&#xC774;&#xC988;-1 &#xAC10;&#xC5FC;&#xC758; &#xD3C9;&#xAC00; &#xD6C4; &#xB044; &#xB355;/scid-&#xC77C;&#xB9AC;&#xB178;&#xC774;-2Rgammacnull &#xC950;&#xC5D0;&#xC11C; &#xC778;&#xAC04; &#xB9BC;&#xD504; &#xC870;&#xC9C1;&#xC758; &#xC548;&#xC815;&#xC801;&#xC778; engraftment. &#xC5D0;&#xC774;&#xC988;-1 &#xAC10;&#xC5FC; &#xB41C; &#xC124;&#xCE58;&#xB958; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; &#xAD00;&#xB828; &#xC138;&#xD3EC; &#xBA74;&#xC5ED; &#xBC18;&#xC751;&#xC744; &#xAC1C;&#xBC1C; &#xC2DC;&#xC5F0; &#xD569;&#xB2C8;&#xB2E4;. CD8 + &#xC138;&#xD3EC; &#xACE0;&#xAC08;, 2 &#xB610;&#xB294; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; &#xC131; &#xAC10;&#xC5FC; &#xD6C4; 5-7 &#xC8FC; &#xC5D0;&#xC774;&#xC988;-1 &#xBD80;&#xD558;, &#xAC15;&#xB825;&#xD55C; &#xBA74;&#xC5ED; &#xC138;&#xD3EC; &#xD65C;&#xC131;&#xD654; &#xBC0F; &#xB9BC;&#xD504; &#xC870;&#xC9C1;&#xC5D0;&#xC11C; &#xBCD1;&#xB9AC;&#xD559;&#xC758; &#xC0C1;&#xB2F9;&#xD55C; &#xC99D;&#xAC00; &#xADC0;&#xCC29;&#xB418; &#xC5C8; &#xB2E4; &#xD558;&#xC9C0;&#xB9CC; CD4/CD8 &#xB354;&#xBE14; &#xC591;&#xC131; thymic T &#xC138;&#xD3EC; &#xD480;&#xC744; &#xC720;&#xC9C0;. &#xC778;&#xAC04;&#xC758; CD8 + &#xC138;&#xD3EC; &#xC21C;&#xD658; 2-3 &#xC8FC; &#xC77C;&#xCC0D; &#xB4F1;&#xC7A5;. &#xC774;&#xB7EC;&#xD55C; &#xB370;&#xC774;&#xD130;&#xB294; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; &#xAC10;&#xC2DC;&#xC640; &#xC5D0;&#xC774;&#xC988;-1 pathobiology &#xBC0F; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; &#xAD00;&#xB828; &#xBA74;&#xC5ED;&#xC758; &#xC5F0;&#xAD6C;&#xC5D0; &#xB300; &#xD55C;&#xC774; humanized &#xB9C8;&#xC6B0;&#xC2A4; &#xBAA8;&#xB378;&#xC758; &#xAD00;&#xB828;&#xC131;&#xC5D0; CD8 + &#xC138;&#xD3EC;&#xC758; &#xC5ED;&#xD560;&#xC744; &#xC9C0;&#xC6D0;&#xD569;&#xB2C8;&#xB2E4;.

CD8 + &#xC138;&#xD3EC; &#xACE0;&#xAC08; &#xAC00;&#xC18D; humanized &#xC950;&#xC5D0; &#xC788;&#xB294; &#xC5D0;&#xC774;&#xC988;-1 immunopathology.

Injerto estable de los tejidos humanos linfoides en ratones despu&#xE9;s de la NOD/scid-IL-2Rgammacnull CD34 + de la reconstituci&#xF3;n de c&#xE9;lulas madre hematopoy&#xE9;ticas permite la evaluaci&#xF3;n de la continua infecci&#xF3;n VIH-1 durante semanas o meses. Se demuestra que el VIH-1-roedores infectados desarrollan el virus espec&#xED;ficos de la respuesta inmune celular. CD8 + depleci&#xF3;n de c&#xE9;lulas, o 2 semanas 5-7 despu&#xE9;s de la infecci&#xF3;n v&#xED;rica, se tradujo en un incremento significativo de VIH-1 de carga, la activaci&#xF3;n de c&#xE9;lulas inmunes robusto, y citopatolog&#xED;a en tejidos linfoides, pero conserva CD4/CD8 doble positivas piscinas de c&#xE9;lulas T t&#xED;micas. Humanos c&#xE9;lulas CD8 + en la circulaci&#xF3;n volvi&#xF3; a aparecer tan temprano como 2-3 semanas. Estos datos apoyan el papel de las c&#xE9;lulas CD8 + en la vigilancia viral y la relevancia de este modelo de rat&#xF3;n humanizado para el estudio del VIH-1 patobiolog&#xED;a y la inmunidad espec&#xED;fica contra el virus.

CD8 + acelera la depleci&#xF3;n de c&#xE9;lulas del VIH-1 en ratones humanizados Inmunopatolog&#xED;a

&#x6162;&#x6027; hiv-1 &#x611F;&#x67D3;&#x901A;&#x5E38;&#x4F1A;&#x5F71;&#x54CD;&#x884C;&#x4E3A;&#x3001; &#x8BA4;&#x77E5;&#x3001; &#x548C;&#x7535;&#x673A;&#x4EBA;&#x7C7B;&#x611F;&#x67D3;&#x75C5;&#x6BD2;&#x7684;&#x4E3B;&#x673A;&#x4E2D;&#x7684;&#x51FD;&#x6570;&#x548C;&#x901A;&#x5E38;&#x79F0;&#x4E3A;&#x827E;&#x6ECB;&#x75C5;&#x6BD2; 1 &#x5173;&#x8054;&#x8BA4;&#x77E5;&#x969C;&#x788D; &#xFF08;&#x624B;&#xFF09;&#x3002;&#x51FA;&#x73B0;&#x8FD9;&#x79CD;&#x60C5;&#x51B5;&#xFF0C;&#x5728;&#x7A0B;&#x5EA6;&#x4E0A;&#xFF0C;&#x7531;&#x4E8E;&#x767D;&#x7EC6;&#x80DE;&#x8FDB;&#x5165;&#x8111;&#x90E8;&#x8840;&#x7BA1;&#x5468;&#x56F4;&#x533A;&#x57DF;&#x7684;&#x5165;&#x53E3;&#x3002;&#x8FD9;&#x79CD;&#x7EC6;&#x80DE;&#x901A;&#x8FC7;&#x5F81;&#x6C42;&#x8840;&#x8111;&#x5C4F;&#x969C;&#x548C;&#x795E;&#x7ECF;&#x5143;&#x7F51;&#x7EDC;&#x7CFB;&#x7EDF;&#x529F;&#x80FD;&#x7D0A;&#x4E71;&#x4FC3;&#x8FDB;&#x75C5;&#x6BD2;&#x6027;&#x611F;&#x67D3;&#x548C;&#x75BE;&#x75C5;&#x3002;&#x4EE5;&#x524D;&#x7684;&#x4F5C;&#x54C1;&#x8868;&#x73B0;&#x51FA;&#x7684; endocannabinoid &#x7CFB;&#x7EDF;&#x8C03;&#x8282;&#x795E;&#x7ECF;&#x514D;&#x75AB;&#x548C;&#x8FD9;&#x79CD;&#x795E;&#x7ECF;&#x5143;&#x548C;&#x80F6;&#x8D28;&#x7EC6;&#x80DE;&#x7684;&#x529F;&#x80FD;&#x3002;&#x672C;&#x6587;&#x6240;&#x8FF0;&#xFF0C;&#x6211;&#x4EEC;&#x8C03;&#x67E5;&#x4E86; CB2R &#x53D7;&#x4F53;&#x8868;&#x8FBE;&#x7684;&#x5C0F;&#x9F20;&#x827E;&#x6ECB;&#x75C5;&#x6BD2; 1 &#x8111;&#x708E; &#xFF08;&#x914D;&#x7F6E;&#x5355;&#x5143;&#xFF09; &#x548C;&#x5177;&#x6709;&#x9AD8;&#x5EA6;&#x9009;&#x62E9;&#x6027;&#x7684; CB2R &#x6FC0;&#x52A8;&#x5242;&#xFF0C;Gp1a&#xFF0C;&#x8C03;&#x8282;&#x75BE;&#x75C5;&#x7684;&#x80FD;&#x529B;&#x3002;&#x611F;&#x67D3;&#x827E;&#x6ECB;&#x75C5;&#x6BD2;&#x7684; 1 &#x4EBA;&#x5355;&#x6838;&#x7EC6;&#x80DE;&#x6E90;&#x6027;&#x5DE8;&#x566C;&#x88AB;&#x6CE8;&#x5165;&#x5C3E;&#x72B6;&#x6838;&#x548C;&#x58F3;&#x6838;&#x7684;&#x514D;&#x75AB;&#x7F3A;&#x9677;&#x5C0F;&#x9F20;&#x4E0E;&#x4EBA;&#x7C7B;&#x5916;&#x5468;&#x8840;&#x6DCB;&#x5DF4;&#x7EC6;&#x80DE; &#xFF08;&#x914D;&#x7F6E;&#x5355;&#x5143;&#x80E1;-PBL) &#x91CD;&#x7EC4;&#x3002;&#x80E1;-PBL/&#x8702;&#x5DE2;&#x5C0F;&#x9F20;&#x5927;&#x8111;&#x663E;&#x793A;&#x5C0F;&#x80F6;&#x8D28;&#x7EC6;&#x80DE;&#x6FC0;&#x6D3B;&#x548C; CB2R&#xFF0C;&#x4F46;&#x4E0D;&#x662F; CB1R &#x6216; GPR55 &#x8868;&#x8FBE;&#x589E;&#x52A0;&#x3002;Gp1a &#x4ECE;&#x5B9E;&#x8D28;&#x4E0A;&#x51CF;&#x5C11;&#x5C0F;&#x9F20;&#x8111;&#x7EC6;&#x80DE;&#x6E17;&#x5165;&#x548C;&#x964D;&#x4F4E; HLA DQ &#x6FC0;&#x6D3B;&#x3002;Gp1a &#x4E0B;&#x8C03;&#x5236; CCR5 &#x8868;&#x8FBE;&#x5BF9;&#x4EBA;&#x7C7B;&#x7EC6;&#x80DE;&#x7684;&#x813E;&#x4E0E; Fas &#x914D;&#x4F53;&#x8868;&#x8FBE;&#x589E;&#x52A0;&#x3002;&#x6211;&#x4EEC;&#x7684;&#x7814;&#x7A76;&#x7ED3;&#x679C;&#x652F;&#x6301;&#x8FD9;&#x4E00;&#x6982;&#x5FF5; CB2 &#x53D7;&#x4F53;&#x6FC0;&#x52A8;&#x5242;&#x53EF;&#x80FD;&#x662F;&#x53EF;&#x884C;&#x7684;&#x6CBB;&#x7597;&#x624B;&#x5019;&#x9009;&#x4EBA;&#x3002;

CB2 &#x53D7;&#x4F53;&#x6FC0;&#x52A8;&#x5242; neuroAIDS &#x5C0F;&#x9F20;&#x6A21;&#x578B;&#x4E2D;&#x7684;&#x514D;&#x75AB;&#x8C03;&#x8282;&#x4F5C;&#x7528;&#x3002;

Chronic HIV-1 infection commonly affects behavioral, cognitive, and motor functions in the infected human host and is commonly referred to as HIV-1-associated neurocognitive disorders (HAND). This occurs, in measure, as a consequence of ingress of leukocytes into brain perivascular regions. Such cells facilitate viral infection and disease by eliciting blood-brain barrier and neuronal network dysfunctions. Previous works demonstrated that the endocannabinoid system modulates neuroimmunity and as such neuronal and glial functions. Herein, we investigated CB2R receptor expression in murine HIV-1 encephalitis (HIVE) and the abilities of a highly selective CB2R agonist, Gp1a, to modulate disease. HIV-1-infected human monocyte-derived macrophages were injected into the caudate and putamen of immunodeficient mice reconstituted with human peripheral blood lymphocytes (hu-PBL/HIVE). Brains of hu-PBL/HIVE mice showed microglial activation and increased expression of CB2R, but not CB1R or GPR55. Gp1a substantively reduced infiltration of human cells into the mouse brain and reduced HLA DQ activation. Gp1a down modulated CCR5 expression on human cells in the spleen with an increase in Fas ligand expression. Our results support the notion that CB2 receptor agonists may be a viable therapeutic candidate for HAND.

