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

Abstract

Reservoirs of virus infection represent the most important reason why HIV-1 cannot be cured with current antiretroviral drugs; now the refractory viral reservoir is shown to be seeded as early as 3 days after infection in a monkey model, even before the virus is detected in the blood. Reservoirs of virus infection, impervious to antiviral drugs, are a serious obstacle to attempts to eradicate human immunodeficiency virus type 1 (HIV-1). Dan Barouch and colleagues explore the timing of the formation of these reservoirs in a monkey model. They find that antiviral treatment as early as three days after infection of macaques with simian immunodeficiency virus — prior to the onset of viraemia — fails to prevent the seeding of viral reservoirs, and the virus eventually rebounds when drug treatment is discontinued. The viral reservoir represents a critical challenge for human immunodeficiency virus type 1 (HIV-1) eradication strategies1,2,3,4,5. 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 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.