Premature Aging of CD4 Cells May Accelerate HIV Disease Progression

Despite extensive research over the past 3 decades, the mechanisms underlying HIV disease progression are still not fully understood. But a report in the January 7, 2009 Journal of Acquired Immune Deficiency Syndromes adds another piece to the puzzle.

Weiwei Cao and colleagues sought to determine whether untreated HIV infection and disease progression is associated with premature aging of memory CD8 and CD4 T-cells and naive CD4 T-cells. CD4 cells direct the body's immune response. Memory CD4 cells are primed to respond when they encounter a previous invader again, while naive cells are able to respond to new pathogens.

The researchers looked at 20 HIV positive men classified as fast progressors (diagnosed with AIDS within 4 years of infection) and 40 men classified as slow progressors in the Multicenter AIDS Cohort Study.

The expression of cell surface markers on frozen T-cells was measured using flow cytometry, indicating their differentiation stage. Differentiation stage reflects the aging of T-cells. As people age, immune function typically declines. In part, this is related to atrophy of the thymus gland in the neck, where newly produced T-cells mature. In addition, T-cell function decreases over time -- a phenomenon known as "immunosenescence" -- as the cells proliferate in response to antigens. Studies suggest this cellular aging occurs more rapidly in the presence of HIV.

Results

• HIV disease progression was associated with:
• Decreased CD28 expression (an indicator of immunosenescence) on both CD4 and CD8 T-cells;
• An increased proportion of intermediate- and late-differentiated CD8 cells;
• Decreased CD31 expression on naive CD4 cells of recent thymic origin (i.e., recently emerged from the thymus).
• Selective depletion of peripherally expanded naive CD4 cells was associated with HIV infection, but not with HIV disease progression.

Based on these findings, the researchers wrote, "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, they added, "suggest that HIV-1 infection induces an accelerated aging of T-lymphocytes, which is associated with the clinical progression to AIDS and death."

The observed loss of CD28 expression "is a feature of senescent T-cells and has functional consequences," the authors explained in their discussion. "A number of studies have shown that in both chronic HIV infection and normal aging, the loss of CD28 expression was coupled with a concurrent decline in telomerase activity, telomere length, and proliferative capacity. Telomeres are chromosomal structures that shorten with each cell division and are the determinant of the cell's proliferative capacity."

Thus, they continued, "the accelerated loss of CD28 on T-cells observed in fast progressors signifies an impaired capacity to proliferate, which may lead to suppressed T-cell immune responses to antigens and result in faster disease progression to AIDS. This is further supported by studies showing that T-cells from long-term non-progressors, compared with progressors, maintain a high capacity to proliferate upon antigenic stimulation." T-cells that lose CD28 do not replicate as well and do not respond as well to foreign antigens, which over time may leave a patient with a narrower immune "repertoire" and impaired ability to respond to new infections. Unlike CD28 loss, the observed CD31 depletion on naive memory CD4 cells "does not resemble natural aging," the researchers noted.

In conclusion, the authors wrote, "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 less-differentiated 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," they continued. "Major advances in treatment have led to the significantly prolonged survival time for HIV-1-infected individuals, but the 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."

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; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA.

2/06/09

Reference

W Cao, BD Jamieson, LE Hultin, and others. Premature Aging of T cells Is Associated with Faster HIV-1 Disease. Journal of Acquired Immune Deficiency Syndromes 50(2): 137-147. February 2009. (Abstract).