Immunoregulation of a CB2 receptor agonist in a murine model of neuroAIDS.

Chroniques du VIH-1 infection affecte g&#xE9;n&#xE9;ralement les fonctions comportementales, cognitives et motrices chez l&#x26;#39;h&#xF4;te infect&#xE9; l&#x26;#39;homme et est commun&#xE9;ment appel&#xE9;e troubles neurocognitifs VIH-1-associ&#xE9;s (MAIN). Cela se produit, dans une large mesure, comme une cons&#xE9;quence de la p&#xE9;n&#xE9;tration des leucocytes dans les r&#xE9;gions p&#xE9;rivasculaires au cerveau. Ces cellules faciliter l&#x26;#39;infection virale et la maladie en provoquant barri&#xE8;re h&#xE9;mato-enc&#xE9;phalique et les dysfonctionnements du r&#xE9;seau de neurones. Des travaux ant&#xE9;rieurs ont d&#xE9;montr&#xE9; que le syst&#xE8;me endocannabino&#xEF;de module neuroimmunity et que ces fonctions neuronales et gliales. Ici, nous avons &#xE9;tudi&#xE9; l&#x26;#39;expression du r&#xE9;cepteur murin CB2R en VIH-1 enc&#xE9;phalite (ruche) et les capacit&#xE9;s d&#x26;#39;un agoniste hautement s&#xE9;lectif CB2R, Gp1a, de moduler la maladie. VIH-1-humains infect&#xE9;s d&#xE9;riv&#xE9;es de monocytes macrophages ont &#xE9;t&#xE9; inject&#xE9;s dans le noyau caud&#xE9; et le putamen de souris immunod&#xE9;ficientes reconstitu&#xE9;es avec des lymphocytes humains du sang p&#xE9;riph&#xE9;rique (hu-PBL/HIVE). Cerveau de souris a montr&#xE9; hu-PBL/HIVE activation de la microglie et une expression accrue de CB2R, mais pas CB1R ou GPR55. Gp1a r&#xE9;duit de mani&#xE8;re substantielle l&#x26;#39;infiltration de cellules humaines dans le cerveau de souris et r&#xE9;duit HLA DQ activation. Gp1a expression modul&#xE9;e par CCR5 sur les cellules humaines dans la rate avec une augmentation de l&#x26;#39;expression du ligand Fas. Nos r&#xE9;sultats appuient l&#x26;#39;id&#xE9;e que les agonistes des r&#xE9;cepteurs CB2 peut &#xEA;tre un candidat th&#xE9;rapeutique viable pour MAIN.

Immunor&#xE9;gulation d&#x26;#39;un agoniste du r&#xE9;cepteur CB2 dans un mod&#xE8;le murin de NeuroSIDA

Chronischer HIV-1-Infektion h&auml;ufig betrifft, Verhaltens-, kognitiven und Motor-Funktionen in den infizierten menschlichen Gastgeber und wird gemeinhin als HIV-1-assoziierte neurokognitive St&ouml;rungen (HAND). In diesem Fall in Ma&szlig;nahme, infolge Eindringen von Leukozyten in perivaskul&auml;ren Hirnregionen. Solche Zellen erleichtern virale Infektionen und Krankheiten durch die Blut - Hirn-Schranke und neuronale Netzwerk Funktionsst&ouml;rungen hervorrufen. Bisherigen Arbeiten gezeigt, dass das Endocannabinoidsystem Neuroimmunity und als solche neuronalen und Gliazellen Funktionen moduliert. Hier untersuchten wir CB2R Rezeptor Ausdruck in murinen HIV-1-Enzephalitis (HIVE) und den F&auml;higkeiten der eine hochselektive CB2R Agonist, Gp1a, um die Krankheit zu modulieren. HIV-1-infizierten menschliche Monozyte abgeleiteten Makrophagen wurden in der Magenfl&auml;che injiziert und Putamen immungeschw&auml;chte M&auml;use, die mit menschlichen peripheren Blut-Lymphozyten (Hu-PBL/HIVE) wieder aufgebaut. Gehirne von Hu-PBL/HIVE M&auml;use zeigte Microglial Aktivierung und erh&ouml;hte Expression von CB2R, aber nicht CB1R oder GPR55. Gp1a inhaltlich reduzierte Infiltration menschlicher Zellen in das Gehirn der Maus und reduzierte HLA DQ-Aktivierung. Gp1a unten modulierte CCR5-Ausdruck auf menschliche Zellen in der Milz mit einer Zunahme der Fas-Ligand-Ausdruck. Unsere Resultate unterst&uuml;tzen das Konzept, dass CB2-Rezeptor-Agonisten eine tragf&auml;hige therapeutische Kandidat f&uuml;r HAND sein k&ouml;nnen.

Immunoregulation der CB2-Rezeptor-Agonisten in einem murinen Modell des NeuroAIDS.

Infezione cronica da HIV-1 comunemente colpisce comportamentale, cognitivo e motore funzioni nell&#39;ospite umano infetto ed &egrave; comunemente indicato come disturbi di HIV-1-associated neurocognitivo (a mano). In questo caso, nella misura, come conseguenza di infiltrazioni di leucociti nelle regioni perivascolari del cervello. Tali cellule facilitano l&#39;infezione virale e malattia da suscitare la barriera emato - encefalica e disfunzioni rete neuronale. Lavori precedenti hanno dimostrato che il sistema degli endocannabinoidi modula neuroimmunity e funzioni come tale neuronali e gliale. Nel presente documento, abbiamo studiato espressione dei recettori CB2R in murino HIV-1 encefalite (alveare) e le abilit&agrave; di un agonista altamente selettivo del CB2R, Gp1a, di modulare malattia. HIV-1-infected umani macrofagi monocyte-derivati sono stati iniettati nel caudato e putamen di topi immunodeficienti ricostituito con linfociti del sangue periferico umano (hu-PBL/alveare). Cervello di topi hu-PBL/alveare ha mostrato attivazione della microglia e aumentata espressione del CB2R, ma non CB1R o GPR55. Gp1a sostanzialmente ridotta infiltrazione di cellule umane nel cervello del mouse e ridotta attivazione HLA DQ. Gp1a gi&ugrave; espressione CCR5 modulata sulle cellule umane nella milza con un aumento nell&#39;espressione di Fas ligando. I nostri risultati supportano l&#39;idea che agonisti del recettore CB2 potrebbero essere un candidato terapeutico praticabile per mano.

Immunoregolazione di un agonista del recettore CB2 in un modello murino di neuroAIDS.

&#x6162;&#x6027;HIV-1&#x611F;&#x67D3;&#x306F;&#x3001;&#x4E00;&#x822C;&#x7684;&#x306B;&#x611F;&#x67D3;&#x3057;&#x305F;&#x30D2;&#x30C8;&#x5BBF;&#x4E3B;&#x5185;&#x3067;&#x3001;&#x884C;&#x52D5;&#x3001;&#x8A8D;&#x77E5;&#x3001;&#x904B;&#x52D5;&#x6A5F;&#x80FD;&#x306B;&#x5F71;&#x97FF;&#x3092;&#x4E0E;&#x3048;&#x3001;&#x4E00;&#x822C;&#x7684;&#x306B;HIV-1&#x95A2;&#x9023;&#x795E;&#x7D4C;&#x8A8D;&#x77E5;&#x969C;&#x5BB3;&#xFF08;&#x624B;&#xFF09;&#x3068;&#x547C;&#x3070;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x3053;&#x308C;&#x306F;&#x3001;&#x8133;&#x8840;&#x7BA1;&#x9818;&#x57DF;&#x3078;&#x306E;&#x767D;&#x8840;&#x7403;&#x306E;&#x4FB5;&#x5165;&#x306E;&#x7D50;&#x679C;&#x3068;&#x3057;&#x3066;&#x3001;&#x6E2C;&#x5B9A;&#x306B;&#x306F;&#x3001;&#x767A;&#x751F;&#x3057;&#x307E;&#x3059;&#x3002;&#x3053;&#x306E;&#x3088;&#x3046;&#x306A;&#x7D30;&#x80DE;&#x306F;&#x3001;&#x8840;&#x6DB2;&#x8133;&#x95A2;&#x9580;&#x3068;&#x795E;&#x7D4C;&#x56DE;&#x8DEF;&#x7DB2;&#x306E;&#x6A5F;&#x80FD;&#x4E0D;&#x5168;&#x3092;&#x8A98;&#x767A;&#x3059;&#x308B;&#x3053;&#x3068;&#x306B;&#x3088;&#x3063;&#x3066;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x611F;&#x67D3;&#x3084;&#x75C5;&#x6C17;&#x3092;&#x5BB9;&#x6613;&#x306B;&#x3057;&#x307E;&#x3059;&#x3002;&#x4EE5;&#x524D;&#x306E;&#x4F5C;&#x54C1;&#x306F;&#x3001;&#x30A8;&#x30F3;&#x30C9;&#x30AB;&#x30CA;&#x30D3;&#x30CE;&#x30A4;&#x30C9;&#xB7;&#x30B7;&#x30B9;&#x30C6;&#x30E0;&#x304C;neuroimmunity&#x3084;&#x795E;&#x7D4C;&#x7D30;&#x80DE;&#x304A;&#x3088;&#x3073;&#x30B0;&#x30EA;&#x30A2;&#x6A5F;&#x80FD;&#x306A;&#x3069;&#x3092;&#x8ABF;&#x7BC0;&#x3059;&#x308B;&#x3053;&#x3068;&#x3092;&#x5B9F;&#x8A3C;&#x3057;&#x305F;&#x3002;&#x3053;&#x3053;&#x3067;&#x3001;&#x6211;&#x3005;&#x306F;&#x3001;&#x75C5;&#x6C17;&#x3092;&#x8ABF;&#x7BC0;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;&#x3001;&#x30DE;&#x30A6;&#x30B9;&#x306E;HIV-1&#x8133;&#x708E;&#xFF08;HIVE&#xFF09;&#x3068;&#x9078;&#x629E;&#x6027;&#x306E;&#x9AD8;&#x3044;CB2R&#x30A2;&#x30B4;&#x30CB;&#x30B9;&#x30C8;&#x3001;Gp1a&#x306E;&#x80FD;&#x529B;&#x306B;CB2R&#x53D7;&#x5BB9;&#x4F53;&#x306E;&#x767A;&#x73FE;&#x3092;&#x8ABF;&#x3079;&#x305F;&#x3002; HIV-1&#x611F;&#x67D3;&#x30D2;&#x30C8;&#x5358;&#x7403;&#x7531;&#x6765;&#x306E;&#x30DE;&#x30AF;&#x30ED;&#x30D5;&#x30A1;&#x30FC;&#x30B8;&#x306F;&#x30D2;&#x30C8;&#x672B;&#x68A2;&#x8840;&#x30EA;&#x30F3;&#x30D1;&#x7403;&#xFF08;hu-PBL/HIVE&#xFF09;&#x3067;&#x518D;&#x69CB;&#x6210;&#x514D;&#x75AB;&#x4E0D;&#x5168;&#x30DE;&#x30A6;&#x30B9;&#x306E;&#x5C3E;&#x72B6;&#x6838;&#x3068;&#x88AB;&#x6BBB;&#x306B;&#x6CE8;&#x5165;&#x3057;&#x305F;&#x3002; hu-PBL/HIVE&#x30DE;&#x30A6;&#x30B9;&#x306E;&#x8133;&#x3067;&#x306F;&#x30DF;&#x30AF;&#x30ED;&#x30B0;&#x30EA;&#x30A2;&#x306E;&#x6D3B;&#x6027;&#x5316;&#x3068;CB2R&#x306E;&#x767A;&#x73FE;&#x5897;&#x52A0;&#x306F;&#x306A;&#x304F;&#x3001;CB1R&#x307E;&#x305F;&#x306F;GPR55&#x3092;&#x793A;&#x3057;&#x305F;&#x3002; Gp1a&#x306F;&#x3001;&#x5B9F;&#x8CEA;&#x7684;&#x306B;&#x30DE;&#x30A6;&#x30B9;&#x306E;&#x8133;&#x306B;&#x30D2;&#x30C8;&#x7D30;&#x80DE;&#x306E;&#x6D78;&#x6F64;&#x3092;&#x6E1B;&#x5C11;&#x200B;&#x200B;&#x3055;&#x305B;&#x3001;HLA DQ&#x306E;&#x6D3B;&#x6027;&#x5316;&#x3092;&#x6E1B;&#x5C11;&#x3055;&#x305B;&#x305F;&#x3002; Fas&#x30EA;&#x30AC;&#x30F3;&#x30C9;&#x767A;&#x73FE;&#x306E;&#x5897;&#x52A0;&#x3068;&#x813E;&#x81D3;&#x306B;&#x304A;&#x3051;&#x308B;&#x30D2;&#x30C8;&#x7D30;&#x80DE;&#x3067;&#x5909;&#x8ABF;&#x3055;&#x308C;&#x305F;CCR5&#x767A;&#x73FE;&#x30C0;&#x30A6;&#x30F3;Gp1a&#x3002;&#x6211;&#x3005;&#x306E;&#x7D50;&#x679C;&#x306F;&#x3001;CB2&#x53D7;&#x5BB9;&#x4F53;&#x30A2;&#x30B4;&#x30CB;&#x30B9;&#x30C8;&#x306F;&#x3001;&#x624B;&#x306E;&#x305F;&#x3081;&#x306E;&#x5B9F;&#x884C;&#x53EF;&#x80FD;&#x306A;&#x6CBB;&#x7642;&#x85AC;&#x306E;&#x5019;&#x88DC;&#x304B;&#x3082;&#x3057;&#x308C;&#x306A;&#x3044;&#x3068;&#x3044;&#x3046;&#x6982;&#x5FF5;&#x3092;&#x30B5;&#x30DD;&#x30FC;&#x30C8;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;

