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 some 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 co-stimulatory 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% or more of their memory CD8 T cells can 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 (abstract and accompanying commentary
appended below) reported that thymectomized 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 prioritized? 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 specializing 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
shows 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 years 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 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.
J. Clin. Invest. doi:10.1172/JCI40855.
Commentary
Reduced thymus activity and infection prematurely age the
immune system
http://www.jci.org/articles/view/40855
Ronald E. Gress, Steven G. Deeks
Published September 21, 2009
The aging process affects all aspects of the immune system,
particularly the T cells. The immune system in older individuals is often
characterized by lower T cell numbers, lower naive/memory T cell ratios, and
lower T cell diversity. Most measures of inflammation increase with age. Why
this happens, and why there is so much person-to-person variability in these
changes, is not known. In this issue of the JCI, Sauce and colleagues show that
removal of the thymus during infancy results in premature onset of many of
these age-associated changes to the immune system (see the related article,
doi:10.1172/JCI39269). The effect of thymectomy was particularly notable in
those individuals who acquired CMV infection. Data from this study, as well as
data from other observational settings, suggest that reduced thymic function
and persistent viral infections combine to accelerate a decline in immunologic
function.
J. Clin. Invest. doi:10.1172/JCI39269.
Research Article
Evidence of premature immune aging in patients thymectomized
during early childhood (free access to full text)
Delphine Sauce1, Martin Larsen1, Solène Fastenackels1, Anne
Duperrier2, Michael Keller3, Beatrix Grubeck-Loebenstein3, Christophe Ferrand2,
Patrice Debré1, Daniel Sidi4 and Victor Appay1
1 Infections and Immunity, INSERM UMRS 945, Avenir Group,
Hôpital Pitié-Salpêtrière, UPMC University of Paris 06, Paris, France.
2 INSERM U645, Etablissement Français du Sang
Bourgogne/Franche-Comté, Besançon, France.
3 Institute for Biomedical Aging Research, Austrian Academy
of Sciences, Innsbruck, Austria.
4 Service de Cardiologie Pédiatrique, Hôpital Necker Enfants
Malades, Paris, France.
Address correspondence to: Victor Appay, Cellular Immunology
Laboratory, INSERM U945, Hôpital Pitié-Salpêtrière, Paris, France. Phone:
33-1-40-77-81-83; Fax: 33-1-42-17-74-90
Published September 21, 2009
Received for publication March 20, 2009, and accepted in
revised form July 16, 2009.
While the thymus is known to be essential for the initial
production of T cells during early life, its contribution to immune development
remains a matter of debate. In fact, during cardiac surgery in newborns, the
thymus is completely resected to enable better access to the heart to correct
congenital heart defects, suggesting that it may be dispensable during
childhood and adulthood. Here, we show that young adults thymectomized during
early childhood exhibit an altered T cell compartment. Specifically, absolute
CD4+ and CD8+ T cell counts were decreased, and these T cell populations showed
substantial loss of naive cells and accumulation of oligoclonal memory cells. A
subgroup of these young patients (22 years old) exhibited a particularly
altered T cell profile that is usually seen in elderly individuals (more than
75 years old). This condition was directly related to CMV infection and the
induction of strong CMV-specific T cell responses, which may exhaust the naive
T cell pool in the absence of adequate T cell renewal from the thymus.
Together, these marked immunological alterations are reminiscent of the immune
risk phenotype, which is defined by a cluster of immune markers predictive of
increased mortality in the elderly. Overall, our data highlight the importance
of the thymus in maintaining the integrity of T cell immunity during adult
life.
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