CTLA-4 Expression on HIV-specific CD4 T cells

At the ongoing Keystone meeting on HIV pathogenesis, being held high amidst the Canadian Rockies at the Whistler Resort, new data was presented today on CTLA-4 expression on HIV-specific CD4 T cells. CTLA-4 is a molecule that can negatively regulate T cell responses by interacting with its ligands CD80 and CD86. Previous studies have shown that levels of CTLA-4 are upregulated on total CD4 T cells in progressive HIV infection and this increase in CTLA-4 expression is associated with immune activation and CD4 T cell anergy. Additionally, CTLA-4 blockade (with an antibody called MDX-010) has been reported to have beneficial effects in SIV-infected macaques. At the Keystone meeting, Daniel Kaufmann from Massachusetts General Hospital reported his analysis of CTLA-4 levels among HIV-specific CD4 T cells in a cohort of 50 infected individuals at various stages of disease. Kaufmann found that HIV Gag-specific CD4 T cells expressed high levels of CTLA-4 on their surface; the mean flourescence intensity (MFI) was 4,520 compared to 658 on CMV-specific CD4 T cells. Kaufmann was able to correlate the MFI with intracellular levels of CTLA-4, and used the latter in subsequent analyses (because it is more easily measurable). Looking at markers of disease progression, Kaufmann found that CTLA-4 levels in Gag-specific CD4 T cells correlated positively with viral load (r²=0.81, p=0.0001) and inversely with CD4 T cell counts (r²=0.58, p=0.001). Breaking the cohort into groups based on disease stage, CTLA-4 levels in Gag-specific CD4 T cells were elevated compared to CMV-specific CD4 T cells at all stages of untreated progressive disease and in individuals on ART. The only exception were a group of elite controllers with viral loads <50 copies in the absence of therapy, these individuals had CTLA-4 levels on their Gag-specific CD4 T cells that were comparable to their CMV-specific CD4 T cells.

In terms of the functionality of the Gag-specific CD4 T cells studied, CTLA-4 levels were lower on cells that made the cytokine IL-2 or both IL-2 and interferon gamma and higher on cells that could make only interferon gamma. Blockade of CTLA-4 in vitro appeared to increase the ability of Gag-specific CD4 T cells to proliferate (from 3.23% to 10.3% in a CFSE assay), while it had no effect on CMV-specific responses. Kaufmann also found that CTLA-4 was often co-expressed with PD-1, another marker of T cell exhaustion that has received much attention recently. However, unlike PD-1, CTLA-4 upregulation was not seen on CD8 T cells in this study. Also, in response to a question, Kaufmann noted that dual blockade of PD-1 and CTLA-4 in vitro did not exert additive effects on CD4 T cell function, in fact it appeared to do the opposite in preliminary experiments. Kaufmann concluded that CTLA-4 is another marker of CD4 T cell exhaustion in HIV that may be amenable to manipulation, but further experiments will be needed to assess the therapeutic potential of CTLA-4 blocking strategies.