HIV-infected sex workers with beneficial HLA-variants are potential hubs for selection of HIV-1 recombinants that may affect disease progression.

Chih-Hao Chang,Daniel Lunn,Tammy L Stuart Chester,Vattipally B Sreenu,Astrid K N Iversen,Francis A Plummer,Nicolaas C Kist,Melissa Herman,John Bell,T Blake Ball,Aris Katzourakis,Ma Luo

doi:10.1038/srep11253

Abstract

Cytotoxic T lymphocyte (CTL) responses against the HIV Gag protein are associated with lowering viremia; however, immune control is undermined by viral escape mutations. The rapid viral mutation rate is a key factor, but recombination may also contribute. We hypothesized that CTL responses drive the outgrowth of unique intra-patient HIV-recombinants (URFs) and examined gag sequences from a Kenyan sex worker cohort. We determined whether patients with HLA variants associated with effective CTL responses (beneficial HLA variants) were more likely to carry URFs and, if so, examined whether they progressed more rapidly than patients with beneficial HLA-variants who did not carry URFs. Women with beneficial HLA-variants (12/52) were more likely to carry URFs than those without beneficial HLA variants (3/61) (p < 0.0055; odds ratio = 5.7). Beneficial HLA variants were primarily found in slow/standard progressors in the URF group, whereas they predominated in long-term non-progressors/survivors in the remaining cohort (p = 0.0377). The URFs may sometimes spread and become circulating recombinant forms (CRFs) of HIV and local CRF fragments were over-represented in the URF sequences (p < 0.0001). Collectively, our results suggest that CTL-responses associated with beneficial HLA variants likely drive the outgrowth of URFs that might reduce the positive effect of these CTL responses on disease progression.

Highlights

Millions of patients are already receiving expensive, life-long anti-HIV treatment, and millions more will require treatment because of the continued spread of HIV-1, in resource-poor settings worldwide
We examined the relationship between the HIV-1 form (homogeneous HIV-1 subtype/sub-subtype (HHS) or circulating recombinant forms (CRFs) versus unique recombinant form (URF)), human leukocyte antigen (HLA) profile and clinical progression rate in HIV-infected female commercial sex workers (CSWs) from the Pumwani slum in Nairobi, Kenya, where several HIV-1 subtypes and CRFs co-circulate[27,28,29]
By regressing on the Bayesian log(odds) we found that patients with URFs were marginally more likely to be in DP2 and that patients with HHSs/CRFs were slightly more likely to be in DP1(Table S1)

Summary

Introduction

Millions of patients are already receiving expensive, life-long anti-HIV treatment, and millions more will require treatment because of the continued spread of HIV-1, in resource-poor settings worldwide (www.unaids.org) The solution to this epidemic will require the development of a preventive vaccine and, potentially, therapeutic vaccines[1]. All CTL responses can select for mutations within or flanking CD8 epitopes, which allows HIV-1 to escape CTL recognition and prevents infected cells from being killed. These mutations may affect HLA binding, T cell receptor contact sites and/or antigen processing[2,7,8,9,10,11]. The risk of superinfection, i.e., a later infection by a second HIV strain, is similar to that of initial infection during the first 6 months and subsequently decreases by approximately half[24,25] but can be difficult to recognize if the superinfecting HIV strain belongs to the same subtype as the HIV strain that initially infected the patient

Methods

Results

Conclusion