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Exhausted & Depleted T Cells in HIV+ Cause Premature Aging & Comorbidities & Frailty
Memory loss: T cell subsets associated with mortality in HIV+ and HIV- veterans
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Reported by Jules Levin
9th Aging and HIV Workshop
NYC Sept 13-14 2018
McDonnell W, Justice A
1Vanderbilt Vaccine Center, , United States
Introduction: Chronic cellular immune activation is a hallmark of HIV infection. The relative depletion of naïve CD4+ and CD8+ T cells and the expansion of memory cell subsets, including pro-inflammatory effector memory (TEM) and effector memory RA+ (TEMRA), are associated with increased risk of cardiometabolic diseases in the general population, but there are fewer data on health outcomes among HIV-infected (HIV+) individuals.
Purpose of the Study: We assessed whether the proportional size of the naïve, activated, memory, TEM and TEMRA compartments was associated with subsequent mortality in HIV+ versus uninfected (HIV-) persons.
Methods: We analyzed data on 1089 subjects (684 HIV+ and 405 HIV-) from the Veterans Aging Cohort Study - Biomarker Cohort, a prospective, longitudinal study of HIV+ veterans and age-, sex-, race/ethnicity- and clinical site-matched HIV- veterans. VACS BC archived peripheral blood mononuclear cells from study subjects in 2005-2007 (defined as baseline). We performed flow cytometry to measure the proportion of 10 classes of CD4+ and CD8+ T cells: naïve, activated CD38+, memory CD45RO+; TEM cells CD45RO+CD28-, and TEMRA cells CD45RA+CD28-CD57+. Deaths occurring through September 30, 2015 were ascertained from the medical record and death certificates. We compared the median baseline proportions of T cell subsets among subjects who subsequently died versus those who remained alive, stratified by HIV status, using Mann-Whitney U tests.
The loss of CD38 function is associated with impaired immune responses, metabolic disturbances, and behavioral modifications including social amnesia possibly related to autism.[10][11]
The CD38 protein is a marker of cell activation. It has been connected to HIV infection, leukemias, myelomas, solid tumors, type II diabetes mellitus and bone metabolism, as well as some genetically determined conditions.
Virus-specific CD8+ T-cell responses play a pivotal role in limiting viral replication. Alterations in these responses, such as decreased cytolytic function, inappropriate maturation, and limited proliferative ability could reduce their ability to control viral replication. Here, we report on the capacity of HIV-specific CD8+ T cells to secrete cytokines and proliferate in response to HIV antigen stimulation. We find that a large proportion of HIV-specific CD8+ T cells that produce cytokines in response to cognate antigen are unable to divide and die during a 48-hour in vitro culture. This lack of proliferative ability of HIV-specific CD8+ T cells is defined by surface expression of CD57 but not by absence of CD28 or CCR7. This inability to proliferate in response to antigen cannot be overcome by exogenous interleukin-2 (IL-2) or IL-15. Furthermore, CD57 expression on CD8+ T cells, CD4+ T cells, and NK cells is a general marker of proliferative inability, a history of more cell divisions, and short telomeres. We suggest, therefore, that the increase in CD57+ HIV-specific CD8+ T cells results from chronic antigen stimulation that is a hallmark of HIV infection. Thus, our studies define a phenotype associated with replicative senescence in HIV-specific CD8+ T cells, which may have broad implications to other conditions associated with chronic antigenic stimulation. http://www.bloodjournal.org/content/101/7/2711?sso-checked=true
--------Chronic antigenic stimulation leads to gradual accumulation of late-differentiated, antigen-specific, oligoclonal T cells, particularly within the CD8+ T-cell compartment. They are characterized by critically shortened telomeres, loss of CD28 and/or gain of CD57 expression and are defined as either CD8+CD28- or CD8+CD57+ T lymphocytes. There is growing evidence that the CD8+CD28- (CD8+CD57+) T-cell population plays a significant role in various diseases or conditions, associated with chronic immune activation such as cancer, chronic intracellular infections, chronic alcoholism, some chronic pulmonary diseases, autoimmune diseases, allogeneic transplantation, as well as has a great influence on age-related changes in the immune system status. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3173691/
HIV has been shown to be constantly replicating in the host, thereby inducing an antigen-dependent clonal expansion of memory T cells that resembles that found in the aging immune system 5. This has led to the concept that HIV patients are subject to premature immunosenescence that occurs independently of aging 63..