NeuroAIDS&#x306E;&#x30DE;&#x30A6;&#x30B9;&#x30E2;&#x30C7;&#x30EB;&#x306B;&#x304A;&#x3051;&#x308B;CB2&#x53D7;&#x5BB9;&#x4F53;&#x30A2;&#x30B4;&#x30CB;&#x30B9;&#x30C8;&#x306E;&#x514D;&#x75AB;&#x8ABF;&#x7BC0;

&#xD589;&#xB3D9;, &#xC778;&#xC9C0;, &#xB9CC;&#xC131; &#xC5D0;&#xC774;&#xC988;-1 &#xAC10;&#xC5FC; &#xC77C;&#xBC18;&#xC801;&#xC73C;&#xB85C; &#xC601;&#xD5A5;&#xC744; &#xBBF8;&#xCE69;&#xB2C8;&#xB2E4; &#xADF8;&#xB9AC;&#xACE0; &#xBAA8;&#xD130; &#xAC10;&#xC5FC; &#xB41C; &#xC778;&#xAC04;&#xC758; &#xD638;&#xC2A4;&#xD2B8; &#xAE30;&#xB2A5; &#xADF8;&#xB9AC;&#xACE0; &#xD754;&#xD788; &#xC5D0;&#xC774;&#xC988;-1 &#xAD00;&#xB828; &#xB41C; neurocognitive &#xC7A5;&#xC560; (&#xC190;) &#xB77C;&#xACE0;. &#xC774; &#xCE21;&#xC815;, &#xBC31;&#xD608;&#xAD6C; &#xB1CC; perivascular &#xC601;&#xC5ED;&#xC73C;&#xB85C;&#xC758; &#xC9C4;&#xC785;&#xC758; &#xACB0;&#xACFC;&#xB85C; &#xBC1C;&#xC0DD;&#xD569;&#xB2C8;&#xB2E4;. &#xC774;&#xB7EC;&#xD55C; &#xC140; &#xB1CC;&#xD608;&#xAD00; &#xBC0F; &#xC2E0;&#xACBD; &#xB124;&#xD2B8;&#xC6CC;&#xD06C; &#xC7A5;&#xC560;&#xB97C; &#xB3C4;&#xCD9C; &#xD558; &#xC5EC; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; &#xC131; &#xAC10;&#xC5FC;&#xACFC; &#xC9C8;&#xBCD1;&#xC744; &#xCD09;&#xC9C4;. &#xC774;&#xC804; &#xC791;&#xD488; endocannabinoid &#xC2DC;&#xC2A4;&#xD15C; &#xBCC0;&#xC870; neuroimmunity&#xC640; &#xAC19;&#xC740; &#xC2E0;&#xACBD; &#xAD50; &#xAE30;&#xB2A5;&#xC744; &#xC2DC;&#xC5F0; &#xD588;&#xB2E4;. &#xC5EC;&#xAE30;, &#xC6B0;&#xB9AC;&#xAC00; murine HIV 1 &#xB1CC;&#xC5FC; (&#xD558;&#xC774;&#xBE0C;)&#xC640; &#xC9C8;&#xBCD1;&#xC744; &#xC870;&#xC808; &#xD558; &#xAE38; &#xD56D;&#xC744; &#xB9E4;&#xC6B0; &#xC120;&#xD0DD;&#xC801; CB2R &#xC81C;, Gp1a, &#xB2A5;&#xB825; CB2R &#xC218;&#xC6A9; &#xCCB4; &#xC2DD; &#xC870;&#xC0AC;. &#xC778;&#xAC04;&#xC758; monocyte &#xD30C;&#xC0DD; &#xB41C; macrophages &#xC5D0;&#xC774;&#xC988;-1 &#xAC10;&#xC5FC;&#xC5D0; &#xAF2C;&#xB9AC;&#xAC00; &#xC8FC;&#xC785; &#xD588;&#xB2E4; &#xD558; &#xACE0; &#xC778;&#xAC04;&#xC758; &#xB9D0; &#xCD08; &#xD608;&#xC561; &#xC138;&#xD3EC; (hu-PBL/&#xD558;&#xC774;&#xBE0C;)&#xC640; putamen immunodeficient &#xB9C8;&#xC6B0;&#xC2A4;&#xC758; &#xC7AC;&#xAD6C;&#xC131;. Hu-PBL/&#xD558;&#xC774;&#xBE0C; &#xC950;&#xC758; &#xB450;&#xB1CC; microglial &#xD65C;&#xC131;&#xD654; &#xBCF4;&#xC5EC; &#xC8FC;&#xBA70; CB2R &#xD558;&#xC9C0; CB1R &#xB610;&#xB294; gpr55&#xC758; &#xC2DD;&#xC744; &#xC99D;&#xAC00; &#xD588;&#xB2E4;. Gp1a&#xB294; &#xC2E4;&#xC9C8;&#xC801; &#xC950;&#xC758; &#xB1CC;&#xC5D0; &#xC778;&#xAC04; &#xC138;&#xD3EC;&#xC758; &#xCE68;&#xD22C;&#xB97C; &#xAC10;&#xC18C; &#xD558; &#xACE0; HLA DQ &#xD65C;&#xC131;&#xD654;&#xB97C; &#xAC10;&#xC18C;. Fas &#xB9AC;&#xAC04;&#xB4DC; &#xC2DD;&#xC758; &#xC99D;&#xAC00;&#xC640; &#xBE44;&#xC7A5;&#xC5D0; &#xC778;&#xAC04;&#xC758; &#xC138;&#xD3EC;&#xC5D0; &#xBCC0;&#xC870; CCR5 &#xC2DD; &#xB2E4;&#xC6B4; Gp1a. &#xC6B0;&#xB9AC;&#xC758; &#xACB0;&#xACFC; CB2 &#xC218;&#xC6A9; &#xCCB4; agonists &#xD6C4;&#xBCF4;&#xB85C; &#xC190; &#xCE58;&#xB8CC; &#xAC00;&#xB2A5;&#xD55C; &#xAC83;&#xC740; &#xAC1C;&#xB150;&#xC744; &#xC9C0;&#xC6D0; &#xD569;&#xB2C8;&#xB2E4;.

Immunoregulation Neuroaids&#xC758; murine &#xBAA8;&#xB378;&#xC5D0;&#xC11C; CB2 &#xC218;&#xC6A9; &#xCCB4; &#xAE38; &#xD56D; &#xC81C;.

Cr&#xF3;nica infecci&#xF3;n VIH-1 suele afectar a las funciones del comportamiento, cognitivas y motoras en el hu&#xE9;sped humano infectado y que com&#xFA;nmente se conoce como trastornos neurocognitivos del VIH-1-asociados (mano). Esto ocurre, en medida, como consecuencia de la entrada de leucocitos en regiones del cerebro perivasculares. Estas c&#xE9;lulas facilitan la infecci&#xF3;n viral y la enfermedad mediante la obtenci&#xF3;n de la barrera hematoencef&#xE1;lica y las disfunciones neuronales de la red. Trabajos anteriores demostraron que el sistema endocannabinoide modula neuroimmunity y como tal las funciones neuronales y gliales. En esto, hemos investigado la expresi&#xF3;n de receptores en CB2R murino VIH-1 encefalitis (COLMENA) y las habilidades de un agonista CB2R altamente selectivo, Gp1a, para modular la enfermedad. VIH-1-infected monocitos humanos derivados de los macr&#xF3;fagos fueron inyectados en el n&#xFA;cleo caudado y el putamen de los ratones inmunodeficientes reconstituidos con linfocitos humanos de sangre perif&#xE9;rica (hu-PBL/HIVE). Los cerebros de los ratones hu-PBL/HIVE mostr&#xF3; la activaci&#xF3;n microglial y la expresi&#xF3;n aumentada de CB2R, pero no CB1R o GPR55. Gp1a sustancial redujo la infiltraci&#xF3;n de c&#xE9;lulas humanas en el cerebro del rat&#xF3;n y la reducci&#xF3;n de la activaci&#xF3;n HLA DQ. Gp1a abajo modulada expresi&#xF3;n de CCR5 en las c&#xE9;lulas humanas en el bazo con un aumento en la expresi&#xF3;n del ligando de Fas. Nuestros resultados apoyan la noci&#xF3;n de que los agonistas de los receptores CB2 puede ser un candidato viable para la terap&#xE9;utica MANO.

Inmunorregulaci&#xF3;n de un agonista del receptor CB2 en un modelo murino de NeuroSIDA

Macrophages serve as a depot for HIV type-1 (HIV-1) in the central nervous system. To efficiently target macrophages, we developed nanocarriers for potential brain delivery of activated nucleoside reverse transcriptase inhibitors (NRTIs) called nano-NRTIs.

Nano-NRTIs: efficient inhibitors of HIV type-1 in macrophages with a reduced mitochondrial toxicity.

