James B. Whitney 1 , 2 , Alison L. Hill 3 , Srisowmya Sanisetty 1 , Pablo Penaloza-MacMaster 1 , Jinyan Liu 1 , Mayuri Shetty 1 , Lily Parenteau 1 , Crystal Cabral 1 , Jennifer Shields 1 , Stephen Blackmore 1 , Jeffrey Y. Smith 1 , Amanda L. Brinkman 1 , Lauren E. Peter 1 , Sheeba I. Mathew 1 , Kaitlin M. Smith 1 , Erica N. Borducchi 1 , Daniel I.S. Rosenbloom 3 , Mark G. Lewis 4 , Jillian Hattersley 5 , Bei Li 5 , Joseph Hesselgesser 5 , Romas Geleziunas 5 , Merlin L. Robb 6 , Jerome H. Kim 6 , Nelson L. Michael 6 , Dan H. Barouch 1 , 2
20 July 2014
The viral reservoir represents a critical challenge facing HIV-1 eradication strategies 1– 5 . 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 very early following mucosal SIV infection of rhesus monkeys and prior to systemic viremia. We initiated suppressive ART in groups of monkeys on days 3, 7, 10, and 14 following intrarectal SIVmac251 infection. Treatment 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 timepoints. In addition, treatment on day 3 abrogated the induction of SIV-specific humoral and cellular immune responses. Nevertheless, following discontinuation of ART after 24 weeks of fully suppressive therapy, virus rebounded in all animals, although animals treated on day 3 exhibited a delayed viral rebound as compared with animals treated on days 7, 10 and 14. The time to viral rebound correlated with total viremia during acute infection and with proviral DNA at the time of ART discontinuation. These data demonstrate that the viral reservoir is seeded very early following intrarectal SIV infection of rhesus monkeys, during the “eclipse” phase, and prior to viremia. This strikingly early seeding of the refractory viral reservoir raises important new challenges for HIV-1 eradication strategies.