PMID- 30602611 OWN - NLM STAT- MEDLINE DCOM- 20191119 LR - 20210617 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 93 IP - 6 DP - 2019 Mar 15 TI - HIV Subtype and Nef-Mediated Immune Evasion Function Correlate with Viral Reservoir Size in Early-Treated Individuals. LID - 10.1128/JVI.01832-18 [doi] LID - e01832-18 AB - The HIV accessory protein Nef modulates key immune evasion and pathogenic functions, and its encoding gene region exhibits high sequence diversity. Given the recent identification of early HIV-specific adaptive immune responses as novel correlates of HIV reservoir size, we hypothesized that viral factors that facilitate the evasion of such responses-namely, Nef genetic and functional diversity-might also influence reservoir establishment and/or persistence. We isolated baseline plasma HIV RNA-derived nef clones from 30 acute/early-infected individuals who participated in a clinical trial of early combination antiretroviral therapy (cART) (<6 months following infection) and assessed each Nef clone's ability to downregulate CD4 and human leukocyte antigen (HLA) class I in vitro We then explored the relationships between baseline clinical, immunological, and virological characteristics and the HIV reservoir size measured 48 weeks following initiation of suppressive cART (where the reservoir size was quantified in terms of the proviral DNA loads as well as the levels of replication-competent HIV in CD4(+) T cells). Maximal within-host Nef-mediated downregulation of HLA, but not CD4, correlated positively with post-cART proviral DNA levels (Spearman's R = 0.61, P = 0.0004) and replication-competent reservoir sizes (Spearman's R = 0.36, P = 0.056) in univariable analyses. Furthermore, the Nef-mediated HLA downregulation function was retained in final multivariable models adjusting for established clinical and immunological correlates of reservoir size. Finally, HIV subtype B-infected persons (n = 25) harbored significantly larger viral reservoirs than non-subtype B-infected persons (2 infected with subtype CRF01_AE and 3 infected with subtype G). Our results highlight a potentially important role of viral factors-in particular, HIV subtype and accessory protein function-in modulating viral reservoir establishment and persistence.IMPORTANCE While combination antiretroviral therapies (cART) have transformed HIV infection into a chronic manageable condition, they do not act upon the latent HIV reservoir and are therefore not curative. As HIV cure or remission should be more readily achievable in individuals with smaller HIV reservoirs, achieving a deeper understanding of the clinical, immunological, and virological determinants of reservoir size is critical to eradication efforts. We performed a post hoc analysis of 30 participants of a clinical trial of early cART who had previously been assessed in detail for their clinical, immunological, and reservoir size characteristics. We observed that the HIV subtype and autologous Nef-mediated HLA downregulation function correlated with the viral reservoir size measured approximately 1 year post-cART initiation. Our findings highlight virological characteristics-both genetic and functional-as possible novel determinants of HIV reservoir establishment and persistence. CI - Copyright (c) 2019 American Society for Microbiology. FAU - Omondi, Fredrick H AU - Omondi FH AD - Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada. FAU - Chandrarathna, Sandali AU - Chandrarathna S AD - Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada. FAU - Mujib, Shariq AU - Mujib S AUID- ORCID: 0000-0002-6206-5622 AD - Department of Medicine, University of Toronto, Toronto, Ontario, Canada. FAU - Brumme, Chanson J AU - Brumme CJ AD - British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada. FAU - Jin, Steven W AU - Jin SW AD - Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada. FAU - Sudderuddin, Hanwei AU - Sudderuddin H AD - Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada. FAU - Miller, Rachel L AU - Miller RL AD - Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada. FAU - Rahimi, Asa AU - Rahimi A AD - Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada. FAU - Laeyendecker, Oliver AU - Laeyendecker O AD - Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. AD - Johns Hopkins University, Baltimore, Maryland, USA. FAU - Bonner, Phil AU - Bonner P AD - Department of Medicine, University of Toronto, Toronto, Ontario, Canada. FAU - Yue, Feng Yun AU - Yue FY AD - Department of Medicine, University of Toronto, Toronto, Ontario, Canada. FAU - Benko, Erika AU - Benko E AD - Department of Medicine, University of Toronto, Toronto, Ontario, Canada. FAU - Kovacs, Colin M AU - Kovacs CM AD - Department of Medicine, University of Toronto, Toronto, Ontario, Canada. AD - Maple Leaf Clinic, Toronto, Ontario, Canada. FAU - Brockman, Mark A AU - Brockman MA AUID- ORCID: 0000-0001-6432-1426 AD - Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada. AD - British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada. AD - Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada. FAU - Ostrowski, Mario AU - Ostrowski M AD - Department of Medicine, University of Toronto, Toronto, Ontario, Canada mario.ostrowski@gmail.com zbrumme@sfu.ca. AD - Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada. FAU - Brumme, Zabrina L AU - Brumme ZL AUID- ORCID: 0000-0002-8157-1037 AD - Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada mario.ostrowski@gmail.com zbrumme@sfu.ca. AD - British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada. LA - eng GR - WT_/Wellcome Trust/United Kingdom GR - R21 AI127029/AI/NIAID NIH HHS/United States GR - UM1 AI126617/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190305 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (Anti-Retroviral Agents) RN - 0 (CD4 Antigens) RN - 0 (HLA Antigens) RN - 0 (nef Gene Products, Human Immunodeficiency Virus) SB - IM MH - Adult MH - Anti-Retroviral Agents/pharmacology MH - CD4 Antigens/immunology MH - CD4-Positive T-Lymphocytes/immunology MH - Down-Regulation/drug effects/immunology MH - HIV/drug effects/*immunology MH - HIV Infections/drug therapy/*immunology MH - HLA Antigens/immunology MH - Humans MH - Immune Evasion/drug effects/*immunology MH - Male MH - Middle Aged MH - Virus Latency/drug effects/immunology MH - Young Adult MH - nef Gene Products, Human Immunodeficiency Virus/*immunology PMC - PMC6401425 OTO - NOTNLM OT - CD4 downregulation OT - HIV reservoir OT - HIV-1 OT - HLA downregulation OT - Nef OT - viral pathogenesis EDAT- 2019/01/04 06:00 MHDA- 2019/11/20 06:00 PMCR- 2019/09/05 CRDT- 2019/01/04 06:00 PHST- 2018/10/15 00:00 [received] PHST- 2018/11/30 00:00 [accepted] PHST- 2019/01/04 06:00 [pubmed] PHST- 2019/11/20 06:00 [medline] PHST- 2019/01/04 06:00 [entrez] PHST- 2019/09/05 00:00 [pmc-release] AID - JVI.01832-18 [pii] AID - 01832-18 [pii] AID - 10.1128/JVI.01832-18 [doi] PST - epublish SO - J Virol. 2019 Mar 5;93(6):e01832-18. doi: 10.1128/JVI.01832-18. Print 2019 Mar 15.