-------Taken together, it is clear that HIV-infected individuals are subjected to continuous antigen stimulation accompanied by an ongoing inflammatory process and loss of CD4+ T cells. In addition to providing useful data on the nature of immunological aging and host cell senescence, the real-time chronological aging of HIV-infected subjects also provides a useful model for studying the effects of CMV by allowing investigators to differentiate age-dependent events from virus-dependent mechanisms of immunosenescence.
In this article, we review the use of classical markers in delineating T cell sub-populations, from "truly naïve" T cells (recent thymic emigrants with no proliferative history) to "exhausted senescent" T cells (poorly proliferative cells that display severe functional abnormalities)
https://onlinelibrary.wiley.com/doi/full/10.1002/cyto.a.22351
-----When T cells encounter their respective antigens they start to differentiate into distinct types of memory cells.
The central memory T cells can be identified as CCR7+CD27+CD28+CD45RA-CD57-KLRG1-PD1-, the effector memory as CCR7-CD27+/- CD28+/-CD45RA-CD57+/-KLRG1+/-PD1+, and finally the TEMRA as CCR7-CD27-CD28-CD45RA+CD57+KLRG1+PD1+/-
-----Natural aging has profound effects on many aspects of human physiology and is mainly thought to be associated with declining biological functions. However it is important to distinguish between healthy aging and pathological aging. The study of altered immune function in aging individuals can explain many different manifestations of the overall aging process, as well as the development of age-related life-threatening disorders including infections, cancers and atherosclerosis 49, 50. Generally, the most striking age-related change observed in studies of the T cell compartment in aging individuals is an increase in the number of CD28- cells, as was predicted by the earlier in vitro studies of Effros and Walford 35. Since CD28- T cells have been previously characterized as "senescent," the T cells populations associated with aging were also been designated as senescent cells, eventually leading to the wider adoption of "immunosenescence" as a general biological concept.
http://www.bloodjournal.org/content/101/7/2711?sso-checked=true
Results: Subjects were predominantly male (95%) and African-American (68%). Among the measured subsets, naïve CD4+ and memory CD8+ T cells were lower in both the HIV+ and HIV- persons who died during follow-up (p<=0.04 for all). However, HIV+ persons who died also had lower CD4+CD45RO+ memory T cells (40.0% in deceased vs. 47.7% in alive, p<0.001) and higher CD4+ TEMRA cells (5.5% vs. 4.4%, p=0.02) at baseline, but these associations were not observed in the HIV-. Furthermore, if CD4+ TEMRA cells were alternately defined as CD4+45RA+CD27-, the mortality difference among the HIV+ persons was consistent (4.0% in deceased vs. 2.8% in alive; p=0.007). Of note, the median percentage of CD4+ TEMRA cells at baseline was approximately 2-fold higher in the HIV+ group compared to the HIV- group among persons aged <45 (5.5% vs. 2.0%), 45-55 (4.2% vs. 2.2%), and >55 (4.8% vs. 2.7%, p<0.0001 for all).
Conclusions: In both HIV+ and HIV- veterans, the depletion of naïve CD4+ cells, possibly reflecting accelerated immunosenescence, was associated with higher risk of death as previously reported. CD4+ TEMRA cells, defined according to two common surface marker phenotypes, were 2-fold higher in HIV+ compared to HIV- persons, and in the HIV+ group CD4+ TEMRA cells were higher.
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