Longitudinal analysis of CCR5 and CXCR4 usage in a cohort of antiretroviral therapy-naive subjects with progressive HIV-1 subtype C infection

Martin R Jakobsen, Kieran Cashin, Michael Roche, Jasminka Sterjovski, Anne Ellett, Katharina Borm, Jacqueline Kaye Flynn, Christian Erikstrup, Maelenn Gouillou, Lachlan Robert Gray, Nitin K Saksena, Bin Wang, Damian F Purcell, Per Kallestrup, Rutendo Zinyama-Gutsire, Exnevia Gomo, Henrik Ullum, Lars Ostergaard, Benhur Lee, Paul Allen RamslandMelissa Churchill, Paul R Gorry

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HIV-1 subtype C (C-HIV) is responsible for most HIV-1 cases worldwide. Although the pathogenesis of C-HIV is thought to predominantly involve CCR5-restricted (R5) strains, we do not have a firm understanding of how frequently CXCR4-using (X4 and R5X4) variants emerge in subjects with progressive C-HIV infection. Nor do we completely understand the molecular determinants of coreceptor switching by C-HIV variants. Here, we characterized a panel of HIV-1 envelope glycoproteins (Envs) (n = 300) cloned sequentially from plasma of 21 antiretroviral therapy (ART)-naive subjects who experienced progression from chronic to advanced stages of C-HIV infection, and show that CXCR4-using C-HIV variants emerged in only one individual. Mutagenesis studies and structural models suggest that the evolution of R5 to X4 variants in this subject principally involved acquisition of an Ile-Gly insertion in the gp120 V3 loop and replacement of the V3 Gly-Pro-Gly crown with a Gly-Arg-Gly motif, but that the accumulation of additional gp120 scaffold mutations was required for these V3 loop changes to confer functional effects. In this context, either of the V3 loop changes could confer possible transitional R5X4 phenotypes, but when present together they completely abolished CCR5 usage and conferred the X4 phenotype. Our results show that the emergence of CXCR4-using strains is rare in this cohort of untreated individuals with advanced C-HIV infection. In the subject where X4 variants did emerge, alterations in the gp120 V3 loop were necessary but not sufficient to confer CXCR4 usage.
Original languageEnglish
Article numbere65950
Number of pages13
JournalPLoS ONE
Issue number6
Publication statusPublished - 2013

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