&#x4EBA;&#x7C7B;&#x514D;&#x75AB;&#x7F3A;&#x9677;&#x75C5;&#x6BD2;&#x7C7B;&#x578B;&#x4E00; &#xFF08;&#x827E;&#x6ECB;&#x75C5;&#x6BD2; 1 &#x578B;&#xFF09; &#x611F;&#x67D3;&#x7684;&#x51E0;&#x4E2A;&#x556E;&#x9F7F;&#x52A8;&#x7269;&#x6A21;&#x578B;&#x53EF;&#x4EE5;&#x53CD;&#x6620;&#x75C5;&#x6BD2;&#x6027;&#x611F;&#x67D3;&#x4EBA;&#x7C7B;&#x7684;&#x8BFE;&#x7A0B;&#x3002;&#x4E3A;&#x6B64;&#xFF0C;&#x6211;&#x4EEC;&#x9010;&#x6B65; hiv-1 &#x611F;&#x67D3;&#x3001; &#x514D;&#x75AB;&#x7684;&#x59A5;&#x534F;&#x548C; neuroinflammatory NOD/scid-IL-2R&gamma;(c)(null) &#x5C0F;&#x9F20;&#x9020;&#x8840; CD34(+) &#x5E72;&#x7EC6;&#x80DE;&#x4E0E;&#x91CD;&#x7EC4;&#x7684;&#x53CD;&#x5E94;&#x4E4B;&#x95F4;&#x7684;&#x5173;&#x7CFB;&#x8FDB;&#x884C;&#x4E86;&#x8C03;&#x67E5;&#x3002;&#x91CD;&#x65B0;&#x586B;&#x5145;&#x7684;&#x8111;&#x819C;&#x53CA;&#x8840;&#x7BA1;&#x5468;&#x56F4;&#x7684;&#x4EBA;&#x8840;&#x6E90;&#x6027;&#x5DE8;&#x566C;&#x7EC6;&#x80DE;&#x5D4C;&#x5408;&#x4F53;&#x52A8;&#x7269;&#x7684;&#x7A7A;&#x683C;&#x3002;&#x5728;&#x6DCB;&#x5DF4;&#x7EC4;&#x7EC7;&#x4E2D;&#x7684;&#x75C5;&#x6BD2;&#x611F;&#x67D3;&#x5230;&#x5927;&#x8111;&#xFF0C;&#x6807;&#x8BB0;&#x4E3A; neuroinflammation&#xFF0C;&#x5E76;&#x5728;&#x4EBA;&#x7C7B;&#x5355;&#x6838;&#x541E;&#x566C;&#x7EC6;&#x80DE;&#x7684;&#x827E;&#x6ECB;&#x75C5;&#x6BD2; 1 &#x590D;&#x5236;&#x5BFC;&#x81F4;&#x52A0;&#x901F;&#x8FDB;&#x5165;&#x4EBA;&#x4F53;&#x7EC6;&#x80DE;&#x3002;&#x8111;&#x819C;&#x708E;&#x548C;&#x4E0D;&#x592A;&#x5E38;&#x7528;&#x7684;&#x8111;&#x708E;&#x540E;&#x5398;&#x7C73; T807 &#x6297;&#x4F53;&#x4ECB;&#x5BFC; CD8(+) &#x7535;&#x6C60;&#x8017;&#x5C3D;&#x3002;&#x6211;&#x4EEC;&#x5F97;&#x51FA;&#x7684;&#x7ED3;&#x8BBA;&#x611F;&#x67D3;&#x827E;&#x6ECB;&#x75C5;&#x6BD2; 1 NOD/scid-IL-2R&gamma;(c)(null) &#x4EBA;&#x6027;&#x5316;&#x5C0F;&#x9F20;&#x53EF;&#x4EE5;&#xFF0C;&#x81F3;&#x5C11;&#x90E8;&#x5206;&#x5730;&#x590D;&#x8FF0;&#x6162;&#x75C5;&#x6BD2; neuropathobiology&#x3002;&#x8FD9;&#x79CD;&#x6A21;&#x5F0F;&#x7684; neuroAIDS &#x53CD;&#x6620;&#x4E86;&#x75C5;&#x6BD2;&#x5B66;&#x3001; &#x514D;&#x75AB;&#x5B66;&#x3001; &#x548C;&#x65E9;&#x671F;&#x75BE;&#x75C5;&#x76F8;&#x5173;&#x795E;&#x7ECF;&#x75C5;&#x7406;&#x5B66;&#x7EC4;&#x4EF6;&#x7684;&#x4EBA;&#x7C7B;&#x75BE;&#x75C5;&#x3002;

&#x4EBA;&#x6027;&#x5316;&#x5C0F;&#x9F20;&#x7684;&#x9010;&#x6B65; hiv-1 &#x611F;&#x67D3;&#x548C;&#x75C5;&#x6BD2;&#x6027; neuropathogenesis &#x4E4B;&#x95F4;&#x7684;&#x8054;&#x7CFB;&#x3002;

Few rodent models of human immunodeficiency virus type one (HIV-1) infection can reflect the course of viral infection in humans. To this end, we investigated the relationships between progressive HIV-1 infection, immune compromise, and neuroinflammatory responses in NOD/scid-IL-2RÎ³(c)(null) mice reconstituted with human hematopoietic CD34(+) stem cells. Human blood-borne macrophages repopulated the meninges and perivascular spaces of chimeric animals. Viral infection in lymphoid tissue led to the accelerated entry of human cells into the brain, marked neuroinflammation, and HIV-1 replication in human mononuclear phagocytes. A meningitis and less commonly an encephalitis followed cM-T807 antibody-mediated CD8(+) cell depletion. We conclude that HIV-1-infected NOD/scid-IL-2RÎ³(c)(null) humanized mice can, at least in part, recapitulate lentiviral neuropathobiology. This model of neuroAIDS reflects the virological, immunological, and early disease-associated neuropathological components of human disease.

Links between progressive HIV-1 infection of humanized mice and viral neuropathogenesis.

Peu de mod&#xE8;les de rongeurs du type de virus de l&#x26;#39;immunod&#xE9;ficience humaine un (VIH-1) infection peut refl&#xE9;ter le cours de l&#x26;#39;infection virale chez l&#x26;#39;homme. &#xC0; cette fin, nous avons &#xE9;tudi&#xE9; les relations entre progressive infection VIH-1, le compromis immunitaire, et les r&#xE9;ponses neuro-inflammatoires dans NOD/scid-IL-2R&#x3B3; (c) (null) les souris reconstitu&#xE9;es avec CD34 humain h&#xE9;matopo&#xEF;&#xE9;tique (+) des cellules souches. L&#x26;#39;homme par le sang macrophages repeupl&#xE9; les m&#xE9;ninges et des espaces p&#xE9;rivasculaires d&#x26;#39;animaux chim&#xE9;riques. L&#x26;#39;infection virale dans les tissus lympho&#xEF;des conduit &#xE0; l&#x26;#39;entr&#xE9;e acc&#xE9;l&#xE9;r&#xE9;e de cellules humaines dans le cerveau, marqu&#xE9;e neuroinflammation, et le VIH-1 dans la r&#xE9;plication de l&#x26;#39;homme phagocytes mononucl&#xE9;aires. Une m&#xE9;ningite et une enc&#xE9;phalite moins fr&#xE9;quemment suivie cM-T807 m&#xE9;di&#xE9;e par les anticorps CD8 (+) la d&#xE9;pl&#xE9;tion des cellules. Nous concluons que le VIH-1-infect&#xE9; NOD/scid-IL-2R&#x3B3; (c) (null) souris humanis&#xE9;es peuvent, au moins en partie, r&#xE9;capituler neuropathobiology lentiviral. Ce mod&#xE8;le de NeuroSIDA refl&#xE8;te les virologiques, immunologiques, et au d&#xE9;but de la maladie associ&#xE9;s &#xE0; des composants neuropathologiques de la maladie humaine.

Liens entre progressiste infection VIH-1 de souris humanis&#xE9;es et Neuropathogenesis virale

Paar Nagetier Modelle des humanen Immundefizienz-Virus Typ 1 (HIV-1) Infektion k&ouml;nnen den Kurs der viralen Infektion beim Menschen widerspiegeln. Zu diesem Zweck untersuchten wir die Beziehungen zwischen progressive HIV-1 Infektion, immun Kompromisse und neuroinflammatorische Antworten in NOD/scid-IL-2R&gamma;(c)(null) M&auml;use mit menschlichen hematopoietic Stammzellen der CD34(+) wiederhergestellt. Menschliche Blut &uuml;bertragbaren Makrophagen neu aufgef&uuml;llt, die Meningen und perivaskul&auml;ren R&auml;ume der Chim&auml;ren Tiere. Virusinfektion im lymphatischen Gewebe f&uuml;hrte zu den beschleunigten Eintrag menschlicher Zellen in das Gehirn, markierte Neuroinflammation und HIV-1-Replikation in menschlichen mononukle&auml;ren Fresszellen. Eine Meningitis und weniger h&auml;ufig eine Enzephalitis folgten cM-T807 antik&ouml;rpervermittelten CD8(+) Zelle Ersch&ouml;pfung. Wir schlie&szlig;en, dass HIV-1-infizierten NOD/scid-IL-2R&gamma;(c)(null) vermenschlicht M&auml;use zumindest teilweise, Lentivirale Neuropathobiology rekapitulieren k&ouml;nnen. Dieses Modell der NeuroAIDS spiegelt die virologischen und immunologischen fr&uuml;hen Krankheit-verbundenen Neuropathologische Komponenten menschlicher Erkrankungen.

Verbindungen zwischen progressive HIV-1 Infektion der humanisierte M&auml;use und virale Neuropathogenesis.

Alcuni modelli di roditori di infezione da virus dell&#39;immunodeficienza umana tipo uno (HIV-1) possono riflettere il corso dell&#39;infezione virale nell&#39;uomo. A tal fine, abbiamo studiato le relazioni tra la progressiva infezione HIV-1, sistema immunitario compromesso e neuroinflammatory risposte nei topi NOD/scid-IL-2R&gamma;(c)(null) ricostituiti con CD34(+) staminali cellule ematopoietiche. Macrofagi umani ematica ripopolarono le meningi e perivascolare spazi degli animali chimerici. Infezione virale nel tessuto linfoide ha condotto alla voce accelerata delle cellule umane nel cervello, contrassegnato neuroinflammation e replica di HIV-1 nei fagociti mononucleari umane. Una meningite e, meno comunemente, un&#39;encefalite seguita cM-T807 anticorpo-mediata cellule deplezione delle cellule. Concludiamo che HIV-1-infected NOD/scid-IL-2R&gamma;(c)(null) umanizzato topi possono, almeno in parte, ripassare lentivirali neuropathobiology. Questo modello di neuroAIDS riflette i virologici, immunologici e precoce associata a malattia neuropatologiche componenti della malattia umana.

Collegamenti tra infezione da HIV-1 progressiva dei topi umanizzati e neuropathogenesis virale.

