HIV remains one of the most important medical challenges, with 37 million people infected worldwide. The ability of HIV-1 to establish long-lived reservoirs in memory CD4+ T cell subsets allows the virus to persist without being detected, preventing its eradication under current treatment regimens. In addition, the well characterised ‘arms-race’ between the immune system and the development of viral escape mutations may influence cellular tropism for different memory CD4+ T cells. Our work focuses on elucidating virus-cell interactions that mediate cellular tropism for key CD4+ memory T cells, known to be viral reservoirs.
Clade C HIV (C-HIV) accounts for >50% of HIV infections world-wide. 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 (Witswatersrand University, South Africa) have mapped regions of neutralizing antibody epitope targets as well as escape mutations for the first three years of infection and demonstrated variable cross-clade neutralization breadth at three years post infection, ranging from 0% to 82%. We have generated 49 functional envelope (Env) glycoproteins from these subjects at 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 1 year) harbouring dual-tropic Envs that weakly supported CXCR4-mediated entry.
We will further characterise key virus-cell interactions including CD4/CCR5 dependence using the Affinofile system, and analyse the mechanism of coreceptor engagement using a panel of CCR5 mutants. Additionally we will investigate the tropism of these viruses for different memory CD4+ T cell subsets, including key viral reservoirs, using GFP expressing Env-pseudotyped reporter viruses. This unique ART-naïve cohort will improve our understanding of how the evolution of Env throughout C-HIV infection influences the infection of cells known to be key viral reservoirs.