Background:
Chronic cytomegalovirus (CMV) infection elicits large T cell responses with significant biological and clinical implications (chronic inflammation and frailty) in HIV infection. Such T cell responses have been shown to target a wide range of CMV proteins. Building on our prior work, we postulated that the breadth and polyfunctionality of T cell responses to an extensive panel of CMV antigens would differ by HIV status.
Methods:
CD4 and CD8 T cell responses to peptide pools spanning 19 CMV open reading frames (ORFs) were measured by intracellular cytokine staining for production of IFN-𝛾, TNF-⍺ and IL-2 in 42 men (20 HIV- and 22 virologically suppressed HIV+) in the Multicenter AIDS Cohort Study. Polyfunctionality of T cell responses was assessed by mean polyfunctionality index of responding cells (= .33 for cells producing 1 cytokine and 1.00 for cells producing 3 cytokines). Differences between HIV- and HIV+ men were assessed by non-parametric Mann-Whitney test. Differences between bivariate Spearman’s correlation coefficients were assessed by Fisher’s Z test, and differences in slope of regressions by least-square linear regression.
Results:
Median numbers of CMV ORFs triggering CD8 T cell responses in HIV+ men were significantly higher than in HIV- men (10 vs. 7, respectively; p=.04). This was primarily due to an excess of responses to late-expressed CMV antigens in HIV+ men. In HIV- men, the numbers of ORFs responded to were strongly and positively correlated with total T cell responses for both CD4 and CD8 T cells (r=0.73, p< .001, and r=0.88, p< 0.00001, respectively); these correlations were present but weaker in HIV+ men (r=0.56, p=.007, and r=0.59, p=.004, respectively; p=.04 for the difference in correlation in CD8 responses by HIV status). Slopes of the regression of total CD4 responses against the number of CD4 responses were lower in HIV+ men than in HIV- men (p=.06). Polyfunctionality of CD4 responses to CMV ORFs was significantly lower in HIV+ men than in HIV- men (mean PI = .33 vs. .59, respectively; p< .001).
Conclusions:
The breadth of CMV-specific CD8 T cell responses was higher and its correlation with the total magnitude of these responses was weaker in HIV+ men than in HIV- men. These results, along with the lower polyfunctionality of CD4 responses and the greater response to late CMV antigens in HIV+ men, suggest that immune control of CMV infection may be different in HIV+ men receiving antiretroviral therapy than in HIV- men with similar lifestyle.