&#x30D2;&#x30C8;&#x514D;&#x75AB;&#x4E0D;&#x5168;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x30BF;&#x30A4;&#x30D7;1&#xFF08;HIV-1&#xFF09;&#x611F;&#x67D3;&#x75C7;&#x306E;&#x3044;&#x304F;&#x3064;&#x304B;&#x306E;&#x9F67;&#x6B6F;&#x985E;&#x30E2;&#x30C7;&#x30EB;&#x3067;&#x306F;&#x3001;&#x30D2;&#x30C8;&#x306E;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x611F;&#x67D3;&#x306E;&#x7D4C;&#x904E;&#x3092;&#x53CD;&#x6620;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;&#x3067;&#x304D;&#x307E;&#x3059;&#x3002;&#x3053;&#x306E;&#x76EE;&#x7684;&#x306E;&#x305F;&#x3081;&#x306B;&#x3001;&#x6211;&#x3005;&#x306F;NOD/scid-IL-2R&#x3B3;&#xFF08;c&#xFF09;&#x306E;&#x30D7;&#x30ED;&#x30B0;&#x30EC;&#x30C3;&#x30B7;&#x30D6;HIV-1&#x611F;&#x67D3;&#x75C7;&#x3001;&#x514D;&#x75AB;&#x59A5;&#x5354;&#x3057;&#x3001;&#x795E;&#x7D4C;&#x708E;&#x75C7;&#x5FDC;&#x7B54;&#xFF08;null&#xFF09;&#x306E;&#x9593;&#x306E;&#x95A2;&#x4FC2;&#x3092;&#x8ABF;&#x3079;&#x305F;&#x30DE;&#x30A6;&#x30B9;&#x306F;&#x3001;&#x30D2;&#x30C8;&#xFF08;+&#xFF09;CD34&#x9020;&#x8840;&#x5E79;&#x7D30;&#x80DE;&#x3067;&#x518D;&#x69CB;&#x6210;&#x3002;&#x30D2;&#x30C8;&#x306E;&#x8840;&#x6DB2;&#x5A92;&#x4ECB;&#x30DE;&#x30AF;&#x30ED;&#x30D5;&#x30A1;&#x30FC;&#x30B8;&#x306F;&#x9AC4;&#x819C;&#x3068;&#x30AD;&#x30E1;&#x30E9;&#x52D5;&#x7269;&#x306E;&#x8840;&#x7BA1;&#x5468;&#x56F2;&#x306E;&#x30B9;&#x30DA;&#x30FC;&#x30B9;&#x3092;&#x518D;&#x4F5C;&#x6210;&#x3002;&#x30EA;&#x30F3;&#x30D1;&#x7D44;&#x7E54;&#x306B;&#x304A;&#x3051;&#x308B;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x611F;&#x67D3;&#x75C7;&#x306F;&#x3001;&#x8133;&#x3001;&#x8457;&#x3057;&#x3044;&#x795E;&#x7D4C;&#x708E;&#x75C7;&#x3001;&#x30D2;&#x30C8;&#x5358;&#x6838;&#x98DF;&#x7D30;&#x80DE;&#x306B;&#x304A;&#x3051;&#x308B;HIV-1&#x8907;&#x88FD;&#x306B;&#x30D2;&#x30C8;&#x7D30;&#x80DE;&#x306E;&#x52A0;&#x901F;&#x30A8;&#x30F3;&#x30C8;&#x30EA;&#x306B;&#x3064;&#x306A;&#x304C;&#x3063;&#x305F;&#x3002;&#x9AC4;&#x819C;&#x708E;&#x3084;&#x8133;&#x708E;&#x3001;&#x3042;&#x307E;&#x308A;&#x4E00;&#x822C;&#x7684;&#x306B;&#x306F;&#x3001;CM-T807&#x6297;&#x4F53;&#x5A92;&#x4ECB;&#x6027;CD8&#xFF08;+&#xFF09;&#x7D30;&#x80DE;&#x306E;&#x67AF;&#x6E07;&#x306B;&#x7D9A;&#x3044;&#x305F;&#x3002;&#x6211;&#x3005;&#x306F;HIV-1&#x611F;&#x67D3;NOD/scid-IL-2R&#x3B3;&#xFF08;C&#xFF09;&#xFF08;null&#xFF09;&#x3092;&#x30D2;&#x30C8;&#x5316;&#x30DE;&#x30A6;&#x30B9;&#x306F;&#x3001;&#x5C11;&#x306A;&#x304F;&#x3068;&#x3082;&#x90E8;&#x5206;&#x7684;&#x306B;&#x306F;&#x3001;&#x30EC;&#x30F3;&#x30C1;&#x30A6;&#x30A4;&#x30EB;&#x30B9;neuropathobiology&#x3092;&#x518D;&#x73FE;&#x3067;&#x304D;&#x308B;&#x3053;&#x3068;&#x3092;&#x7D50;&#x8AD6;&#x4ED8;&#x3051;&#x3066;&#x3044;&#x308B;&#x3002; neuroAIDS&#x306E;&#x3053;&#x306E;&#x30E2;&#x30C7;&#x30EB;&#x306F;&#x3001;&#x30D2;&#x30C8;&#x306E;&#x75BE;&#x60A3;&#x306E;&#x3001;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x5B66;&#x514D;&#x75AB;&#x5B66;&#x3001;&#x65E9;&#x671F;&#x75BE;&#x60A3;&#x95A2;&#x9023;&#x795E;&#x7D4C;&#x75C5;&#x7406;&#x5B66;&#x7684;&#x6210;&#x5206;&#x3092;&#x53CD;&#x6620;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;

&#x30D2;&#x30C8;&#x5316;&#x30DE;&#x30A6;&#x30B9;&#x306E;&#x30D7;&#x30ED;&#x30B0;&#x30EC;&#x30C3;&#x30B7;&#x30D6;HIV-1&#x611F;&#x67D3;&#x3068;&#x30A6;&#x30A4;&#x30EB;&#x30B9;Neuropathogenesis&#x9593;&#x306E;&#x30EA;&#x30F3;&#x30AF;

&#xC778;&#xAC04; &#xBA74;&#xC5ED; &#xACB0;&#xD54D; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; &#xD0C0;&#xC785; 1 (hiv-1) &#xAC10;&#xC5FC;&#xC758; &#xBA87; &#xAC00;&#xC9C0; &#xC124;&#xCE58;&#xB958; &#xBAA8;&#xB378; &#xC778; &#xAC04;&#xC5D0; &#xC788;&#xB294; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; &#xC131; &#xAC10;&#xC5FC;&#xC758; &#xACFC;&#xC815;&#xC744; &#xBC18;&#xC601;&#xD560; &#xC218; &#xC788;&#xB2E4;. &#xC774; &#xC704;&#xD574; &#xC6B0;&#xB9AC; &#xC9C4;&#xBCF4;&#xC801;&#xC778; &#xC5D0;&#xC774;&#xC988;-1 &#xAC10;&#xC5FC;, &#xBA74;&#xC5ED; &#xC190;&#xC0C1; NOD/scid-IL-2R&gamma;(c)(null) &#xC0DD;&#xC950; &#xC778;&#xAC04; &#xC870; &#xD608; CD34(+) &#xC904;&#xAE30; &#xC138;&#xD3EC;&#xC640; &#xD568;&#xAED8; &#xC7AC;&#xAD6C;&#xC131;&#xC5D0;&#xC11C; neuroinflammatory &#xC751;&#xB2F5; &#xC0AC;&#xC774;&#xC758; &#xAD00;&#xACC4;&#xB97C; &#xC870;&#xC0AC; &#xD588;&#xB2E4;. &#xC778;&#xAC04;&#xC758; &#xD608;&#xC561;&#xC744; &#xB9E4;&#xAC1C;&#xB85C; &#xD55C; &#xB300; &#xC2DD; &#xC138;&#xD3EC; &#xB2E4;&#xC2DC; meninges&#xACFC; perivascular chimeric &#xB3D9;&#xBB3C;&#xC758; &#xACF5;&#xAC04;. &#xB9BC;&#xD504; &#xC870;&#xC9C1;&#xC5D0;&#xC11C; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; &#xAC10;&#xC5FC; neuroinflammation, &#xC778;&#xAC04;&#xC758; &#xB2E8; &#xC2DD; &#xC138;&#xD3EC;&#xC5D0;&#xC11C; HIV 1 &#xBCF5;&#xC81C; &#xB41C; &#xB450;&#xB1CC;&#xC5D0; &#xC778;&#xAC04; &#xC138;&#xD3EC;&#xC758; &#xAC00;&#xC18D;&#xB41C; &#xD56D;&#xBAA9;&#xC744; &#xC774;&#xB04C;&#xC5C8;&#xB2E4;. &#xD55C; &#xC218; &#xB9C9; &#xC5FC;&#xACFC; &#xC790;&#xC8FC;&#xB294; &#xB1CC;&#xC5FC; cM T807 &#xD56D; &#xCCB4; &#xC911;&#xC7AC; CD8(+) &#xC140; &#xACE0;&#xAC08;&#xC744; &#xB530; &#xB790; &#xB2E4;. &#xC6B0;&#xB9AC;&#xB294; &#xC5D0;&#xC774;&#xC988;-1 &#xAC10;&#xC5FC; NOD/scid-IL-2R&gamma;(c)(null) humanized &#xB9C8;&#xC6B0;&#xC2A4; lentiviral neuropathobiology &#xC815;&#xB9AC; &#xBD80;&#xBD84;&#xC5D0;&#xC11C; &#xC801;&#xC5B4;&#xB3C4; &#xC218;, &#xACB0;&#xB860;. Neuroaids&#xC774;&#xC774; &#xBAA8;&#xB378; virological, &#xBA74;&#xC5ED;, &#xADF8;&#xB9AC;&#xACE0; &#xCD08;&#xAE30; &#xC9C8;&#xBCD1; &#xAD00;&#xB828; &#xB41C; neuropathological&#xC758; &#xAD6C;&#xC131; &#xC694;&#xC18C; &#xC778;&#xAC04;&#xC758; &#xC9C8;&#xBCD1;&#xC744; &#xBC18;&#xC601;&#xD569;&#xB2C8;&#xB2E4;.

Humanized &#xC950;&#xC758; &#xC9C4;&#xBCF4;&#xC801;&#xC778; &#xC5D0;&#xC774;&#xC988;-1 &#xAC10;&#xC5FC; &#xBC0F; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; &#xC131; neuropathogenesis &#xC0AC;&#xC774;&#xC758; &#xB9C1;&#xD06C;.

Pocos modelos de roedores de tipo virus de inmunodeficiencia humana uno (VIH-1) la infecci&#xF3;n puede reflejar el curso de la infecci&#xF3;n viral en los seres humanos. Para ello, hemos investigado las relaciones entre progresiva infecci&#xF3;n VIH-1, compromiso inmunol&#xF3;gico, y las respuestas neuroinflamatorios en NOD/scid-IL-2R&#x3B3; (c) (null) ratones reconstituidos con hematopoy&#xE9;tico humano CD34 (+) las c&#xE9;lulas madre. Humanos transmitidos por la sangre vuelve a llenar los macr&#xF3;fagos de las meninges y espacios perivasculares de animales quim&#xE9;ricos. La infecci&#xF3;n viral en el tejido linfoide llev&#xF3; a la entrada acelerada de las c&#xE9;lulas humanas en el cerebro, marc&#xF3; la neuroinflamaci&#xF3;n, y el VIH-1 de replicaci&#xF3;n en los fagocitos mononucleares humanos. Una meningitis y con menor frecuencia una encefalitis seguido CM-T807 mediada por anticuerpos CD8 (+) la depleci&#xF3;n de c&#xE9;lulas. Se concluye que el VIH-1-infectada NOD/scid-IL-2R&#x3B3; (c) (nula) ratones humanizados pueden, al menos en parte, recapitular neuropathobiology lentiviral. Este modelo de neuroSIDA refleja los virol&#xF3;gicos, inmunol&#xF3;gicos y principios de la enfermedad asociada a los componentes neuropatol&#xF3;gicos de la enfermedad humana.

V&#xED;nculos entre la progresiva infecci&#xF3;n VIH-1 de los ratones humanizados y neuropatog&#xE9;nesis viral

