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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
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JAIDS Jan 7 2009
"....We conclude that HIV-1 infection induces premature aging of both memory T cells and naive CD4+ T cells; in particular, the fast progressors (FPs) experience accelerated aging of lymphocytes, as evidenced by a greater accumulation of T-cell subsets associated with chronological aging.....
....Aging of immune cells during HIV-1 infection is supported by our observation that there is a depletion of naive and an enrichment of intermediate- and late-differentiated CD8+ T cells, which were also found to be correlates of HIV-1 progression....
......Narrowing of the T-cell repertoire may subsequently impair the generation of new immune responses to infections.....
....In conclusion, our data suggest that HIV-1 pathogenesis involves an accelerated aging of both naive CD4+ T cells and memory CD4+ and CD8+ T cells. The expansion of aged T-cell clones may lead to the homeostatic contraction of the lessdifferentiated and more functional T-cell populations, leading to a more rapid progression to AIDS and death. Whether highly active antiretroviral therapy can reverse or retard this process is not yet clear and needs to be investigated, although 1 study has shown that accumulation of aged T cells continues in highly active antiretroviral therapy-treated patients with increased CD4+ T cells and long-term viral suppression.....
.....continuous HIV stimulation and the natural aging process may act together to induce immunosenecence and raise a particular challenge for continued immune control of HIV-1 and long-term survival. Therefore, 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....
.....We also acknowledge that HIV-specific CD4+ and CD8+ T cells make up a very small percentage of the total antigen-specific T-cell pool. As our measurements were performed on the total T-cell population, the results may not reflect changes in HIV-1-specific T cells. However, we believe that changes in the total T-cell population may be at least as important as changes in HIV-1-specific T cells in terms of progression to AIDS, as AIDS involves decreased immunity to a wide spectrum of infectious agents. Indeed, high proportions of CMV-specific CD8+ T cells have been documented during chronic HIV infection.63 The presence of expanded populations of latestage T lymphocytes has been documented in other viral infections (Epstein-Barr virus, cytomegalovirus, and influenza) and in cancer11; conditions commonly contracted by HIV-1-infected individuals, particularly in those at an immunosuppressed stage. A common feature of all these diseases is long-term chronic antigenic stimulation of the immune system by either virus or tumor-associated antigen. Thus the accelerated immunological aging observed in chronic HIV-1 infection, especially in those with an advanced disease status, may be a consequence of continuous HIV-1 infection and a multitude of other antigens and is best reflected by our assessment of the general T-cell population."

Premature Aging of T cells Is Associated With Faster HIV-1 Disease Progression
Weiwei Cao, MD, PhD,* Beth D. Jamieson, PhD, Lance E. Hultin, BS, Patricia M. Hultin, Rita B. Effros, PhD, and Roger Detels, MD, MS
JAIDS Jan 9 2009
From the *Department of Medicine, Danbury Hospital, Danbury, CT; Department of Epidemiology, School of Public Health, University of California, Los Angeles, CA; Department of Medicine, Division of Hematology and Oncology; and Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA. This research was supported by National Institutes of Health grant U01 AI03540 and R01 AI058845. Correspondence to: Roger Detels, MD, MS, Department of Epidemiology, School of Public Health, University of California, Los Angeles, CA 90095 (e-mail:
Objective: To determine if untreated HIV-1 infection and progression is associated with premature aging of memory CD8+ and CD4+ T cells and naive CD4+ T cells.
Methods: Twenty HIV-1-infected fast progressors and 40 slow progressors were included in our study, using risk set sampling. The expression of cell surface markers reflecting the differentiation stages of lymphocytes was measured using flow cytometry analyses performed on cryopreserved peripheral blood mononuclear cells.
Results: We found that HIV-1 disease progression is associated with a decreased CD28 median florescence intensity on CD4+ and CD8+ T cells; an increased proportion of intermediate- and late-differentiated CD8+ T cells and a decreased CD31 median florescence intensity on naive CD4+ T cells of recent thymic origin. A selective depletion of peripherally expanded naive CD4+ T cells was found to be associated with HIV-1 infection but not with HIV-1 disease progression.
Conclusions:The overall change during HIV-1 infection and progression is associated with a shift in the T-cell population toward an aged conformation, which may be further compromised by impaired renewal of the less-differentiated CD4+ T-cell population. 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.
