Accelerated aging of the immune system in HIV infection
Richard Jefferys, TAG
Over the years since AIDS was first recognised, 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: naive cells and memory cells. naive cells are those that have yet to encounter a pathogen or other antigen that they recognise, while memory cells are typically the descendants of naive 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 naive 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 naive T cells into becoming memory T cells over a lifetime drains the naive 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 naive to memory cells gradually shifts as we age. In HIV infection, this process is accelerated, and naive 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 naive CD8 T cells. Loss of CD28 expression on CD4 cells was also significantly associated with disease progression.
Changes in naive CD4 T cells were more subtle, as the relative proportion of naive 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, fifills 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 naive T cells has emerged as a clear correlate of a good immunological response to treatment. 
Conversely, slow naive 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 naive 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 years CROI is online (under the Tuesday webcasts, it is the second presentation in the Symposium on Aging and AIDS). 
TAG Basic Science Weblog. (20 Jan 2009)
- Cao W et al. Premature aging of T cells Is associated with faster HIV-1 disease progression. J Acquir Immune Defic Syndr. 2009 Jan 7. [Epub ahead of print]
- Fry TJ, Mackall CL.What limits immune reconstitution in HIV infection? Divergent tools converge on thymic function. AIDS. 2001 Sep 28;15(14):1881-2.
- Effros R. Immune Exhaustion in Aging and AIDS: Parallel Mechanisms and Possible Solutions. Symposium: Aging and AIDS. Tuesday 4pm.