Publication Date:
2014-07-22
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126858/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126858/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Whitney, James B -- Hill, Alison L -- Sanisetty, Srisowmya -- Penaloza-MacMaster, Pablo -- Liu, Jinyan -- Shetty, Mayuri -- Parenteau, Lily -- Cabral, Crystal -- Shields, Jennifer -- Blackmore, Stephen -- Smith, Jeffrey Y -- Brinkman, Amanda L -- Peter, Lauren E -- Mathew, Sheeba I -- Smith, Kaitlin M -- Borducchi, Erica N -- Rosenbloom, Daniel I S -- Lewis, Mark G -- Hattersley, Jillian -- Li, Bei -- Hesselgesser, Joseph -- Geleziunas, Romas -- Robb, Merlin L -- Kim, Jerome H -- Michael, Nelson L -- Barouch, Dan H -- AI060354/AI/NIAID NIH HHS/ -- AI078526/AI/NIAID NIH HHS/ -- AI084794/AI/NIAID NIH HHS/ -- AI095985/AI/NIAID NIH HHS/ -- AI096040/AI/NIAID NIH HHS/ -- AI100645/AI/NIAID NIH HHS/ -- R01 AI084794/AI/NIAID NIH HHS/ -- R56 AI091514/AI/NIAID NIH HHS/ -- T32 AI007245/AI/NIAID NIH HHS/ -- U19 AI078526/AI/NIAID NIH HHS/ -- U19 AI095985/AI/NIAID NIH HHS/ -- U19 AI096040/AI/NIAID NIH HHS/ -- UM1 AI100645/AI/NIAID NIH HHS/ -- UM1 AI100663/AI/NIAID NIH HHS/ -- England -- Nature. 2014 Aug 7;512(7512):74-7. doi: 10.1038/nature13594. Epub 2014 Jul 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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. ; Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts 02138 USA. ; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. ; Bioqual, Rockville, Maryland 20852, USA. ; Gilead Sciences, Foster City, California 94404, USA. ; US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25042999" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Anti-Retroviral Agents/administration & dosage/pharmacology/therapeutic use
;
Carrier State/drug therapy/virology
;
DNA, Viral/analysis/biosynthesis/blood
;
Disease Models, Animal
;
Female
;
Kinetics
;
Macaca mulatta/immunology/*virology
;
Male
;
Proviruses/genetics
;
RNA, Viral/blood
;
Rectum/virology
;
Simian Acquired Immunodeficiency Syndrome/drug therapy/immunology/*virology
;
Simian Immunodeficiency Virus/drug effects/*growth &
;
development/immunology/physiology
;
Time Factors
;
Treatment Failure
;
*Viral Load/drug effects
;
Viremia/drug therapy/*virology
;
Virus Replication/drug effects
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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