Host genetic and viral determinants of HIV-1 RNA set-point among HIV-1 seroconverters from sub-Saharan Africa.


Mackelprang, RD; Carrington, M; Thomas, KK; Hughes, JP; Baeten, JM; Wald, A; Farquhar, C; Fife, K; Campbell, MS; Kapiga, S; Gao, X; Mullins, JI; Lingappa, JR; (2014) Host genetic and viral determinants of HIV-1 RNA set-point among HIV-1 seroconverters from sub-Saharan Africa. Journal of virology. ISSN 0022-538X DOI: https://doi.org/10.1128/JVI.01573-14

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Abstract

We quantified the collective impact of source partner HIV-1 RNA levels, human leukocyte antigen (HLA) alleles, and innate responses through toll-like receptor (TLR) alleles on HIV-1 set-point. Data came from HIV-1 seroconverters in African HIV-1 serodiscordant couple cohorts. Linear regression was used to determine associations with set-point and R(2) to estimate variation explained by covariates. The strongest predictors of set-point were HLA alleles (B*53:01, B*14:01, and B*27:03) and plasma HIV-1 levels of the transmitting partner, which explained 13% and 10% of variation in set-point, respectively. HLA-A concordance between partners and TLR polymorphisms (TLR2-rs3804100, TLR7-rs179012) were also associated with set-point, explaining 6% and 5% of variation, respectively. Overall, these factors and genital factors of the transmitter (i.e. male circumcision, bacterial vaginosis and use of acyclovir) explained 46% of variation in set-point. We found that both innate and adaptive immune responses, together with plasma HIV-1 levels of the transmitting partner, explain almost half of the variation in viral load set-point. After HIV-1 infection, uncontrolled virus replication leads to a rapid increase in HIV-1 concentrations. Once host immune responses develop, however, HIV-1 levels reach a peak and subsequently decline until they reach a stable level that may persist for years. This stable HIV-1 set-point represents an equilibrium between the virus and host responses, and is predictive of later disease progression and transmission potential. Understanding how host and virus factors interact to determine HIV-1 set-point may elucidate novel mechanisms or biological pathways for treating HIV-1 infection. We identified host and virus factors that predict HIV-1 set-point in people who recently acquired HIV-1, finding that both innate and adaptive immune responses, along with factors that likely influence HIV-1 virulence and inoculum, explain ∼46% of the variation in HIV-1 set-point.

Item Type: Article
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Infectious Disease Epidemiology
PubMed ID: 25473042
Web of Science ID: 348562800015
URI: http://researchonline.lshtm.ac.uk/id/eprint/2026681

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