Differences in coreceptor specificity contribute to alternative tropism of HIV-1 subtype C for CD4+ T-cell subsets, including stem cell memory T-cells

Background: CD4(+) memory T-cells are a major target for infection by HIV-1, whereby latent provirus can establish and endure suppressive antiretroviral therapies. Although HIV-1 subtype C strains (C-HIV) account for the majority of HIV-1 infections worldwide, the susceptibility of CD4(+) memory T-cells to infection by CCR5-(R5) and CXCR4-using (X4) C-HIV is unknown. Here, we quantified the susceptibility of naive and memory CD4(+) T-cell subsets, including stem cell memory T-cells (T-SCM), to infection by HIV-1 subtype C (C-HIV) strains from treatment-naive subjects who progressed from chronic to advanced stages of disease whilst either maintaining CCR5-using (R5) viruses (subjects 1503 and 1854), or who experienced emergence of dominant CXCR4-using (X4) strains (subject 1109). Findings: We show that R5 and X4 C-HIV viruses preferentially target memory and naive CD4(+) T-cell subsets, respectively. While T-SCM were susceptible to infection by both R5 and X4 C-HIV viruses, the proportion of infected CD4(+) T-cells that were T-SCM was higher for R5 strains. Mutagenesis studies of subject 1109 viruses established the V3 region of env as the determinant underlying the preferential targeting of naive CD4(+) T-cells by emergent X4 C-HIV variants in this subject. In contrast, the tropism of R5 C-HIV viruses for CD4(+) T-cell subsets was maintained from chronic to advanced stages of disease in subjects 1503 and 1854. Conclusions: This study provides new insights into the natural history of tropism alterations for CD4(+) T-cell subsets by C-HIV strains during progression from chronic to advanced stages of infection. Although not preferentially targeted, our data suggest that T-SCM and other memory CD4(+) T-cells are likely to be viral reservoirs in subjects with X4 C-HIV infection.