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

• Published in: Retrovirology Vol. 11; no. 1; p. 97
• Main Authors: Cashin, Kieran, Paukovics, Geza, Jakobsen, Martin R, Oestergaard, Lars, Churchill, Melissa J, Gorry, Paul R, Flynn, Jacqueline K
• Format: Journal Article
• Language: English
• Published: 01.01.2014
• Subjects: Human immunodeficiency virus 1
• ISSN: 1742-4690; 1742-4690
• DOI: 10.1186/s12977-014-0097-5

Background: CD4 super(+) 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 super(+) 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 super(+) T-cell subsets, including stem cell memory T-cells (T sub(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 super(+) T-cell subsets, respectively. While T sub(SCM) were susceptible to infection by both R5 and X4 C-HIV viruses, the proportion of infected CD4 super(+) T-cells that were T sub(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 super(+) T-cells by emergent X4 C-HIV variants in this subject. In contrast, the tropism of R5 C-HIV viruses for CD4 super(+) 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 super(+) 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 sub(SCM) and other memory CD4 super(+) T-cells are likely to be viral reservoirs in subjects with X4 C-HIV infection.