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

摘要

病毒感染库(抗病毒药物对其无可奈何)是根除"1-型人免疫缺陷病毒"(HIV-1)的相关工作所面临的一个严重障碍。Dan Barouch及同事在一个猴子模型中对这些库的形成时机进行了研究。他们发现,在恒河猴感染"猿免疫缺陷病毒"之后最早三天内、在病毒血症产生之前所进行的抗病毒治疗未能防止病毒库的形成,当药物治疗中断时病毒最终会反弹。%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 anti-retroviral 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 SIV_(MAC251) 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.