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

Retrovirology

Jacqueline K Flynn³  Paul R Gorry³  Melissa J Churchill²  Lars Østergaard⁴  Martin R Jakobsen¹  Geza Paukovics⁶  Kieran Cashin⁵ 

[1] Department of Biomedicine, Aarhus University, Aarhus 237551, Denmark;Department of Microbiology, Monash University, Melbourne 3010, Australia;Department of Infectious Diseases, Monash University, Melbourne 3004, Australia;Department of Infectious Diseases, Aarhus University, Aarhus 237551, Denmark;Department of Microbiology and Immunology, University of Melbourne, Melbourne 3010, Australia;Burnet Institute Flow Cytometry Core Facility, Melbourne 3004, Australia

关键词: TSCM;    CD4+;    T-cell;    Subtype C;    HIV-1;   

Others  :  1152003
DOI  :  10.1186/s12977-014-0097-5

 received in 2014-09-22, accepted in 2014-10-23,  发布年份 2014

【 摘 要 】

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 naïve 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-naïve 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 naïve 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 naïve 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.

【 授权许可】

   
2014 Cashin et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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