&#x6B63;&#x5728;&#x8FDB;&#x884C;&#x7684;&#x4EBA;&#x7C7B;&#x514D;&#x75AB;&#x7F3A;&#x9677;&#x75C5;&#x6BD2;&#x6240;&#x81F4;&#x7684;&#x795E;&#x7ECF;&#x5143;&#x635F;&#x4F24;&#x7C7B;&#x578B; 1 &#xFF08;&#x827E;&#x6ECB;&#x75C5;&#x6BD2; 1 &#x578B;&#xFF09; &#x611F;&#x67D3;&#x7684;&#x4EBA;&#x6027;&#x5316; NOD/scid-IL-2R&gamma;(c)(null) &#x5C0F;&#x9F20;&#x51FA;&#x751F;&#x4E0E; CD34 &#x9633;&#x6027;&#x9020;&#x8840;&#x5E72;&#x7EC6;&#x80DE;&#x79FB;&#x690D;&#x8FDB;&#x884C;&#x4E86;&#x8C03;&#x67E5;&#x3002;&#x5C0F;&#x9F20;&#x611F;&#x67D3;&#x5728; 5 &#x4E2A;&#x6708;&#x7684;&#x5E74;&#x9F84;&#x548C;&#x9075;&#x5FAA; 15 &#x5468;&#x4FDD;&#x6301;&#x5927;&#x91CF;&#x8840;&#x6D46;&#x75C5;&#x6BD2;&#x52A0;&#x8F7D;&#x548C;&#x663E;&#x793A;&#x7684; CD4(+) T &#x7EC6;&#x80DE;&#x7684;&#x4EBA;&#x6570;&#x51CF;&#x5C11;&#x3002;&#x51C6;&#x4E32;&#x884C;&#x8D28;&#x5B50;&#x78C1;&#x5171;&#x632F;&#x6CE2;&#x8C31;&#x6D4B;&#x8BD5;&#x663E;&#x793A;&#x9009;&#x62E9;&#x6027;&#x51CF;&#x5C11;&#x76AE;&#x8D28; N-&#x4E59;&#x9170;&#x5929;&#x95E8;&#x51AC;&#x6C28;&#x9178;&#x5728;&#x53D7;&#x611F;&#x67D3;&#x7684;&#x52A8;&#x7269;&#x3002;&#x5F25;&#x6563;&#x5F20;&#x91CF;&#x6210;&#x50CF;&#x663E;&#x793A;&#x76AE;&#x5C42;&#x7070;&#x8D28;&#x7684;&#x7ED3;&#x6784;&#x6027;&#x53D8;&#x5316;&#x3002;&#x795E;&#x7ECF;&#x5143;&#x548C;&#x80F6;&#x8D28;&#x7EC6;&#x80DE;&#x6807;&#x8BB0;&#xFF0C;&#x6B7B;&#x540E;&#x514D;&#x75AB;&#x8367;&#x5149;&#x8111;&#x7EC4;&#x7EC7;&#x8003;&#x8BD5;&#x7684;&#x591A;&#x5149;&#x8C31;&#x6210;&#x50CF;&#x955C;&#x88AB;&#x6355;&#x83B7;&#xFF0C;&#x5E76;&#x91CF;&#x5316;&#x7684;&#x5F62;&#x6001;&#x8BA1;&#x91CF;&#x5B66;&#x548C;&#x8367;&#x5149;&#x53D1;&#x5C04;&#xFF0C;&#x8868;&#x660E;&#x533A;&#x57DF;&#x51CF;&#x5C11;&#x9762;&#x795E;&#x7ECF;&#x548C;&#x7A81;&#x89E6;&#x7684;&#x4F53;&#x7CFB;&#x7ED3;&#x6784;&#x3002;&#x8FD9;&#x4F53;&#x73B0;&#x5728;&#x5FAE;&#x7BA1;&#x76F8;&#x5173;&#x86CB;&#x767D; 2&#x3001; &#x7A81;&#x89E6;&#x4F53;&#x7D20;&#x548C;&#x4E1D;&#x6297;&#x539F;&#x7684;&#x635F;&#x5931;&#x3002;&#x8FD9;&#x662F;&#x9996;&#x9879;&#x7814;&#x7A76;&#xFF0C;&#x5C31;&#x6211;&#x4EEC;&#x6240;&#x77E5;&#xFF0C;&#x827E;&#x6ECB;&#x75C5;&#x6BD2; 1 &#x4EBA;&#x6027;&#x5316;&#x5C0F;&#x9F20;&#x611F;&#x67D3;&#x540E;&#x8BC1;&#x660E;&#x4E22;&#x5931;&#x795E;&#x7ECF;&#x5143;&#x7684;&#x5B8C;&#x6574;&#x6027;&#x3002;&#x4E3A;&#x6B64;&#xFF0C;&#x6A21;&#x578B;&#x5141;&#x8BB8;&#x8FDB;&#x884C;&#x4E2D;&#x75C5;&#x6BD2;&#x7684;&#x590D;&#x5236;&#x548C;&#x75C5;&#x6BD2;&#x76F8;&#x5173;&#x7684;&#x795E;&#x7ECF;&#x53D8;&#x6027;&#x4E4B;&#x95F4;&#x5173;&#x7CFB;&#x7684;&#x7814;&#x7A76;&#x3002;

&#x671F;&#x95F4;&#x9010;&#x6B65; hiv-1 &#x611F;&#x67D3;&#x7684;&#x4EBA;&#x6027;&#x5316;&#x5C0F;&#x9F20;&#x795E;&#x7ECF;&#x5143;&#x5B8C;&#x6574;&#x6027;&#x635F;&#x5931;&#x3002;

Neuronal damage induced by ongoing human immunodeficiency virus type 1 (HIV-1) infection was investigated in humanized NOD/scid-IL-2RÎ³(c)(null) mice transplanted at birth with human CD34-positive hematopoietic stem cells. Mice infected at 5 months of age and followed for up to 15 weeks maintained significant plasma viral loads and showed reduced numbers of CD4(+) T-cells. Prospective serial proton magnetic resonance spectroscopy tests showed selective reductions in cortical N-acetyl aspartate in infected animals. Diffusion tensor imaging revealed structural changes in cortical gray matter. Postmortem immunofluorescence brain tissue examinations for neuronal and glial markers, captured by multispectral imaging microscopy and quantified by morphometric and fluorescence emission, showed regional reduction of neuronal soma and synaptic architectures. This was evidenced by loss of microtubule-associated protein 2, synaptophysin, and neurofilament antigens. This study is the first, to our knowledge, demonstrating lost neuronal integrity after HIV-1 infection in humanized mice. As such, the model permits studies of the relationships between ongoing viral replication and virus-associated neurodegeneration.

Loss of neuronal integrity during progressive HIV-1 infection of humanized mice.

L&#xE9;sions neuronales induite par le virus de type cours de l&#x26;#39;immunod&#xE9;ficience humaine 1 (VIH-1) infection a &#xE9;t&#xE9; &#xE9;tudi&#xE9;e dans NOD/scid-IL-2R&#x3B3; humanis&#xE9; (c) (null) les souris transplant&#xE9;es &#xE0; la naissance de l&#x26;#39;homme avec CD34-positives cellules souches h&#xE9;matopo&#xEF;&#xE9;tiques. Souris infect&#xE9;es &#xE0; 5 mois d&#x26;#39;&#xE2;ge et de suivi pour un maximum de 15 semaines conserv&#xE9; des charges virales plasmatiques significatives et ont montr&#xE9; une r&#xE9;duction du nombre de CD4 (+) T-cellules. Futurs s&#xE9;rie magn&#xE9;tique du proton essais spectroscopie de r&#xE9;sonance a montr&#xE9; des r&#xE9;ductions s&#xE9;lectives de corticale N-ac&#xE9;tyl aspartate chez les animaux infect&#xE9;s. Diffusion Tensor Imaging a r&#xE9;v&#xE9;l&#xE9; des changements structurels dans la mati&#xE8;re grise corticale. Autopsie des examens d&#x26;#39;immunofluorescence de tissus c&#xE9;r&#xE9;braux pour les marqueurs neuronales et gliales, captur&#xE9;s par microscopie imagerie multispectrale et quantifi&#xE9;s par l&#x26;#39;&#xE9;mission de fluorescence, morphom&#xE9;triques et a montr&#xE9; une r&#xE9;duction r&#xE9;gionale du soma neuronal et architectures synaptiques. Cela a &#xE9;t&#xE9; attest&#xE9; par la perte de microtubule-associated protein 2, synaptophysine, et des antig&#xE8;nes de neurofilaments. Cette &#xE9;tude est la premi&#xE8;re, &#xE0; notre connaissance, ce qui d&#xE9;montre perdu l&#x26;#39;int&#xE9;grit&#xE9; neuronale apr&#xE8;s le VIH-1 chez les souris humanis&#xE9;es. En tant que tel, le mod&#xE8;le permet l&#x26;#39;&#xE9;tude des relations entre la r&#xE9;plication virale et le virus continue neurod&#xE9;g&#xE9;n&#xE9;rescence associ&#xE9;e &#xE0; la.

Perte de l&#x26;#39;int&#xE9;grit&#xE9; neuronale Pendant progressif du VIH-1 infection de souris humanis&#xE9;es

Neuronale Sch&auml;den induziert durch laufende humanen Immundefizienz-Virus Typ 1 (HIV-1) Infektion wurde untersucht, humanisierte NOD/scid-IL-2R&gamma;(c)(null) M&auml;usen bei der Geburt mit humanen CD34-positiven h&auml;matopoetischen Stammzellen transplantiert. M&auml;use infiziert 5 Monate alt und bis zu 15 Wochen folgte gepflegt virale erhebliche Plasma l&auml;dt und zeigten reduzierte Anzahl von CD4(+) T-Zellen. Prospektive serielle Proton Magnetresonanz-Spektroskopie-Tests zeigten selektive K&uuml;rzungen in kortikalen N-Acetyl-Aspartat in infizierten Tieren. Diffusion Tensor Bildgebung offenbart strukturelle Ver&auml;nderungen im kortikalen grauen Substanz. Post mortem Immunofluoreszenz Gehirn Gewebe Pr&uuml;fungen f&uuml;r neuronale und Gliazellen Marker, von multispektralen Bildverarbeitung Mikroskopie erfasst und quantifiziert von morphometrischer und Fluoreszenz-Emission, zeigte regionale Verringerung der neuronalen Soma und synaptische Architekturen. Dies wurde durch den Verlust des Microtubule-verbundenen Protein 2, Synaptophysin und Neurofilament Antigene belegt. Diese Studie ist die erste, nach unserem Wissen verlorene neuronale Integrit&auml;t nach HIV-1 Infektion humanisierte M&auml;usen demonstriert. Das Modell erlaubt als solche Studien &uuml;ber die Beziehungen zwischen laufenden Virusreplikation und Virus-assoziierte Neurodegeneration.

Verlust der neuronale Integrit&auml;t w&auml;hrend der progressiven HIV-1 Infektion humanisierte M&auml;use.

Danno neuronale indotta dal virus di immunodeficienza umana in corso tipo 1 (HIV-1) infezione &egrave; stato studiato in umanizzato NOD/scid-IL-2R&gamma;(c)(null) topi trapiantati alla nascita con cellule staminali ematopoietiche CD34-positivi umane. Topi infettati all&#39;et&agrave; di 5 mesi e seguiti fino a 15 settimane mantennero significativo plasma virale carichi e ha mostrato la riduzione del numero di linfociti T CD4(+). Test di spettroscopia di risonanza magnetica protonica prospettico seriale ha mostrati riduzioni selettive nella corticale N-acetil aspartato in animali infetti. Imaging di tensore di diffusione ha rivelato cambiamenti strutturali in materia grigia corticale. Esami di tessuto cerebrale post-mortem immunofluorescenza per marker neuronale e gliale, catturato da microscopia imaging multispettrale e quantificato mediante emissione di fluorescenza e morfometrici, ha mostrato una riduzione regionale del soma neuronale e sinaptiche architetture. Ci&ograve; &egrave; stato evidenziato dalla perdita del microtubule-associated protein 2, sinaptofisina e antigeni neurofilamento. Questo studio &egrave; il primo, a nostra conoscenza, dimostrando integrit&agrave; neuronale perso dopo l&#39;infezione di HIV-1 nei topi umanizzati. Come tale, il modello permette studi delle relazioni tra replicazione virale in corso e neurodegenerazione associata a virus.

Perdita di integrit&agrave; neuronale durante l&#39;infezione da HIV-1 progressiva dei topi umanizzati.

