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Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys.

Whitney JB, Hill AL, Sanisetty S, Penaloza-MacMaster P, Liu J, Shetty M, Parenteau L, Cabral C, Shields J, Blackmore S, Smith JY, Brinkman AL, Peter LE, Mathew SI, Smith KM, Borducchi EN, Rosenbloom DI, Lewis MG, Hattersley J, Li B, Hesselgesser J, Geleziunas R, Robb ML, Kim JH, Michael NL, Barouch DH - Nature (2014)

Bottom Line: Treatment with ART on day 3 blocked the emergence of viral RNA and proviral DNA in peripheral blood and also substantially reduced levels of proviral DNA in lymph nodes and gastrointestinal mucosa as compared with treatment at later time points.The time to viral rebound correlated with total viraemia during acute infection and with proviral DNA at the time of ART discontinuation.This strikingly early seeding of the refractory viral reservoir raises important new challenges for HIV-1 eradication strategies.

View Article: PubMed Central - PubMed

Affiliation: 1] Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts 02139, USA.

ABSTRACT
The viral reservoir represents a critical challenge for human immunodeficiency virus type 1 (HIV-1) eradication strategies. However, it remains unclear when and where the viral reservoir is seeded during acute infection and the extent to which it is susceptible to early antiretroviral therapy (ART). Here we show that the viral reservoir is seeded rapidly after mucosal simian immunodeficiency virus (SIV) infection of rhesus monkeys and before systemic viraemia. We initiated suppressive ART in groups of monkeys on days 3, 7, 10 and 14 after intrarectal SIVMAC251 infection. Treatment with ART on day 3 blocked the emergence of viral RNA and proviral DNA in peripheral blood and also substantially reduced levels of proviral DNA in lymph nodes and gastrointestinal mucosa as compared with treatment at later time points. In addition, treatment on day 3 abrogated the induction of SIV-specific humoral and cellular immune responses. Nevertheless, after discontinuation of ART following 24 weeks of fully suppressive therapy, virus rebounded in all animals, although the monkeys that were treated on day 3 exhibited a delayed viral rebound as compared with those treated on days 7, 10 and 14. The time to viral rebound correlated with total viraemia during acute infection and with proviral DNA at the time of ART discontinuation. These data demonstrate that the viral reservoir is seeded rapidly after intrarectal SIV infection of rhesus monkeys, during the 'eclipse' phase, and before detectable viraemia. This strikingly early seeding of the refractory viral reservoir raises important new challenges for HIV-1 eradication strategies.

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Early ART impacts AUC VL and time to viral rebound.Log AUC VL and interpolated time of viral rebound derived from the model fits are shown in monkeys that initiated ART on days 3, 7, 10, and 14 of infection (N=4 animals per group).
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Figure 13: Early ART impacts AUC VL and time to viral rebound.Log AUC VL and interpolated time of viral rebound derived from the model fits are shown in monkeys that initiated ART on days 3, 7, 10, and 14 of infection (N=4 animals per group).

Mentions: To gain mechanistic insight into the kinetics of the viral rebound, we utilized viral dynamics modeling15,16 (see Methods; Extended Data Fig. 6; Extended Data Table 2). Initiation of ART on day 3 as compared with days 7, 10, and 14 resulted in lower modeled residual viral loads at the time of ART discontinuation (P=0.01) and a trend towards a greater viral growth rate R0 during viral rebound (P=0.06), but no difference in post-rebound setpoint viral loads (Extended Data Fig. 7). Average R0 during viral rebound was 4.2 ± 1.8 in the day 3 treated animals as compared with 2.3 ± 0.6 in the day 14 treated animals (P=0.05; Extended Data Fig. 7), presumably reflecting the partially effective SIV-specific immune responses in the latter group (Fig. 2). Total plasma viremia during acute infection was interpolated and calculated as the area under the curve for pre-ART viral loads (AUC VL) (Extended Data Fig. 8). Consistent with recent findings in acute HIV-1 infection in humans16, the AUC VL during acute infection correlated with levels of proviral DNA in PBMC (P<0.0001; Fig. 5a), LNMC (P=0.005; Fig. 5b), and GMMC (P=0.04; data not shown) at the time of ART discontinuation. Moreover, both the AUC VL (P<0.0001; Fig. 5c) and proviral DNA in PBMC at the time of ART discontinuation (P=0.003; Fig. 5d) correlated inversely with the interpolated time to viral rebound. These data suggest that total plasma viremia during acute infection and proviral DNA immediately prior to ART discontinuation may predict the time to viral recrudescence.


Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys.

