title: Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys.
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.
authors.affiliation: 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.
authors.forename: James B
authors.initials: JB
authors.lastname: Whitney
authors.affiliation: Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts 02138 USA.
authors.forename: Alison L
authors.initials: AL
authors.lastname: Hill
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Srisowmya
authors.initials: S
authors.lastname: Sanisetty
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Pablo
authors.initials: P
authors.lastname: Penaloza-MacMaster
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Jinyan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Mayuri
authors.initials: M
authors.lastname: Shetty
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Lily
authors.initials: L
authors.lastname: Parenteau
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Crystal
authors.initials: C
authors.lastname: Cabral
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Shields
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Blackmore
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Jeffrey Y
authors.initials: JY
authors.lastname: Smith
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Brinkman
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Peter
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Sheeba I
authors.initials: SI
authors.lastname: Mathew
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Kaitlin M
authors.initials: KM
authors.lastname: Smith
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Erica N
authors.initials: EN
authors.lastname: Borducchi
authors.affiliation: Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts 02138 USA.
authors.forename: Daniel I S
authors.initials: DI
authors.lastname: Rosenbloom
authors.affiliation: Bioqual, Rockville, Maryland 20852, USA.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Lewis
authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
authors.forename: Jillian
authors.initials: J
authors.lastname: Hattersley
authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
authors.forename: Bei
authors.initials: B
authors.lastname: Li
authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Hesselgesser
authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
authors.forename: Romas
authors.initials: R
authors.lastname: Geleziunas
authors.affiliation: US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, USA.
authors.forename: Merlin L
authors.initials: ML
authors.lastname: Robb
authors.affiliation: US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, USA.
authors.forename: Jerome H
authors.initials: JH
authors.lastname: Kim
authors.affiliation: US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, USA.
authors.forename: Nelson L
authors.initials: NL
authors.lastname: Michael
authors.affiliation: 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.
authors.forename: Dan H
authors.initials: DH
authors.lastname: Barouch
mesh_terms: D000818:Animals; D044966:Anti-Retroviral Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D002353:Carrier State / Q000188:drug therapy / Q000821:virology; D004279:DNA, Viral / Q000032:analysis / Q000096:biosynthesis / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D007700:Kinetics; D008253:Macaca mulatta / Q000276:immunology / Q000821:virology*; D008297:Male; D011533:Proviruses / Q000235:genetics; D012367:RNA, Viral / Q000097:blood; D012007:Rectum / Q000821:virology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000276:immunology / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000254:growth & development* / Q000276:immunology / Q000502:physiology; D013997:Time Factors; D017211:Treatment Failure; D019562:Viral Load / Q000187:drug effects; D014766:Viremia / Q000188:drug therapy / Q000821:virology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D044966:Anti-Retroviral Agents; D004279:DNA, Viral; D012367:RNA, Viral