Background:  Despite a close phylogenetic relationship between the viruses, the clinical course of disease in HIV-2 infection is distinct from that of HIV-1. The majority of HIV-2-infected individuals experience non-progressive disease and maintain normal CD4 counts. Proviral burden of HIV-2 is similar to that of HIV-1, yet plasma viral load, transmission rates, and mortality rates are all reduced by comparison. Identifying correlates of protection in HIV-2 could provide missing links in the understanding of immune-mediated protection against HIV infection or progression to disease.

Methods:  We conducted a cross-sectional study of HIV Gag-specific T cell function in 39 HIV-1- and 33 HIV-2-infected Gambians. We quantified the Gag peptide-specific CD4⁺ T cell response by intracellular cytokine staining for interferon-gamma (IFN-g) and interleukin-2 (IL-2) and examined surface expression of CD57 for evidence of terminal differentiation. In addition, we monitored the proliferative capacity of HIV-specific CD4⁺ and CD8⁺ T cells using a CFSE-based assay. ANOVA and Mann Whitney tests were utilized for statistical comparisons.

Results:  CD4⁺ T cells specific for HIV were detected more frequently among HIV-2-infected individuals. The proportion of CD4⁺ T cells producing either IFN-g or IL-2 in response to Gag peptides was 3- to 6-fold higher among asymptomatic HIV-2⁺ individuals. The HIV-2-specific CD4⁺ T cell response was functionally heterogeneous, comprised of cells producing either IFN-g or IL-2 and a unique polyfunctional IFNg⁺IL-2⁺ population found exclusively among HIV-2⁺ donors. HIV-2-specific CD4⁺ T cells maintained a superior proliferative capacity and were predominantly non-terminally differentiated (CD57^­). The disparity in CD4⁺ T cell responses between asymptomatic HIV-1- and HIV-2-infected donors was not associated with differences in the proliferative capacity of HIV-specific CD8⁺ T cells.

Conclusions:  HIV-2-infected individuals with non-progressive disease mount a functionally superior HIV-specific CD4⁺ T cell response compared with HIV-1⁺ individuals or HIV-2⁺ progressors. This response is principally distinguished by a non-terminally differentiated, polyfunctional population of cytokine-producing cells with preserved proliferative capacity. In contrast to the diminished or absent HIV-1-specific CD4⁺ T cell response, a strong, functionally diverse, and heterogeneous HIV-2-specific CD4⁺ helper T cell response may be a contributing factor in the attenuated clinical phenotype of HIV-2 infection.