Increasing evidence has suggested that HIV-1-infected individuals experience similar immunologic changes as the uninfected elderly.1,2 The phenotypic and functional alterations in T cells observed during human aging are often referred to as immunosenescence, which is thought to be a consequence of persistent T-cell activation and proliferation driven by repeated antigenic exposure experienced over the lifetime. Immunosenescence may lead to a generalized decline in immune responses and increased susceptibility of the elderly to infections.3 By analogy, during HIV-1 infection, accelerated aging of T cells, or immunosenescence, may occur due to the continuous highly productive viral replication, which persistently stimulates immune cells.4 Studies have suggested that T cells have a defined proliferative lifespan. In cell culture, they inevitably reach a state of replicative senescence after repeated antigen-driven cell divisions, with loss of proliferative capacity and other striking functional changes.5
One characteristic feature of senescent T cells is the complete and permanent loss of the CD28 costimulatory molecule.6,7 The CD28 molecule is essential for effective T-cell activation, upregulating cytokine expression, augmenting proliferation, and providing essential survival signals for T cells.8 CD282 T cells are functionally distinct from CD28+ T cells.9,10 Both HIV-1 disease and aging10-13 affect proportions of T cells that are CD282, but there has been conflicting data regarding the relationship of these cells to HIV-1 disease progression. Some researchers report that the accumulation of CD282CD8+ T cells is associated with a decline of CD4+ cell counts14 or AIDS development,15 whereas others have suggested that CD28 expression on CD4+ but not CD8+ T cells is independently associated with disease progression.16,17 Furthermore, the expression of CD28 and CD57 on individual CD8+ T cells is thought to be inversely related.18 The CD57+ T cells are latestage cells derived from CD572 T cells.19 A recent study20 reported that the CD57 expression on HIV-1-specific CD8+ T cells defines the proliferative defects after antigenic stimulation in vitro better than the lack of CD28 expression. An elevated proportion of CD8+ T cells expressing CD57 has been observed in both aging18 and HIV-1 infection,21 but there is no clear evidence showing that this marker is associated with clinical progression in HIV-1-infected adults. Thus, it would be informative to assess the coexpression patterns of CD28 and CD57 in the context of HIV-1 infection and to identify which one is the more relevant marker for HIV-1 disease progression.
Another indicator for aging of the memory T-cell population is the distribution of T cells with distinct differentiation phenotypes.22 During T-cell differentiation, antigen-primed cells sequentially lose the expression of CD28 and CD27. Although the loss of CD45RA has long been associated with a memory T-cell phenotype, reexpression of CD45RA has been found among terminally differentiated T cells.1,23,24 T-cell subsets may be positioned into the putative linear differentiation pathway mainly based on the expression of these markers.25 Elevated proportions of highly differentiated T cells in both the CD4+ and CD8+ T-cell compartments have been observed over the different stages of HIV-1 infection.24,26 It will therefore be informative to determine whether HIV-1-infected individuals with distinct disease progression rates have disparate distributions of differentiated T-cell subsets.
One well-known immunological alteration observed during normal aging is the homeostatic change in the naive CD4+ T-cell compartment. The peripheral naive CD4+ T-cell pool in adults is maintained by 2 following pathways: continued emigration of newly generated CD4+ T cells from the thymus [so called recent thymic emigrants (RTE)] and expansion of existing naive CD4+ T cells in the periphery.27,28 CD31 is a differentiation antigen expressed on all RTE. These cells are thought to undergo peripheral homeostatic proliferation after emigrating from the thymus and during this process lose CD31 expression and become CD312-naive CD4+ T cells.29-31 Thus, CD31 expression provides a sensitive measure of the proliferation history of the naive CD4+ T cells.31,32 Studies have shown that CD31+-naive CD4+ cells also have a proliferative history, which is much shorter than their CD312 counterparts.28,33 The use of RTE to represent CD31+ cells herein is for ease only and reflects that in the differentiation scheme, these cells are less differentiated than the CD312-naive CD4+ T cells. With human aging, the size of the peripheral naive CD4+ T-cell pool remains fairly stable, despite the constant decline in the frequencies of naive CD4+ T cells coexpressing CD31, reflecting a reduced thymic output and a counterbalancing increased postthymic naive cell proliferation.28 As studies have shown that HIV-1 may induce thymic involution or atrophy,34 we question whether HIV-1 infection induces a significant alteration in naive CD4+ T-cell homeostasis similar to that observed during aging, due to either altered T-cell generation by the thymus and/or peripheral mechanisms such as increased homeostatic T-cell proliferation, and whether this change is related to HIV-1 disease progression.
To address the above proposed questions, we designed a unique study by directly identifying 2 groups of HIV-1-infected men who had similar age and CD4 level at early stage of HIV-1 infection and then progressed to AIDS in distinctly different rates. We conclude that HIV-1 infection induces premature aging of both memory T cells and naive CD4+ T cells; in particular, the fast progressors (FPs) experience accelerated aging of lymphocytes, as evidenced by a greater accumulation of T-cell subsets associated with chronological aging.
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