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Background:  Immune activation plays a central role in HIV pathogenesis leading to anergy, immune dysregulation, and CD4 T-cell decline. CD38 expression on CD8 T cells is an easily measured and valid marker of immune activation. We hypothesized that CD38CD8 expression would prospectively predict HIV progression independent of plasma HIV-1 viral load, HIV-1 resistance profile and use of HAART.

Methods:  We studied HIV-infected patients in care obtaining CD38CD8 measurements at enrollment and every 3 to 6 months. CD4 T-cell counts, plasma HIV-1 viral loads and resistance assays were obtained per usual clinical guidelines. We measured the median number of CD38 molecules per CD8 T cell (CD38CD8 expression) by relative fluorescent intensity using fluorochrome-labeled CD38 and flow cytometry (Becton Dickinson, San Jose, CA). A generalized linear mixed model was used to assess the relationship between CD38CD8 expression and CD4 T-cell count over time, adjusting for plasma HIV-1 viral load and using the log₁₀ of continuous measures. We adjusted for serial correlation using a spatial power covariance structure.

Results:  From October 2001 through September 2004, we followed 79 subjects (median baseline CD4 T-cell count was 428 cells/mm³, range 32 to 1410; median baseline CD38CD8 expression was 2226 molecules/cell, range 636 to 19,092); 23 (29%) subjects were on HAART. Of 29 subjects with HIV-1 resistance profiles, 19 (66%) had wild type, 6 (21%) had reverse transcriptase mutations only and 4 (13%) had significant protease mutations. The log₁₀ of CD38CD8 expression predicted a significant decline in the log₁₀ of CD4 T-cell count (regression slope = –0.2981, p = 0.003) independent of plasma viral load or HAART use; resulting in a 3% decline in absolute CD4 T-cell count per 10% increase in absolute CD38CD8 expression. Among patients with any drug-resistant virus the regression slope for CD8CD38 expression and CD4 T cell count was –1.2991, p = 0.002.

Conclusions:  CD8CD38 expression in patients predicted declines in CD4 T-cell counts independent of plasma HIV-1 viral load, use of HAART or HIV-1 resistance profile validating the dominant role of immune activation in HIV pathogenesis. While further studies are needed to demonstrate the clinical benefit of monitoring CD38CD8 expression, clinical trials should include CD38CD8 monitoring and therapeutic discovery for HIV disease should additionally focus on modifying immune activation.

Keywords: immune activation; CD38 expression; HIV pathogenesis