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Rapid Aging of HIV Immune System Reported in
2011 and Earlier by Rita Effros & UCLA Researchers.
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But this was essentially not followed up on. Rita Effros, long-time immunologist at UCLA, and others predicted we would have this aging problem but these findings & predictions got little attention except by a few immunology & HIV researchers like Alan Landay, Joe Margolick, Keri Althoff & Seems Desai who did research & discussed these issues. It was much earlier that Rita Effros first reported (1996; https://journals.lww.com/aidsonline/Citation/1996/07000/Shortened_telomeres_in_the_expanded_CD28_CD8__cell.1.aspx) these problems than these 2011 publications. But overall these problems & predictions were ignored. now we are left with trying to deal with this & sort through these issues now. Jules Levin
Rita Effros lecture 2014: Human T Cell Aging: Telomere Loss, Inflammation and Links to Disease
New Research Finds HIV causes rapid aging in key infection-fighting cells: "Successful ART treatment does not fully reconstitute the CD31-CD4+ naïve T-cell subset"
"Successful ART treatment does not fully reconstitute the CD31-CD4+ naïve T-cell subset"
"in individuals infected with HIV-1, these cells underwent unexpectedly rapid aging - the equivalent of 20 to 30 years of aging within three years of infection. They also found that the number of CD31- T-cells, which are more quickly pulled into the fight against new pathogens, had fallen drastically......The researchers also investigated whether appropriate treatment could reverse this aging effect. They examined cells from HIV-positive individuals who had been on antiretroviral therapy for two years and whose therapy had successfully kept HIV-1 under control. They found that while the therapy kept their viral loads at undetectable levels, it did not entirely restore their immune systems, suggesting a reason why younger HIV-positive people still become ill with conditions more common to older people....our results help to explain some of the clinical observations that have been documented in HIV-infected people and emphasize the need for developing therapeutic approaches directed at improving the naive immune cell compartment"....HIV-1 infection in the young cohort was associated with lower absolute numbers of, and shorter telomere lengths within, both CD45RA+CD31+CD4+ and CD45RA+CD31-CD4+ T-cell subsets in comparison to age-matched seronegative controls, changes that resembled seronegative individuals who were decades older. Longitudinal analysis provided evidence of thymic emigration and reconstitution of CD45RA+CD31+CD4+ T-cells two years post-ART, but minimal reconstitution of the CD45RA+CD31-CD4+ subset, which could impair de novo immune responses
Role of CD8 T Cell Replicative Senescence in Human Aging and in HIV-mediated Immunosenescence - Review
Jeffrey N. Dock and Rita B. Effros
Aging and Disease Volume 2, Number 5; 382-397, October 2011
Department of Pathology & Laboratory Medicine and UCLA AIDS Institute, David
Geffen School of Medicine, Los Angeles, CA
Rita Effros in 2009: https://www.natap.org/2009/HIV/Effros-MucosalImmunity.pdf
our data suggest that HIV-1 pathogenesis involves an accelerated aging of both naive CD4+ T cells and memory CD4+ and CD8+ T cells......Our results suggest that HIV-1 infection induces an accelerated aging of T lymphocytes, which is associated with the clinical progression to AIDS and death.
to retard the loss of immune function, strategies need to be developed specifically to prevent or reverse the accumulation of senescent cells or rejuvenate senescent T cells by repairing their functional defects. Therapeutic approaches, which have been proposed, include physically removing aged T cells to make room for the more functional earlier subsets and pharmaceutically enhancing telomerase to retard the shortening of telomere length....
