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Hyperactivated CD38 Cells Higher With
HIV and May Drive Chronic Inflammation
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International Workshop on HIV and Aging, October 13-14, 2022
By Mark Mascolini for NATAP and Virology Education
Levels of hyperactivated (CD38+ HLADR+) CD38 cells proved significantly higher in antiretroviral-treated people than in HIV-negative people [1]. Researchers from the University of Maryland suggested that persistent CD38 expression in CD38 cells of people responding to antiretroviral therapy (ART) may be one factor that spurs a chronic inflammatory state potentially contributing to comorbidities in people with HIV.
One way to explain higher comorbidity rates in people with than without HIV is faster cell aging due to chronic inflammation resulting from overactivation of CD4 and CD38 cells. HIV infection increases CD38 expression, and high expression of CD38 on T cells marks hyperactivation of the immune system. But the role of CD38 expression in the chronic inflammation seen in people with HIV remains incompletely understood.
To address that question the University of Maryland team weighed the impact of CD38 on expression of cytokines-markers of inflammation and activation-on CD38 cells of people with or without HIV infection. The investigators compared the proportion of cytotoxic CD38+ CD38 cells in peripheral blood mononuclear cells of HIV-positive and negative people. After stimulating cells for 5 days, they measured production of interferon-gamma (IFN-g) and tumor necrosis factor alpha (TNF-a) in CD38+ and CD38+ HLADR+ (hyperactivated) CD38 cells in a subset of HIV-positive people taking ART. To further clarify the role of CD38 in cytokine production, they stimulated CD38 cells with HIV Gag-specific peptide in the presence or absence of 78c, a CD38 inhibitor.
The analysis included 485 HIV-positive people not taking ART, 291 taking ART, and 119 HIV-negative controls. Average percentage of CD38+ CD38 cells proved significantly higher in HIV-positive people not taking ART than in the ART-treated group or HIV-negative controls (P < 0.0001). HIV-positive people taking ART also had a significantly higher percentage of CD38+ CD38 cells than people without HIV (P < 0.0001). In addition, the frequency of hyperactivated (CD38+ HLA DR+) CD38 cells was significantly higher in ART-treated people with HIV than in healthy controls (P < 0.005).
Stimulation of CD38 cells with HIV Gag peptide enhanced CD38 and HLADR expression on CD38 cells (P < 0.005) as well as production of the cytokines IFN-g and TNF-a. In addition, CD38 cells that produced IFN-g and TNF-a expressed CD38 at significantly higher levels than did CD38 cells that did not produce IFN-g and TNF-a. Cells cultured with the CD38 inhibitor 78c had significantly reduced production of the pro-inflammatory cytokines IFN-g and TNF-a than cells cultured without 78c (P < 0.05).
The University of Maryland researchers concluded that high numbers of CD38-positive CD38 cells persist in people with HIV who maintain an undetectable viral load with ART. They added that inhibiting CD38 improves the impact of hyperactivated CD38-positive T cells by damping the proinflammatory immune response. Thus, they proposed, "CD38 may be one of the driving factors for a chronic, inflammatory state, ultimately increasing the risk for comorbidities and end-organ damage."
Reference
1. Mathur P, Kottilil S, Ghosh A. Persistent CD38 expression on CD38 T lymphocytes contributes to chronic inflammation in people with HIV, despite ART. International Workshop on HIV and Aging, October 13-14, 2022. Abstract 2.
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