HIV remains one of the most important medical challenges to mankind, with 37 million people infected worldwide, of which 50% are infected with clade C HIV (C-HIV). The ability of HIV-1 to establish long-lived reservoirs in memory CD4+ T cell subsets allow the virus to persist without being detected, preventing its eradication under current treatment regimens. In addition, the well characterised ‘arms-race’ between the immune systems response and the development of viral escape mutations may influence cellular tropism for different memory CD4+ T cell subsets. Our work focuses on elucidating key virus-cell interactions that mediate cellular tropism for CD4+ memory T cell subsets.
We have established a longitudinal cohort of C-HIV viruses from five ART-naïve individuals enrolled in the CAPRISA 002 Acute Infection Study. Our collaborators demonstrated plasma derived from these individuals three years post infection showed variable cross-clade neutralisation breadth, ranging from 0% to 82%. In addition, our collaborators have mapped regions of neutralising antibody epitope targets as well as escape mutations for the first three years of infection for three of these subjects. For this study, 49 functional envelope (Env) glycoproteins were generated from three-time points; enrolment, one year and three years post enrolment. Coreceptor usage characterisation revealed all Envs efficiently utilised CCR5 for entry, with Envs from one subject at the one-year time-point harbouring dual-tropic Envs that weakly supported CXCR4-mediated entry.
Future experiments will investigate tropism of these viruses for different memory CD4+ T cell subsets utilising GFP expressing Env-pseudotyped reporter viruses. In addition, we will characterise CD4/CCR5 dependence using the Affinofile system, and analyse the mechanism of coreceptor engagement using a panel of CCR5 mutants. Overall this unique ART-naïve cohort will improve our understanding of how the evolution of Env throughout C-HIV infection influences tropism for cells known to be key viral reservoirs.