"it is estimated that by 2015, more than 50% of all HIV-infected individuals in the U.S. will be older than 50 years of age [22]
ABSTRACT: As humans age, their immune systems undergo a process known as immunosenescence. This global aging of the immune system is associated with increased susceptibility to infectious diseases and cancer, reduced effectiveness of vaccination, increased autoimmune phenomena, and tissue damage due to dysregulated inflammation. One hallmark feature of immunosenescence is the accumulation of late-differentiated memory CD8 T cells with features of replicative senescence, such as inability to proliferate, absence of CD28 expression, shortened telomeres, loss of telomerase activity, and enhanced secretion of inflammatory cytokines. The proportion of senescent CD8 T cells increases progressively with age, and often consists of oligoclonal populations that are specific for cytomegalovirus (CMV) antigens. In addition, there is evidence that senescent memory CD8 T cells acquire suppressive functions and may also contribute to carcinogenesis. Chronic HIV disease, even when controlled through antiretroviral therapy (ART), is associated with accelerated immunosenescence, as evidenced by the higher numbers of senescent memory CD8 T cells and increased inflammatory milieu. Interestingly, even in HIV disease, a high proportion of late-differentiated, putatively senescent, memory CD8 T cells are specific for CMV antigens. As in age-related immunosenescence, these HIV-associated changes result in dysregulated immunity, chronic diseases linked to inflammatory damage, and increased morbidity and mortality. This review explores the evidence for CD8 T cell replicative senescence in vitro and in vivo, in the context of both chronological aging and HIV-mediated immunosenescence. We also highlight an important gap in our understanding of human immunosenescence, since all the studies to date have focused on peripheral blood, which contains a minority of the total body lymphocyte population.
HIV disease in relatively young cohorts is associated with changes in immune parameters that are remarkably similar to age-associated immune-senescence, including thymic involution, reduced circulating naïve T cells, decreased CD4/CD8 ratio, increased levels of proinflammatory cytokines, increased susceptibility to infectious disease and cancer, and reduced effectiveness of vaccines [9]. Moreover, new evidence, based on telomere and phenotypic studies, indicates that it is not only the CD8 T cell population that undergoes premature aging during HIV disease, but also specific naïve CD4 T cell subpopulations.
Similar to aging, HIV disease is associated with relatively high levels of immune activation and systemic inflammation. Common biomarkers of this process include elevated levels of activated CD4 and CD8 T cells, high CD8 T cell counts, increased levels of inflammatory cytokines such as IL-1β, IL-6 and TNFα, and activation of the coagulation pathway [9, 123]
Chronic HIV disease, even when controlled through antiretroviral therapy (ART), is associated with accelerated immunosenescence, as evidenced by the higher numbers of senescent memory CD8 T cells and increased inflammatory milieu. Interestingly, even in HIV disease, a high proportion of late-differentiated, putatively senescent, memory CD8 T cells are specific for CMV antigens. As in age-related immunosenescence, these HIV-associated changes result in dysregulated immunity, chronic diseases linked to inflammatory damage, and increased morbidity and mortality. .......
Antigen-driven differentiation towards the end stage of replicative senescence in CD8 T cells is an important component of both age- and HIV-mediated immunosenescence and the IRP. However, one important caveat regarding these observations is that most of our knowledge on immunosenescence in humans has been derived from studies on peripheral blood, which contains only 2% of total body lymphocytes. At this time, little is known about the dynamics of CD8 T cell aging in other tissues, especially the GI tract, which houses 60% of total body lymphocytes and is a major reservoir for HIV infection. As we move forward in defining the contribution of CD8 T cell replicative senescence to human immunosenescence, it will be critical to elucidate aging dynamics of lymphocytes in the GI tract. Our own preliminary studies suggest that T cells from the GI tract may be more antigen-experienced and further
HIV infection is generally believed to be causing "accelerated immunosenescence," due in large part to effects from chronic immune activation and inflammation.....HIV disease is known to cause a 3-fold higher risk of death from all-cause mortality [130]. As expected, approximately 50% of the deaths in HIV patients on ART were attributed to AIDS-defining conditions, such as opportunistic infections [131, 132]. However, the remaining deaths are due to non-AIDS defining age-related illnesses associated with inflammation, including cardiovascular disease, kidney disease, liver disease, osteoporosis, non-AIDS cancers, neurologic disease and frailty [132-139]. Corroborating these data, studies indicate an increase in inflammatory markers, such as CRP, in HIV infected patients is independently correlated with accelerated progression to AIDS and an increase all cause mortality [140-142]. For this reason HIV infection is generally believed to be causing "accelerated immunosenescence," due in large part to effects from chronic immune activation and inflammation [143].
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