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HIV subtype and Nef-mediated immune evasion function correlate with viral reservoir size in early-treated individuals.

Omondi FH, et al. J Virol. 2019.


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 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 cART (<6 months following infection) and assessed each Nef clone's ability to downregulate CD4 and HLA class I in vitro We then explored the relationships between baseline clinical, immunologic and virologic characteristics, and HIV reservoir size measured 48 weeks following initiation of suppressive cART (where reservoir size was quantified in terms of proviral DNA loads as well as 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, Nef-mediated HLA downregulation function was retained in final multivariable models adjusting for established clinical and immunologic correlates of reservoir size. Finally, HIV subtype B infected persons (N=25) harbored significantly larger viral reservoirs compared to non-B infected persons (2 CRF01_AE and 3 subtype G infections). 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 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 clinical, immunologic and virologic 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, immunologic and reservoir size characteristics. We observed that HIV subtype and autologous Nef-mediated HLA downregulation function correlated with viral reservoir size measured approximately one year post-cART initiation. Our findings highlight virologic characteristics - both genetic and functional - as possible novel determinants of HIV reservoir establishment and persistence.

Copyright © 2019 American Society for Microbiology.


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