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

TitleRapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys.
Publication TypeJournal Article
Year of Publication2014
AuthorsWhitney 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 DIS, Lewis MG, Hattersley J, Li B, Hesselgesser J, Geleziunas R, Robb ML, Kim JH, Michael NL, Barouch DH
JournalNature
Volume512
Issue7512
Pagination74-7
Date Published08/07/2014
ISSN1476-4687
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.

DOI10.1038/nature13594
Alternate JournalNature
PubMed ID25042999
PubMed Central IDPMC4126858
Grant ListAI060354 / AI / NIAID NIH HHS / United States
AI078526 / AI / NIAID NIH HHS / United States
AI084794 / AI / NIAID NIH HHS / United States
AI095985 / AI / NIAID NIH HHS / United States
AI096040 / AI / NIAID NIH HHS / United States
AI100645 / AI / NIAID NIH HHS / United States
R01 AI084794 / AI / NIAID NIH HHS / United States
U19 AI078526 / AI / NIAID NIH HHS / United States
U19 AI095985 / AI / NIAID NIH HHS / United States
U19 AI096040 / AI / NIAID NIH HHS / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
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