Whitney JB, Hill AL, Sanisetty S, Penaloza-MacMaster P, Liu J, Shetty M, Parenteau L, Cabral C, Shields J, Blackmore S, Smith JY, Brinkman AL, Peter LE, Mathew SI, Smith KM, Borducchi EN, Rosenbloom DI, Lewis MG, Hattersley J, Li B, Hesselgesser J, Geleziunas R, Robb ML, Kim JH, Michael NL, Barouch DH - Nature (2014)

Early ART impacts AUC VL and time to viral rebound.Log AUC VL and interpolated time of viral rebound derived from the model fits are shown in monkeys that initiated ART on days 3, 7, 10, and 14 of infection (N=4 animals per group).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126858&req=5

Figure 13: Early ART impacts AUC VL and time to viral rebound.Log AUC VL and interpolated time of viral rebound derived from the model fits are shown in monkeys that initiated ART on days 3, 7, 10, and 14 of infection (N=4 animals per group).
Mentions: To gain mechanistic insight into the kinetics of the viral rebound, we utilized viral dynamics modeling15,16 (see Methods; Extended Data Fig. 6; Extended Data Table 2). Initiation of ART on day 3 as compared with days 7, 10, and 14 resulted in lower modeled residual viral loads at the time of ART discontinuation (P=0.01) and a trend towards a greater viral growth rate R0 during viral rebound (P=0.06), but no difference in post-rebound setpoint viral loads (Extended Data Fig. 7). Average R0 during viral rebound was 4.2 ± 1.8 in the day 3 treated animals as compared with 2.3 ± 0.6 in the day 14 treated animals (P=0.05; Extended Data Fig. 7), presumably reflecting the partially effective SIV-specific immune responses in the latter group (Fig. 2). Total plasma viremia during acute infection was interpolated and calculated as the area under the curve for pre-ART viral loads (AUC VL) (Extended Data Fig. 8). Consistent with recent findings in acute HIV-1 infection in humans16, the AUC VL during acute infection correlated with levels of proviral DNA in PBMC (P<0.0001; Fig. 5a), LNMC (P=0.005; Fig. 5b), and GMMC (P=0.04; data not shown) at the time of ART discontinuation. Moreover, both the AUC VL (P<0.0001; Fig. 5c) and proviral DNA in PBMC at the time of ART discontinuation (P=0.003; Fig. 5d) correlated inversely with the interpolated time to viral rebound. These data suggest that total plasma viremia during acute infection and proviral DNA immediately prior to ART discontinuation may predict the time to viral recrudescence.

Bottom Line: Treatment with ART on day 3 blocked the emergence of viral RNA and proviral DNA in peripheral blood and also substantially reduced levels of proviral DNA in lymph nodes and gastrointestinal mucosa as compared with treatment at later time points.The time to viral rebound correlated with total viraemia during acute infection and with proviral DNA at the time of ART discontinuation.This strikingly early seeding of the refractory viral reservoir raises important new challenges for HIV-1 eradication strategies.

View Article: PubMed Central - PubMed

Affiliation: 1] Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts 02139, USA.

ABSTRACT
The viral reservoir represents a critical challenge for human immunodeficiency virus type 1 (HIV-1) eradication strategies. However, it remains unclear when and where the viral reservoir is seeded during acute infection and the extent to which it is susceptible to early antiretroviral therapy (ART). Here we show that the viral reservoir is seeded rapidly after mucosal simian immunodeficiency virus (SIV) infection of rhesus monkeys and before systemic viraemia. We initiated suppressive ART in groups of monkeys on days 3, 7, 10 and 14 after intrarectal SIVMAC251 infection. Treatment with ART on day 3 blocked the emergence of viral RNA and proviral DNA in peripheral blood and also substantially reduced levels of proviral DNA in lymph nodes and gastrointestinal mucosa as compared with treatment at later time points. In addition, treatment on day 3 abrogated the induction of SIV-specific humoral and cellular immune responses. Nevertheless, after discontinuation of ART following 24 weeks of fully suppressive therapy, virus rebounded in all animals, although the monkeys that were treated on day 3 exhibited a delayed viral rebound as compared with those treated on days 7, 10 and 14. The time to viral rebound correlated with total viraemia during acute infection and with proviral DNA at the time of ART discontinuation. These data demonstrate that the viral reservoir is seeded rapidly after intrarectal SIV infection of rhesus monkeys, during the 'eclipse' phase, and before detectable viraemia. This strikingly early seeding of the refractory viral reservoir raises important new challenges for HIV-1 eradication strategies.

Show MeSH
Related in: MedlinePlus