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&#xC9C0;&#xC18D;&#xC801;&#xC778; &#xC778;&#xAC04; &#xBA74;&#xC5ED; &#xACB0;&#xD54D; &#xBC14;&#xC774;&#xB7EC;&#xC2A4;&#xC5D0; &#xC758;&#xD574; &#xC720;&#xBC1C; &#xB41C; &#xC2E0;&#xACBD; &#xC190;&#xC0C1;&#xC744; &#xC785;&#xB825; 1 (hiv-1) &#xAC10;&#xC5FC; &#xC778;&#xAC04;&#xC758; CD34 &#xC591;&#xC131; &#xC870; &#xD608; &#xC904;&#xAE30; &#xC138;&#xD3EC;&#xB294; &#xCD9C;&#xC0DD; &#xC2DC; &#xC774;&#xC2DD; humanized NOD/scid-IL-2R&gamma;(c)(null) &#xB9C8;&#xC6B0;&#xC2A4;&#xC5D0;&#xC11C; &#xC870;&#xC0AC; &#xB418;&#xC5C8;&#xB2E4;. &#xB9C8;&#xC6B0;&#xC2A4; &#xAC10;&#xC5FC; &#xC0DD; &#xD6C4; 5 &#xAC1C;&#xC6D4;, &#xCD5C;&#xB300; 15 &#xC8FC; &#xB4A4; &#xC720;&#xC9C0; &#xC911;&#xC694; &#xD55C; &#xD50C;&#xB77C;&#xC988;&#xB9C8; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; &#xC131; &#xB85C;&#xB4DC; &#xD558; &#xACE0; CD4(+) T-&#xC138;&#xD3EC;&#xC758; &#xC22B;&#xC790;&#xB97C; &#xAC10;&#xC18C;&#xB97C; &#xBCF4;&#xC600;&#xB2E4;. &#xC608;&#xBE44; &#xC9C1;&#xB82C; &#xC591;&#xC131;&#xC790; &#xC790;&#xAE30; &#xACF5;&#xBA85; &#xBD84;&#xAD11;&#xD559; &#xD14C;&#xC2A4;&#xD2B8; &#xAC10;&#xC5FC; &#xB41C; &#xB3D9;&#xBB3C;&#xC5D0;&#xC11C; &#xB300;&#xB1CC; &#xD53C; &#xC9C8;&#xC758; N-acetyl aspartate &#xC120;&#xD0DD;&#xC801; &#xAC10;&#xC18C;&#xB97C; &#xBCF4;&#xC600;&#xB2E4;. &#xD655;&#xC0B0; &#xD150;&#xC11C; &#xC601;&#xC0C1; &#xACF5;&#xAC1C; &#xB300;&#xB1CC; &#xBC31; &#xC9C8; &#xAD6C;&#xC870; &#xBCC0;&#xACBD;. &#xC2E0;&#xACBD; &#xBC0F; &#xAD50; &#xD45C;&#xC2DD;&#xC5D0; &#xB300; &#xD55C; &#xC0AC;&#xD6C4; &#xBA74;&#xC5ED; &#xD615;&#xAD11; &#xAC80;&#xC0AC; &#xB1CC; &#xC870;&#xC9C1; &#xAC80;&#xC0AC; &#xC6D0;&#xACA9; &#xC601;&#xC0C1; &#xD604;&#xBBF8;&#xACBD; &#xCEA1;&#xCC98;&#xD558;&#xACE0; &#xD615;&#xD0DC;&#xD559; &#xBC0F; &#xD615;&#xAD11; &#xBC29;&#xCD9C;, &#xC9C0;&#xC5ED; &#xAC10;&#xC18C; &#xC2E0;&#xACBD; &#xC18C;&#xB9C8;&#xC640; &#xC2DC; &#xB0C5; &#xC2A4; &#xAD6C;&#xC870;&#xB97C; &#xBCF4;&#xC5EC;&#xC8FC; &#xD558; &#xC5EC; &#xACC4;&#xB7C9; &#xD569;&#xB2C8;&#xB2E4;. &#xC774;&#xAC83;&#xC740; &#xC190;&#xC2E4; microtubule &#xAD00;&#xB828; &#xB2E8;&#xBC31;&#xC9C8; 2, synaptophysin, neurofilament &#xD56D; &#xC6D0;&#xC5D0; &#xC758;&#xD574; &#xC785;&#xC99D; &#xB418;&#xC5C8;&#xB2E4;. &#xC774; &#xC5F0;&#xAD6C;&#xB294; &#xBA3C;&#xC800;, &#xC6B0;&#xB9AC;&#xC758; &#xC9C0;&#xC2DD;, &#xC778;&#xAC04; &#xB2F5;&#xAC8C; &#xB41C; &#xC950;&#xC5D0; &#xC788;&#xB294; &#xC5D0;&#xC774;&#xC988;-1 &#xAC10;&#xC5FC; &#xD6C4; &#xC190;&#xC2E4;&#xB41C; &#xC2E0;&#xACBD; &#xBB34;&#xACB0;&#xC131;&#xC744; &#xBCF4;&#xC5EC;&#xC8FC;&#xB294;. &#xC774;&#xC640; &#xAC19;&#xC774; &#xBAA8;&#xB378; &#xC9C0;&#xC18D;&#xC801;&#xC778; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; &#xC131; &#xBCF5;&#xC81C; &#xBC0F; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; &#xAD00;&#xB828; neurodegeneration &#xC0AC;&#xC774;&#xC758; &#xAD00;&#xACC4;&#xC758; &#xC5F0;&#xAD6C;&#xB97C; &#xD5C8;&#xC6A9;&#xD569;&#xB2C8;&#xB2E4;.

Humanized &#xC950;&#xC758; &#xC9C4;&#xBCF4;&#xC801;&#xC778; &#xC5D0;&#xC774;&#xC988;-1 &#xAC10;&#xC5FC; &#xC2DC; &#xC2E0;&#xACBD; &#xBB34;&#xACB0;&#xC131;&#xC758; &#xC190;&#xC2E4;.

Da&#xF1;o neuronal inducida por curso virus de inmunodeficiencia humana tipo 1 (VIH-1) la infecci&#xF3;n fue investigada en NOD/scid-IL-2R&#x3B3; humanizado (c) (nula) ratones trasplantados en el nacimiento con humanos CD34-positivas las c&#xE9;lulas madre hematopoy&#xE9;ticas. Los ratones infectados a los 5 meses de edad y un seguimiento de hasta 15 semanas mantuvieron una carga viral significativos y mostraron una reducci&#xF3;n en el n&#xFA;mero de CD4 (+) las c&#xE9;lulas T. Prospectivos serie de protones magn&#xE9;ticos pruebas de espectroscopia por resonancia mostr&#xF3; reducciones selectivas en la corteza de N-acetil aspartato en los animales infectados. Difusi&#xF3;n de im&#xE1;genes de tensor de manifiesto los cambios estructurales en la sustancia gris cortical. Post-mortem del tejido cerebral ex&#xE1;menes de inmunofluorescencia de marcadores neuronales y gliales, capturados por microscop&#xED;a de im&#xE1;genes multiespectrales y cuantificados por la emisi&#xF3;n de fluorescencia y morfometr&#xED;a, mostr&#xF3; una reducci&#xF3;n regional del soma neuronal y las arquitecturas sin&#xE1;pticas. Esto qued&#xF3; en evidencia por la p&#xE9;rdida de la prote&#xED;na asociada a los microt&#xFA;bulos-2, sinaptofisina, neurofilamentos y los ant&#xED;genos. Este estudio es el primero, a nuestro entender, lo que demuestra la integridad neuronal perdido despu&#xE9;s de la infecci&#xF3;n VIH-1 en ratones humanizados. Como tal, el modelo permite estudios de las relaciones entre la replicaci&#xF3;n viral en curso y la neurodegeneraci&#xF3;n asociada con el virus.

La p&#xE9;rdida de integridad neuronal durante la progresiva infecci&#xF3;n VIH-1 de los ratones humanizados

It is estimated that 4 to 5 million people are currently co-infected with Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV). HIV/HCV co-infection is associated with unique health risks including increased hepatotoxicity of antiretrovirals, accelerated progression of HCV and liver diseases. The standard interferon-based therapy is effective only in about 50% of patients and often is associated with autoimmune and neuro-psychiatric complications. The treatment of co-infection (HIV/HCV) requires new strategic approaches. To this end, the formulations of an amphiphatic α-helical peptide, a positively charged analog of C5A peptide derived from the HCV NS5A protein, with a reported virocidal activity were prepared by electrostatic coupling with anionic poly(amino acid)-based block copolymers. The self-assembled antiviral peptide nanocomplexes (APN) were ca. 35 nm in size, stable at physiological pH and ionic strength, and retained in vitro antiviral activity against HCV and HIV. Moreover, incorporation of the peptide into APN attenuated its cytotoxicity associated with the positive charge. In vivo APN were able to decrease the viral load in mice transplanted with human lymphocytes and HIV-1-infected. Overall, these findings indicate the potential of these formulations for stabilization and delivery of antiviral peptides while maintaining their functional activity.

Antiviral peptide nanocomplexes as a potential therapeutic modality for HIV/HCV co-infection.

Antiviral therapy using nucleoside reverse transcriptase inhibitors (NRTIs) is neurotoxic and has low efficiency in eradication of HIV-1 harbored in central nervous system (CNS). Previously, we reported that active 5'-triphosphates of NRTIs encapsulated in cationic nanogels (nano-NRTIs) suppress HIV-1 activity more efficiently than NRTIs and exhibit reduced mitochondrial toxicity [Vinogradov SV, Poluektova LY, Makarov E, Gerson T, Senanayake MT. Nano-NRTIs: efficient inhibitors of HIV type-1 in macrophages with a reduced mitochondrial toxicity. Antivir Chem Chemother. 2010; 21:1-14. Makarov E, Gerson T, Senanayake T, Poluektova LY, Vinogradov. Efficient suppression of Human Immunodeficiency Virus in Macrophages by Nano-NRTIs. Antiviral Res. 2010; 86(1):A38-9]. Here, we demonstrated low neurotoxicity and excellent antiviral activity of nano-NRTIs decorated with the peptide (AP) binding brain-specific apolipoprotein E receptor. Nano-NRTIs induced lower levels of apoptosis and formation of reactive oxygen species, a major cause of neuron death, than free NRTIs. Optimization of size, surface decoration with AP significantly increased brain accumulation of nano-NRTIs. The efficient CNS delivery of nano-NRTIs resulted in up to 10-fold suppression of retroviral activity and reduced virus-associated inflammation in humanized mouse model of HIV-1 infection in the brain. Our data provide proof of the advanced efficacy of nano-NRTIs as safer alternative of current antiviral drugs.

Nano-NRTIs demonstrate low neurotoxicity and high antiviral activity against HIV infection in the brain.

Human-specific HIV-1 and hepatitis co-infections significantly affect patient management and call for new therapeutic options. Small xenotransplantation models with human hepatocytes and hematolymphoid tissue should facilitate antiviral/antiretroviral drug trials. However, experience with mouse strains tested for dual reconstitution is limited, with technical difficulties such as risky manipulations with newborns and high mortality rates due to metabolic abnormalities. The best animal strains for hepatocyte transplantation are not optimal for human hematopoietic stem cell (HSC) engraftment, and vice versa. We evaluated a new strain of highly immunodeficient nonobese diabetic/Shi-scid (severe combined immunodeficiency)/IL-2Rγc(null) (NOG) mice that carry two copies of the mouse albumin promoter-driven urokinase-type plasminogen activator transgene for dual reconstitution with human liver and immune cells. Three approaches for dual reconstitution were evaluated: i) freshly isolated fetal hepatoblasts were injected intrasplenically, followed by transplantation of cryopreserved HSCs obtained from the same tissue samples 1 month later after treosulfan conditioning; ii) treosulfan conditioning is followed by intrasplenic simultaneous transplantation of fetal hepatoblasts and HSCs; and iii) transplantation of mature hepatocytes is followed by mismatched HSCs. The long-term dual reconstitution was achieved on urokinase-type plasminogen activator-NOG mice with mature hepatocytes (not fetal hepatoblasts) and HSCs. Even major histocompatibility complex mismatched transplantation was sustained without any evidence of hepatocyte rejection by the human immune system. 

Human hepatocytes and hematolymphoid dual reconstitution in treosulfan-conditioned uPA-NOG mice.

Host-species specificity of the human immunodeficiency virus (HIV) limits pathobiologic, diagnostic and therapeutic research investigations to humans and non-human primates. The emergence of humanized mice as a model for viral infection of the nervous system has overcome such restrictions enabling research for HIV-associated end organ disease including behavioral, cognitive and neuropathologic deficits reflective of neuroAIDS. Chronic HIV-1 infection of NOD/scid-IL-2Rgcnull mice transplanted with human CD34+ hematopoietic stem cells (CD34-NSG) leads to persistent viremia, profound CD4+ T lymphocyte loss and infection of human monocyte-macrophages in the meninges and perivascular spaces. Murine cells are not infected with virus.

Associations between brain microstructures, metabolites, and cognitive deficits during chronic HIV-1 infection of humanized mice.

Progressive human immunodeficiency viral (HIV) infection commonly leads to a constellation of cognitive, motor, and behavioral impairments. These are collectively termed HIV-associated neurocognitive disorders (HAND). While antiretroviral therapy (ART) reduces HAND severity, it does not affect disease prevalence. Despite decades of research, there remain no biomarkers for HAND and all potential comorbid conditions must first be excluded for a diagnosis to be made. To this end, we now report that manganese (Mn(2+))-enhanced magnetic resonance imaging (MEMRI) can reflect brain region-specific HIV-1-induced neuropathology in chronically virus-infected NOD/scid-IL-2Rγc(null) humanized mice. MEMRI diagnostics mirrors the abilities of Mn(2+) to enter and accumulate in affected neurons during disease. T1 relaxivity and its weighted signal intensity are proportional to Mn(2+) activities in neurons. In 16-week virus-infected humanized mice, altered MEMRI signal enhancement was easily observed in affected brain regions. These included, but were not limited to, the hippocampus, amygdala, thalamus, globus pallidus, caudoputamen, substantia nigra, and cerebellum. MEMRI signal was coordinated with levels of HIV-1 infection, neuroinflammation (astro- and micro-gliosis), and neuronal injury. MEMRI accurately demonstrates the complexities of HIV-1-associated neuropathology in rodents that reflects, in measure, the clinical manifestations of neuroAIDS as it is seen in a human host.

