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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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Viral decay kinetics after treatment with ARTLog plasma viral RNA (copies/ml) in rhesus monkeys infected with SIVmac251 and following initiation of ART on days 3, 7, 10, and 14 of infection (a) or with no ART (b). Assay sensitivity is 50 RNA copies/ml. Red arrows indicate initiation of ART. Black dots below x-axis indicate sampling timepoints.
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Figure 1: Viral decay kinetics after treatment with ARTLog plasma viral RNA (copies/ml) in rhesus monkeys infected with SIVmac251 and following initiation of ART on days 3, 7, 10, and 14 of infection (a) or with no ART (b). Assay sensitivity is 50 RNA copies/ml. Red arrows indicate initiation of ART. Black dots below x-axis indicate sampling timepoints.

Mentions: We inoculated 20 Indian origin adult rhesus monkeys (Macaca mulatta) that did not express the protective MHC class I alleles Mamu-A*01, Mamu-B*08, and Mamu-B*17 with 500 TCID50 SIVmac2518–10 by the intrarectal route. We initiated ART on days 3, 7, 10, and 14 following infection with a pre-formulated cocktail of tenofovir, emtricitabine, and dolutegravir (see Methods), and a control group received no ART (n=4/group). ART was administered daily by subcutaneous injection for 24 weeks. Treatment on day 3 following infection resulted in no detectable viremia (<50 RNA copies/ml)11 at any timepoint in 4 of 4 monkeys (Fig. 1a). In contrast, treatment on days 7, 10, and 14 abruptly interrupted the exponential growth of the virus and reduced plasma viral RNA to undetectable levels within 3–4 weeks. The mean levels of plasma viral RNA at the time of ART initiation in these groups of monkeys were 5.88 log copies/ml (day 7), 7.11 log copies/ml (day 10), and 7.50 log copies/ml (day 14), which were comparable with the levels of plasma viral RNA in untreated controls at these timepoints (Fig. 1b). Viral dynamics modeling12 revealed an initial exponential growth rate of 1.5 ± 0.5 per day, corresponding to a basic reproductive ratio of R0 = 9.5 ± 5.1 (see Methods; Extended Data Fig. 1; Extended Data Table 1). An exponential decay rate of plasma viremia following ART initiation of 0.60 ± 0.17 per day was observed in all the treated groups, corresponding to a 1.3 ± 0.4 day half-life of infected cells (Extended Data Fig. 1).


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)

Viral decay kinetics after treatment with ARTLog plasma viral RNA (copies/ml) in rhesus monkeys infected with SIVmac251 and following initiation of ART on days 3, 7, 10, and 14 of infection (a) or with no ART (b). Assay sensitivity is 50 RNA copies/ml. Red arrows indicate initiation of ART. Black dots below x-axis indicate sampling timepoints.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Viral decay kinetics after treatment with ARTLog plasma viral RNA (copies/ml) in rhesus monkeys infected with SIVmac251 and following initiation of ART on days 3, 7, 10, and 14 of infection (a) or with no ART (b). Assay sensitivity is 50 RNA copies/ml. Red arrows indicate initiation of ART. Black dots below x-axis indicate sampling timepoints.
Mentions: We inoculated 20 Indian origin adult rhesus monkeys (Macaca mulatta) that did not express the protective MHC class I alleles Mamu-A*01, Mamu-B*08, and Mamu-B*17 with 500 TCID50 SIVmac2518–10 by the intrarectal route. We initiated ART on days 3, 7, 10, and 14 following infection with a pre-formulated cocktail of tenofovir, emtricitabine, and dolutegravir (see Methods), and a control group received no ART (n=4/group). ART was administered daily by subcutaneous injection for 24 weeks. Treatment on day 3 following infection resulted in no detectable viremia (<50 RNA copies/ml)11 at any timepoint in 4 of 4 monkeys (Fig. 1a). In contrast, treatment on days 7, 10, and 14 abruptly interrupted the exponential growth of the virus and reduced plasma viral RNA to undetectable levels within 3–4 weeks. The mean levels of plasma viral RNA at the time of ART initiation in these groups of monkeys were 5.88 log copies/ml (day 7), 7.11 log copies/ml (day 10), and 7.50 log copies/ml (day 14), which were comparable with the levels of plasma viral RNA in untreated controls at these timepoints (Fig. 1b). Viral dynamics modeling12 revealed an initial exponential growth rate of 1.5 ± 0.5 per day, corresponding to a basic reproductive ratio of R0 = 9.5 ± 5.1 (see Methods; Extended Data Fig. 1; Extended Data Table 1). An exponential decay rate of plasma viremia following ART initiation of 0.60 ± 0.17 per day was observed in all the treated groups, corresponding to a 1.3 ± 0.4 day half-life of infected cells (Extended Data Fig. 1).

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