Aging, HIV infection and the immune system
1 October 2009. Related: Basic science.
Richard Jefferys, TAG
In the November 9th issue of New York Magazine, David France reports on the emerging issue of accelerated aging in people with HIV infection. The article offers a series of disturbing vignettes about the complications some individuals are facing as they age, such as bone problems and impaired cognitive function, and raises important questions about how much attention is being paid to the issue by current research, particularly in terms of pursuing new therapeutic options. 
However, beyond mentioning inflammation, the piece does not really delve into the underlying immunological parallels between HIV infection and aging and consider how they might fit into the picture. This is a potentially important omission, as there is accumulating evidence that the accelerated aging of the immune system that has been documented in people with HIV is likely to be related to many of the clinical phenomena described in France’s article.
Although it’s not the sort of research that makes the front pages, the last decade or so has seen considerable progress in understanding the relationship between immune parameters and aging, and these studies provide a valuable frame of reference. Perhaps most importantly, an “immune risk phenotype” associated with mortality in the elderly has been described in considerable detail. 
The major features are an inverted CD4/CD8 T cell ratio, decreased proliferative responses and IL-2 production by T cells, increased levels of inflammatory cytokines (such as IL-6) and increased numbers of CD8 T cells lacking the CD28 costimulatory receptor (typically described as senescent cells). All of these immunological perturbations are also seen in HIV infection.
Studies have also found that people with the chronic viral infections cytomegalovirus (CMV) and Epstein-Barr virus (EBV) face a greater likelihood of acquiring the immune risk phenotype in old age. The clinical manifestations associated with the phenotype include bone loss and increased fracture risk, cognitive impairment, increased susceptibility to infections and an increased incidence of cancers and cardiovascular, kidney and liver disease.
The overarching theme that is emerging from this research – although it is still in its infancy – is that a lifetime of antigenic challenges (in the form of all the pathogens an individual is exposed to) gradually erodes immune system resources, and this plays a major role in aging. This erosion of immune system resources has multiple facets:
- A steady decline in naive T cell production by the thymus from a torrent in childhood to a trickle in old age.
- Activation of antigen-specific naive T cells every time a new pathogen is encountered, which depletes the naive T cell pool and leads to a subset of these pathogen-specific cells maturing into memory cells (the impact of these episodes of naive T cell activation is minor when the thymus is vigorously producing new cells to replace those lost, but increases as thymic output declines).
- Repeated stimulation of memory T cells by pathogens, which can eventually lead to memory T cell senescence.
Chronic pathogens (that are controlled rather than cleared) play a particularly important role because they place a persistent drain on immune system resources, as indicated by the way that memory T cell responses to CMV accumulate over time, such that 25-30% of CD8 T cells can be CMV-specific in an infected elderly person. Untreated HIV infection has an even greater effect; a young individual with AIDS typically will have lost almost all their naive T cells and 20-50% of their memory CD8 T cells will be HIV-specific. As shown recently in a study of the MACS cohort, a fast accumulation of senescent CD8 T cells lacking the CD28 molecule is associated with rapid progression from HIV infection to AIDS. 
Additional insight into how immunological aging relates to health may come from people who have had their thymus removed (a thymectomy) at birth. This procedure is sometimes performed to enable better access to the heart to correct congenital heart defects. A recent study published in the Journal of Clinical Investigation reported that thymectomised individuals show evidence of accelerated aging of the immune system similar to the immune risk phenotype, but it is not yet known whether this will lead to the same clinical manifestations seen in the elderly.  Continued follow-up will be crucial to gaining a better understanding of the relationship between the immunological and clinical consequences of aging.
In terms of HIV infection, the issue of accelerated aging raises many new questions and considerations for future research:
- Is immunology research in HIV adequately prioritised? The main clinical research network in the US, the AIDS Clinical Trials Group (ACTG), once had a specific immunology research committee but it was dissolved a few years ago and squished into a broader committee designated “Translational Research and Drug Development” (TRADD). There may be a case for re-establishing a specific immunology committee within the network.
- Do current research funding mechanisms offer adequate support for multidisciplinary and translational research? The spectrum of clinical manifestations associated with accelerated aging calls for collaborative research between groups specialising in many different disciplines (e.g. immunology, virology, pharmacology, toxicology, musculoskeletal system, cardiovascular, renal, liver, etc.), and support for this type of complex collaboration may call for the design of a specific funding mechanism (RFA). Exploration of novel therapies also requires support for conducting translational clinical research, which can be difficult and complicated to obtain under current grant procedures.
- Will earlier initiation of antiretroviral therapy prevent accelerated aging? Long term follow-up from studies such as ACTG 384 clearly show that earlier suppression of HIV is associated with an almost complete normalization of many potentially important immune parameters including the CD4/ CD8 T cell ratio, the ratio of naive T cells to memory T cells and levels of immune activation.  In contrast, among individuals initiating therapy at lower CD4 T cell counts, these parameters improve but do not come close to mirroring those of uninfected individuals even after seven or more of continuous HIV suppression. This may suggest that people who start treatment earlier will be at less risk for accelerated aging, but this has not yet been established.
- To what extent do drug toxicities contribute to accelerated aging? The fact that there are many close parallels between the immunology of HIV infection and aging argues strongly against drug toxicity being the primary cause, but there are clearly specific toxicities that can contribute to problems such as bone loss and cardiovascular disease. Research needs to parse out the role of drug toxicities so that safer treatments can be developed.
- Can novel therapies be developed to delay or reverse accelerated aging? The current data suggest a number of key targets for therapeutic research, including: enhancing thymic function to boost naive T cell production, reducing immune activation/inflammation and reducing numbers of senescent immune cells. Research is ongoing in these and other areas but greater resources, coordination and prioritization is needed.
TAG’s Hepatitis Coinfection Project and Michael Palm Project are currently collaborating with several other community activists, including HIV i-Base, to produce a comprehensive report and advocacy recommendations on HIV and aging. The report will be released next year prior to the International AIDS Conference.
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