A large body of data points to CMV infection as the strongest risk factor for the development of the “immune risk profile” (IRP) in elderly individuals without HIV infection, a profile that is associated with ill health (including neurocognitive decline) and relatively earlier mortality. The association between the IRP and CMV infection is linked to large accumulations of CMV-specific CD4 and CD8 T cells displaying a senescent phenotype (lacking expression of the co-stimulatory molecule CD28). A new paper in PLoS One reports results of a comprehensive evaluation of CMV-specific T cell responses in individuals at varying stages of HIV infection, both on and off antiretroviral therapy, in comparison to matched HIV-negative controls. The goal of the study was to gain insight into whether CMV-specific CD4 and CD8 T cell expansions occur at an earlier age in people with HIV and might therefore contribute to the accelerated onset of immunosenescence.
The researchers found that CD8 T cells responses to two major CMV antigens (the pp65 and IE proteins) were consistently higher in people with HIV compared to age-matched controls, even at the earliest stages of infection. The same pattern held true for CD4 T cells although the number of CMV-specific cells was lower compared to CD8 T cells. The highest levels were seen among individuals on antiretroviral therapy; on average 6% of their peripheral blood CD8 T cells were specific for pp65 or IE antigens. Because CMV encodes many other proteins, the researchers estimate that an average of around 20% of CD8 T cells were CMV-specific in this group, a strikingly high number. The authors conclude that “longitudinal studies to determine whether CMV drives early immunosenescence during HIV disease are warranted.”
PLoS ONE 5(1): e8886. doi:10.1371/journal.pone.0008886
David M. Naeger1, Jeffrey N. Martin1,2, Elizabeth Sinclair1, Peter W. Hunt1, David R. Bangsberg3, Frederick Hecht1, Priscilla Hsue1, Joseph M. McCune1, Steven G. Deeks1
1 Department of Medicine, University of California San Francisco, San Francisco, California, United States of America, 2 Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America, 3 Massachusetts General Hospital, Harvard Medical School, Harvard Initiative for Global Health, Boston, Massachusetts, United States of America
Background
In healthy, HIV seronegative, CMV seropositive adults, a large proportion of T cells are CMV-specific. High-level CMV-specific T cell responses are associated with accelerated immunologic aging (“immunosenesence”) in the elderly population. The impact of untreated and treated HIV infection on the frequency of these cells remains undefined.
Methodology/Principal Findings
We measured the proportion of CD4+ and CD8+ T cells responding to CMV pp65 and IE proteins was measured using flow cytometry in 685 unique HIV seronegative and seropositive individuals. The proportion of CMV-specific CD8+ T cells was consistently higher in the HIV-seropositive subjects compared to the HIV-seronegative subjects. This HIV effect was observed even in patients who lacked measurable immunodeficiency. Among the HIV-seropositive subjects, CMV-specific CD8+ T cell responses were proportionately lower during recent infection, higher during chronic untreated infection and higher still during long-term antiretroviral treated infection. The CD8+ T cell response to just two CMV proteins (pp65 and IE) was approximately 6% during long-term therapy, which was over twice that seen in HIV-seronegative persons. CMV-specific CD4+ T cell responses followed the same trends, but the magnitude of the effect was smaller.
Conclusions/Significance
Long-term successfully treated HIV infected patients have remarkably high levels of CMV-specific effector cells. These levels are similar to that observed in the elderly, but occur at much younger ages. Future studies should focus on defining the potential role of the CMV-specific inflammatory response in non-AIDS morbidity and mortality, including immunosenescence.
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