@article{b655fa3bc7ac4208a81792c892b50bb0,
title = "HIV subtype and nef-mediated immune evasion function correlate with viral reservoir size in early-treated individuals",
abstract = "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{\textquoteright}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{\textquoteright}s R=0.61, P=0.0004) and replication-competent reservoir sizes (Spearman{\textquoteright}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.",
keywords = "CD4 downregulation, HIV reservoir, HIV-1, HLA downregulation, Nef, Viral pathogenesis",
author = "Omondi, {Fredrick H.} and Sandali Chandrarathna and Shariq Mujib and Brumme, {Chanson J.} and Jin, {Steven W.} and Hanwei Sudderuddin and Miller, {Rachel L.} and Asa Rahimi and Oliver Laeyendecker and Phil Bonner and Yue, {Feng Yun} and Erika Benko and Kovacs, {Colin M.} and Brockman, {Mark A.} and Mario Ostrowski and Brumme, {Zabrina L.}",
note = "Funding Information: We thank Gursev Anmole and Natalie Kinloch for technical assistance and helpful discussions and Viviane Dias Lima for helpful statistical discussions. We gratefully thank the clinical trial participants, without whom this research would not be possible. This research was funded in part by a Canadian HIV Cure Enterprise team grant from the Canadian Institutes for Health Research (CIHR), in partnership with the Canadian Foundation for AIDS Research (CANFAR) and the International AIDS Society (IAS) (HIG-133050 to M.A.B., M.O., and Z.L.B.); by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number UM1AI126617, with cofunding support from the National Institute on Drug Abuse, the National Institute of Mental Health, and the National Institute of Neurological Disorders and Stroke (to M.A.B., M.O., and Z.L.B.); by NIH award R21A127029 (to Z.L.B. and M.A.B.); and by project grants from the CIHR (PJT-148621 and PJT-159625 to Z.L.B. and M.A.B.). F.H.O. is supported by the Canadian Queen Elizabeth II Diamond Jubilee Scholarships program, a joint initiative of the Rideau Hall Foundation, Community Foundations of Canada, and the Association of Universities and Colleges of Canada, and also received a fellowship from the Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE), a DELTAS Africa Initiative (grant number DEL-15-006). The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS) Alliance for Accelerating Excellence in Science in Africa (AESA) and is supported by the New Partnership for Africa{\textquoteright}s Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust (grant number 107752/Z/15/Z) and the UK government. S.W.J. was supported by a Frederick Banting and Charles Best CIHR MSc award. M.A.B. holds a Canada Research Chair, Tier 2, in Viral Pathogenesis and Immunity. Z.L.B. is supported by a scholar award from the Michael Smith Foundation for Health Research. The views expressed in this publication are those of the authors and not necessarily those of AAS, the NEPAD Agency, the Wellcome Trust, or the UK government. Funding Information: Alliance for Accelerating Excellence in Science in Africa (AESA) and is supported by the New Partnership for Africa{\textquoteright}s Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust (grant number 107752/Z/15/Z) and the UK government. S.W.J. was supported by a Frederick Banting and Charles Best CIHR MSc award. M.A.B. holds a Canada Research Chair, Tier 2, in Viral Pathogenesis and Immunity. Z.L.B. is supported by a scholar award from the Michael Smith Foundation for Health Research. Funding Information: This research was funded in part by a Canadian HIV Cure Enterprise team grant from the Canadian Institutes for Health Research (CIHR), in partnership with the Canadian Foundation for AIDS Research (CANFAR) and the International AIDS Society (IAS) (HIG-133050 to M.A.B., M.O., and Z.L.B.); by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number UM1AI126617, with cofunding support from the National Institute on Drug Abuse, the National Institute of Mental Health, and the National Institute of Neurological Disorders and Stroke (to M.A.B., M.O., and Z.L.B.); by NIH award R21A127029 (to Z.L.B. and M.A.B.); and by project grants from the CIHR (PJT-148621 and PJT-159625 to Z.L.B. and M.A.B.). F.H.O. is supported by the Canadian Queen Elizabeth II Diamond Jubilee Scholarships program, a joint initiative of the Rideau Hall Foundation, Community Foundations of Canada, and the Association of Universities and Colleges of Canada, and also received a fellowship from the Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE), a DELTAS Africa Initiative (grant number DEL-15-006). The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS) Publisher Copyright: {\textcopyright} 2019 American Society fo Microbiology. All Rights Reserved.",
year = "2019",
month = mar,
day = "1",
doi = "10.1128/JVI.01832-18",
language = "English (US)",
volume = "93",
journal = "Journal of virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "6",
}