Manganese-Enhanced Magnetic Resonance Imaging Reflects Brain Pathology During Progressive HIV-1 Infection of Humanized Mice.

Humanized mice are frequently utilized in bench to bedside therapeutic tests to combat human infectious, cancerous and degenerative diseases. For the fields of hematology-oncology, regenerative medicine, and infectious diseases, the immune deficient mice have been used commonly in basic research efforts. Obstacles in true translational efforts abound, as the relationship between mouse and human cells in disease pathogenesis and therapeutic studies requires lengthy investigations. The interplay between human immunity and mouse biology proves ever more complicated when aging, irradiation, and human immune reconstitution are considered. All can affect a range of biochemical and behavioral functions. To such ends, we show age- and irradiation-dependent influences for the development of macrocytic hyper chromic anemia, myelodysplasia, blood protein reductions and body composition changes. Humanization contributes to hematologic abnormalities. Home cage behavior revealed day and dark cycle locomotion also influenced by human cell reconstitutions. Significant age-related day-to-day variability in movement, feeding and drinking behaviors were observed. We posit that this data serves to enable researchers to better design translational studies in this rapidly emerging field of mouse humanization. 

Influence of age, irradiation and humanization on NSG mouse phenotypes.

Human immunodeficiency virus type 1 (HIV-1) infection impairs liver function, and liver diseases have become a leading cause of morbidity in infected patients. The immunopathology of liver damage caused by HIV-1 remains unclear. We used chimeric mice dually reconstituted with a human immune system and hepatocytes to address the relevance of the model to pathobiology questions related to human hepatocyte survival in the presence of systemic infection. TK-NOG males were transplanted with mismatched human hematopoietic stem/progenitor cells and hepatocytes, human albumin concentration and the presence of human immune cells in blood were monitored for hepatocytes and immune reconstitution, and mice were infected with HIV-1. HIV-1-infected animals showed a decline in human albumin concentration with a significant reduction in percentage of human hepatocytes compared to uninfected mice. The decrease in human albumin levels correlated with a decline in CD4 cells in the liver and with an increase in HIV-1 viral load. HIV-1 infection elicited proinflammatory response in the immunological milieu of the liver in HIV-infected mice compared to uninfected animals, as determined by upregulation of IL23, CXCL10 and multiple toll-like receptor expression. The inflammatory reaction associated with HIV-1 infection  could contribute to the depletion and dysfunction of hepatocytes. The dual reconstituted TK-NOG mouse model is a feasible platform to investigate hepatocyte-related HIV-1 immunopathogenesis.This article has an associated First Person interview with the first author of the paper.

Human hepatocyte depletion in the presence of HIV-1 infection in dual reconstituted humanized mice.

Antiretroviral drug (ARV) metabolism is linked largely to hepatic cytochrome P450 activity. One ARV drug class known to be metabolized by intestinal and hepatic CYP3A are the protease inhibitors (PIs). Plasma drug concentrations are boosted by CYP3A inhibitors such as cobisistat and ritonavir (RTV). Studies of such drug-drug interactions are limited since the enzyme pathways are human specific. While immune-deficient mice reconstituted with human cells are an excellent model to study ARVs during human immunodeficiency virus type 1 (HIV-1) infection, they cannot reflect human drug metabolism. Thus, we created a mouse strain with the human pregnane X receptor, constitutive androstane receptor, and CYP3A4/7 genes on a NOD.Cg- /JicTac background (hCYP3A-NOG) and used them to evaluate the impact of human CYP3A metabolism on ARV pharmacokinetics. In proof-of-concept studies we used nanoformulated atazanavir (nanoATV) with or without RTV. NOG and hCYP3A-NOG mice were treated weekly with 50 mg/kg nanoATV alone or boosted with nanoformulated ritonavir (nanoATV/r). Plasma was collected weekly and liver was collected at 28 days post-treatment. Plasma and liver atazanavir (ATV) concentrations in nanoATV/r-treated hCYP3A-NOG mice were 2- to 4-fold higher than in replicate NOG mice. RTV enhanced plasma and liver ATV concentrations 3-fold in hCYP3A-NOG mice and 1.7-fold in NOG mice. The results indicate that human CYP3A-mediated drug metabolism is reduced compared with mouse and that RTV differentially affects human gene activity. These differences can affect responses to PIs in humanized mouse models of HIV-1 infection. Importantly, hCYP3A-NOG mice reconstituted with human immune cells can be used for bench-to-bedside translation.

Antiretroviral Drug Metabolism in Humanized PXR-CAR-CYP3A-NOG Mice.

HIV-HCV co-infection causes rapid progression of liver fibrosis. These outcomes to liver cirrhosis can be improved, but not stopped by specific antiviral therapies. Due to high significance of HIV-HCV interactions for morbidity and mortality in co-infected patients, our attention was attracted to the multi-component pathogenesis of fibrosis progression as the transition to end-stage liver disease development. In this study, we hypothesize that increased matrix stiffness enhances apoptosis in HCV-HIV-co-infected hepatocytes and that capturing of apoptotic bodies (AB) derived from these infected hepatocytes by hepatic stellate cells (HSC) drives the fibrosis progression. As the source of viruses, JFH1 (HCV genotype 2a) and HIV-1 (either purified or containing in infected macrophage supernatants) were chosen. Using Huh7.5-CYP (RLW) cells and primary human hepatocytes mono-infected with HCV and HIV or co-infected, we have shown that both HCV and HIV RNA levels were increased in co-infected cells, which was accompanied by hepatocyte apoptosis. This apoptosis was attenuated by azidothymidine treatment. The levels of both infections and apoptosis were more prominent in primary hepatocytes cultured on substrates mimicking fibrotic stiffness (24 kPa-stiff) compared to substrates mimicking healthy liver (2.4 kPa-soft). The engulfment of AB from pathogen-exposed hepatocytes activated pro-fibrotic mRNAs in HSC. Overall, the increased matrix stiffness is not only a consequence of liver inflammation/fibrosis, but the condition that further accelerates liver fibrosis development. This is attributed to the switching of HSC to pro-fibrotic phenotype by capturing of excessive amounts of apoptotic HCV- and HIV-infected hepatocytes.

Matrix stiffness regulate apoptotic cell death in HIV-HCV co-infected hepatocytes: Importance for liver fibrosis progression.

Microglia are the principal innate immune defense cells of the centeral nervous system (CNS) and the target of the human immunodeficiency virus type one (HIV-1). A complete understanding of human microglial biology and function requires the cell's presence in a brain microenvironment. Lack of relevant animal models thus far has also precluded studies of HIV-1 infection. Productive viral infection in brain occurs only in human myeloid linage microglia and perivascular macrophages and requires cells present throughout the brain. Once infected, however, microglia become immune competent serving as sources of cellular neurotoxic factors leading to disrupted brain homeostasis and neurodegeneration.

Human Interleukin-34 facilitates microglia-like cell differentiation and persistent HIV-1 infection in humanized mice.

Hepatitis B virus (HBV) infection and alcoholism are major public health problems worldwide, contributing to the development of end-stage liver disease. Alcohol intake affects HBV infection pathogenesis and treatment outcomes. HBV-specific cytotoxic T lymphocytes (CTLs) play an important role in HBV clearance. Many previous studies have focused on alcohol-induced impairments of the immune response. However, it is not clear whether alcohol alters the presentation of HBV peptide-major histocompatibility complex (MHC) class I complexes on infected hepatocytes resulting in escape of its recognition by CTLs. Hence, the focus of this study was to investigate the mechanisms by which ethanol metabolism affects the presentation of CTL epitope on HBV-infected hepatocytes. As demonstrated here, although continuous cell exposure to acetaldehyde-generating system (AGS) increased HBV load in HepG2.2.15 cells, it decreased the expression of HBV core peptide 18-27-human leukocyte antigen-A2complex (CTL epitope) on the cell surface. Moreover, we observed AGS-induced suppression of chymotrypsin- and trypsin-like proteasome activities necessary for peptide processing by proteasome as well as a decline in IFNγ-stimulated immunoproteasome (IPR) function and expression of PA28 activator and immunoproteasome subunits LMP7 and LMP2. Furthermore, IFNγ-induced activation of peptide-loading complex (PLC) components, such as transporter associated with antigen processing (TAP1) and tapasin, were suppressed by AGS. The attenuation of IPR and PLC activation was attributed to AGS-triggered impairment of IFNγ signaling in HepG2.2.15 cells. Collectively, all these downstream events reduced the display of HBV peptide-MHC class I complexes on the hepatocyte surface, which may suppress CTL activation and the recognition of CTL epitopes on HBV-expressing hepatocytes by immune cells, thereby leading to persistence of liver inflammation. Our study shows that in HBV-expressing HepG2.2.15 cells, acetaldehyde alters HBV peptide processing by suppressing chymotrypsin- and trypsin-like proteasome activities and decreases IFNγ-stimulated immunoproteasome function and expression of PA28 activator and immunoproteasome subunits. It also suppresses IFNγ-induced activation of peptide-loading complex (PLC) components due to impairment of IFNγ signaling via the JAK-STAT1 pathway. These acetaldehyde-induced dysfunctions reduced the display of HBV peptide-MHC class I complexes on the hepatocyte surface, thereby leading to persistence of HBV infection.

Article	Year
CD8+ cell depletion accelerates HIV-1 immunopathology in humanized mice. Journal of immunology (Baltimore, Md. : 1950)\| PubMed ID: 20495069	2010
Immunoregulation of a CB2 receptor agonist in a murine model of neuroAIDS. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology\| PubMed ID: 20549374	2010
Nano-NRTIs: efficient inhibitors of HIV type-1 in macrophages with a reduced mitochondrial toxicity. Antiviral chemistry & chemotherapy\| PubMed ID: 21045256	2010
Links between progressive HIV-1 infection of humanized mice and viral neuropathogenesis. The American journal of pathology\| PubMed ID: 21088215	2010
Loss of neuronal integrity during progressive HIV-1 infection of humanized mice. The Journal of neuroscience : the official journal of the Society for Neuroscience\| PubMed ID: 21368026	2011
Antiviral peptide nanocomplexes as a potential therapeutic modality for HIV/HCV co-infection. Biomaterials\| PubMed ID: 23403120	2013
Nano-NRTIs demonstrate low neurotoxicity and high antiviral activity against HIV infection in the brain. Nanomedicine : nanotechnology, biology, and medicine\| PubMed ID: 23845925	2014
Human hepatocytes and hematolymphoid dual reconstitution in treosulfan-conditioned uPA-NOG mice. The American journal of pathology\| PubMed ID: 24200850	2014
Associations between brain microstructures, metabolites, and cognitive deficits during chronic HIV-1 infection of humanized mice. Molecular neurodegeneration\| PubMed ID: 25523827	2014
Manganese-Enhanced Magnetic Resonance Imaging Reflects Brain Pathology During Progressive HIV-1 Infection of Humanized Mice. Molecular neurobiology\| PubMed ID: 26063593	2016
Influence of age, irradiation and humanization on NSG mouse phenotypes. Biology open\| PubMed ID: 26353862	2015
Human hepatocyte depletion in the presence of HIV-1 infection in dual reconstituted humanized mice. Biology open\| PubMed ID: 29361613	2018
Antiretroviral Drug Metabolism in Humanized PXR-CAR-CYP3A-NOG Mice. The Journal of pharmacology and experimental therapeutics\| PubMed ID: 29476044	2018
Matrix stiffness regulate apoptotic cell death in HIV-HCV co-infected hepatocytes: Importance for liver fibrosis progression. Biochemical and biophysical research communications\| PubMed ID: 29679566	2018
Human Interleukin-34 facilitates microglia-like cell differentiation and persistent HIV-1 infection in humanized mice. Molecular neurodegeneration\| PubMed ID: 30832693	2019
Acetaldehyde suppresses the display of HBV-MHC class I complexes on HBV-expressing hepatocytes. American journal of physiology. Gastrointestinal and liver physiology\| PubMed ID: 31141391	2019

Edward Makarov

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