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Premature Aging of CD4 T-Cells By HIV May Accelerate Disease Progression:

A new study has potentially indicated why LTNPs are successful at keeping HIV under control.  The mechanisms underlying HIV disease progression are still not fully understood. A report in the January 7, 2009 Journal of Acquired Immune Deficiency Syndromes sheds a new light on the years of tireless research that has sought to answer the question of why some HIV infected individuals survive longer than others.

Weiwei Cao and colleagues at Danbury Hospital in Connecticut sought to find out whether untreated HIV infection and disease progression is associated with premature aging of naive CD4 T-cells and memory CD8 and CD4 T-cells. CD4 T-cells (also known as effector T cells or T_h cells) play an important role in establishing and maximizing the capabilities of the body’s immune system. CD4T-cells are primed to respond when they encounter a previous observed invader, while naive cells are able to respond to new pathogens.

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

The team evaluated the expression of certain cell surface markers on T-cells that indicate their stage of differentiation. Differentiation stage reflects the aging of T-cells. As people age, immune function typically declines. This is in part related to the normal atrophy of the thymus gland in the neck, where newly produced T-cells migrate to mature and be trained to respond to antigen. Consequently, as the T-cells proliferate in the body and are used up in response to antigens over time, over all T-cell function decreases. This is known as "immunosenescence". Immunosenescence is also sometimes seen as the result of the continuous challenge to a variety of antigens such as viruses.  Studies have suggested this cellular aging is accelerated in people infected with HIV.

The researchers found that HIV disease progression was associated with decreased CD28 expression (an indicator of immunosenescence) on both CD4 and CD8 T-cells. Expression of the CD28 marker indicates weather the cell has been activated or not.  Cells with high expression of CD28 have not been activated and are considered naïve.
They also observed an increased proportion of intermediate- and late-differentiated CD8 T-cells and decreased CD31 expression on naive CD4 T-cells of recent thymic origin (i.e., recently emerged from the thymus).

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 authors explained that the observed decrease in the intensity of CD28 expression is a feature of senescent T-cells and has functional consequences. "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."

They explained that "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 the fact that T-cells from long term non-progressors, compared with progressors, maintain a high capacity to proliferate upon antigenic stimulation.”  In short, T-cells have reduced CD28 expression do not replicate as well and do not respond as well to foreign antigens. Over time this may leave a patient with a smaller immune "repertoire" and an impaired ability to respond to new infections. Unlike CD28 loss, the observed CD31 depletion on naive memory CD4 T-cells "does not resemble natural aging," the researchers noted.

"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."

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."

 

Premature Aging of T cells Is Associated With Faster HIV-1 Disease Progression;

 Wei et al; JAIDS Journal of Acquired Immune Deficiency Syndromes: Volume 50(2)February 2009;pp 137-147