Over the years since AIDS was first recognized, a number of pathogenesis theories have posited that HIV infection causes an accelerated aging of the immune system. Some of the earliest, most hypothetical ideas along these lines suggested that the effects of HIV would be irreversible; thankfully, the success of antiretroviral therapies in restoring immune competence has since shown that this is not the case. Advances in the understanding of the immunological changes that accompany aging have recently allowed a more sophisticated and informed perspective on the parallels with HIV infection to be developed. At the forefront of this field of study is UCLA researcher Rita Effros, and the latest study from her group has just appeared online in the Journal of AIDS.
Fundamental to understanding this research is the division of the main cellular players of the human adaptive immune system (CD4 and CD8 T cells and B cells) into two large pools: naïve cells and memory cells. Naïve cells are those that have yet to encounter a pathogen or other antigen that they recognize, while memory cells are typically the descendants of naïve cells that have done battle with a pathogen (or a faux or attenuated pathogen in the form of a vaccine) in the past. Crucially, maintenance of naïve T cells depends on the output of newly produced cells from the thymus; production is robust in childhood but dwindles after adolescence and becomes a relative trickle in old age. Every infection and vaccination that recruits naïve T cells into becoming memory T cells over a lifetime drains the naïve pool, and while the thymus can “top up” the pool relatively quickly when young, this cannot be accomplished later in life and the ratio of naïve to memory cells gradually shifts as we age. In HIV infection, this process is accelerated, and naïve T cell (and B cell) numbers decline as disease progresses. In parallel, the proportion of memory cells showing evidence of exhaustion and dysfunction increases. Although the extent of the dysfunction is less dramatic, this accumulation of exhausted memory T cells is also seen in aging.
One key marker of T cell dysfunction in the elderly is the loss of the co-stimulatory molecule CD28. In their new paper, Effos and colleagues use data from the MACS cohort to show that faster disease progression in HIV infection is associated with more rapid accumulation of CD28-negative CD8 T cells, in tandem with more rapid loss of naïve CD8 T cells. Loss of CD28 expression on CD4 cells was also significantly associated with disease progression. Changes in naïve CD4 T cells were more subtle, as the relative proportion of naïve CD4 T cells to memory CD4 T cells in the peripheral blood did not decrease significantly as the absolute numbers of blood CD4 T cells declined. These findings are notably in line with the well-documented impact of age on the progression of HIV infection, because they suggest that older individuals are starting from a worse position immunologically (studies have consistently found that older individuals progress faster on average when compared to their younger counterparts).
In the discussion section of the paper, the authors state: “It has been suggested that the expansion of a few memory T-cell clones, directed at a restricted number of epitopes, fills up the ‘immunological space.’ Narrowing of the T-cell repertoire may subsequently impair the generation of new immune responses to infections and may also account for the close correlation between the high proportions of CD28-CD8+ T cells and reduced vaccine responses in the elderly. Therefore, despite a significant number of CD8 T cells observed during HIV-1 infection, the CD8+ T-cell compartment is mostly comprised of functionally defective CD28- T cells.”
The extent to which these immunological perturbations can be corrected by antiretroviral therapy is still not fully clear, but thymic output of naïve T cells has emerged as a clear correlate of a good immunological response to treatment. Conversely, slow naïve T cell repletion is associated with poor CD4 T cell count increases and a persistently elevated risk of clinical illness. One consequence of these findings is that therapies that might have the potential to boost naïve T cell production are being studied as potential immune-based therapies in HIV infection. Effros and colleagues also note that strategies to restore function to senescent T cells are under investigation, and approaches to deplete dysfunctional cells (with the aim of allowing functional cells to expand and take their place) are also being considered.
For further background on this topic, a webcast of a talk given by Rita Effros at last year's CROI is available online (under the Tuesday webcasts, it is the second presentation in the Symposium on Aging and AIDS).
J Acquir Immune Defic Syndr. 2009 Jan 7. [Epub ahead of print]
Premature Aging of T cells Is Associated With Faster HIV-1 Disease Progression.
Cao W, Jamieson BD, Hultin LE, Hultin PM, Effros RB, Detels R.
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.
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