Abstract
Antiretroviral therapy (ART) effectively extends the life expectancy of human immunodeficiency virus (HIV)-infected individuals; however, age-related morbidities have emerged as major clinical concerns. In this context, coinfection with cytomegalovirus (CMV) accelerates immune senescence and elevates risk for other age-related morbidities, possibly through increased inflammation. We investigated potential relationships between CMV memory inflation, immune senescence, and inflammation by measuring markers of inflammation and telomere lengths of different lymphocyte subsets in HIV-infected individuals seropositive for anti-CMV antibodies. Our study cohort consists mainly of middle aged men who have sex with men (MSM) and heterosexuals who are stable under long-term ART. Median levels of IL-6, TNF-α, and CRP were significantly higher in those coinfected with CMV. Lymphocyte telomere length in general correlated with age, but for 32/32 subjects tested, there was a consistent hierarchy of telomere lengths with CD8+ T cells’ shorter than the general lymphocyte population, CD57+CD8+ T cells’ shorter than CD8+ T cells’ and CMV-specific CD57+CD8+ T cells’ the shortest of all. Telomeres of HIV-specific CD8+ T cells were longer than those of CMV-specific CD8+ T cells in all cases tested and over 10 years, CMV-specific CD8+ T cell telomeres of two HIV-infected individuals eroded faster than those of HIV-specific CD8+ T cells. These data indicate that CMV-specific CD8+ T cells of HIV-infected individuals are the lymphocytes closest to telomere-imposed replicative senescence. Exhaustive proliferation of CMV-specific CD8+ T cells in HIV-infected individuals is a potential source of senescent lymphocytes affecting systemic immune function and inflammation.
Highlights
Infection with cytomegalovirus (CMV) is very common and usually problematic only in cases of congenital infection, immune suppression, or immune deficiency [1,2,3,4,5]
After excluding individuals coinfected with hepatitis C virus (HCV), we measured levels of IL-1, IL-6, tumor necrosis factor (TNF)-α, and CRP in plasma samples from 153 human immuno deficiency virus (HIV)-infected individuals characterized for CMV infection status, age, gender, duration of infection, antiretroviral therapy (ART), lymphocyte subset counts, plasma HIV load, CMV-specific T cell immunity, and T cell subset T cell receptor excision circles (TREC) frequency
These data show a broad range in levels of common markers of inflammation in HIV-infected individuals with increased median levels of proinflammatory cytokines IL-6 and TNF-α and of the acute-phase protein CRP in the group coinfected with CMV
Summary
Infection with cytomegalovirus (CMV) is very common and usually problematic only in cases of congenital infection, immune suppression, or immune deficiency [1,2,3,4,5]. Following primary infection, human (H)CMV persists for life in latently infected cells with periodic reactivation contained by the immune system. CMV Immunity and Telomere Length undergo a process termed memory inflation, in which their magnitude increases disproportionately with age, compared to responses against other persistent viruses [6,7,8,9]. Broader population-based studies associate HCMV infection with development of agerelated morbidities, especially cardiovascular disease [14, 15]. These findings raise the possibility that either through proinflammatory effects of viral reactivation or through long-term influence on immune system character, persistent HCMV infection promotes development of age-related morbidities
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