Rapporteur reports
Track A: HIV Basic Science report by John Zaunders
Michael Lederman gave an insightful plenary on our current
understanding of the mechanisms underpinning CD4 T cell loss which
leads to the eventual collapse of the host immune system.
To do their job, populations of viral antigen-specific effector T
cells must expand and contract as needed. In addition, central memory T
cells undergo homeostatic proliferation to maintain their numbers. It
is now believed that elevated activation of T cells and their turnover,
particularly of central memory cells, underlies HIV pathogenesis. SIV
infection in rhesus macaques, which exhibit high viral loads and
progressive infection, leads to high levels of activation of their T
cells. This compares with SIV infection in the natural hosts, sooty
mangabeys, which also have high viral loads, but do not develop
immunodeficiency and have low levels of T cell activation. T cell
activation is usually measured as increased levels of CD38 on the cell
surface, but this may be due to either a response to viral antigen, or
could be due to a “bystander” effect of high levels of cytokines. In
untreated HIV infection, not only is there increased activation but
there is also increased turnover of T cells, as measured by Ki-67 and
BrdU labelling. Again, this could be due to either antigen responses or
bystander cytokine responses. There is evidence that the T cells which
are activated and undergoing turnover are T cells that are not
HIV-antigen specific. Furthermore, there is increased production of
cytokines, particularly the gamma-chain cytokines IL-2 and IL-15. Taken
together, these results suggest that increased turnover of central
memory T cells in HIV infection is due mainly to the cytokine bystander
effect. This could be enhanced as a result of the drastic depletion of
CD4+ T cells from gut-associated lymphoid tissue during primary HIV
infection. It appears that due to this effect on gut tissues, there is
increased translocation of microbial products, such as
lipopolysaccharide, peptidoglycan and bacterial 16S DNA, from the lumen
of the gut into the plasma. These products may bind to toll-like
receptors (TLR’s) specialized to detect infections, and cause further T
cell activation. This effect of TLR agonists on T cell activation and
turnover can be reproduced in vitro, but leads to cell death, rather
than normal homeostasitic proliferation. Therefore, a model can be
envisaged of T cell activation due to HIV replication, being reinforced
by signals due to high levels of cytokines from effector cells, in
addition to the presence of TLR agonists. Overall, this leads to
chronically elevated activation, turnover and cell death due to viral
replication in activated CD4+ T cells. Interrupting the cycle of
activation may present an opportunity to rectify CD4 decline.
Track B: Clinical Research, Treatment and Care report by Sean Emery
Younger men take to the stage with less enthusiasm and bridled passion. Far younger men have long since shackled their desire for beautiful plumage. Brian Gazzard tackled the complex issue of Aging and AIDS with bravado, colour, movement and refreshingly substance.
Underpinning this summary were some essential ingredients. Firstly, the role of aging and important clinical outcomes for people with HIV is likely to be of relevance only in those places where appreciable improvements in life expectancy can be realised through the use of combination antiretroviral therapy as part of a comprehensive treatment and care environment. A thirty year old man diagnosed with HIV in a country of the developing world is less likely to be troubled by the consequences of an aging physiology than an equivalent patient in developed countries, who could quite reasonably be looking at a more or less near-normal life expectancy. Secondly, we need not (and indeed should not) make the issue of aging complex. It is likely that 'real truths are explained by simple solutions'. This issue should be approached from a reductioinst perspective.
Professor Gazzard proposed that a complex clinical picture might most probably represent the consequences of interactions between 1). HIV with a range of well described phenomena linked to increased rates of senescence (telomere shortening, increased rates of cellular apoptosis and oxidative stress as measured by free radicals). We have known for a long time that older people with HIV do far worse than younger people, 2). An aging physiology where risks for a number of fatal and non-fatal outcomes are already increased (renal and liver disease, aberrant bone metabolism and the 'geriatric giants' (atheroma, neoplasia and dementia), 3). The extent to which antiretroviral therapy contributes directly to end organ damage through toxicity in addition to the well known poorer performance of these drugs when used in older people, and 4). a revisionist view of the role of HIV in the pathogenesis of diseases not previously believed to be directly affected by HIV infection (cardiovascular, renal and hepatic diseases, and non-AIDS defining cancers.
In concluding, Professor Gazzard compelled us to recognise that death is inevitable for us all. Meaningful improvements in outcome for people with HIVand increasing age might not be achievable beyond a certain point. This should not deter us from seeking answers through research. Importantly, in the context of a physiology perturbed by HIV it is probable that clinical and laboratory investigations would inform the pathogenesis of age related diseases in all humans.
Track C: Biomedical Prevention report by Nick Walsh
This plenary tied together the importance of evidenced based treatment roll-out with the important biomedical concepts of the immune response to HIV as a driver of progression and how HIV is related to the innate human aging process.
Dr. Debrework Zewdie discussed the importance of integrating research in prevention and treatment programs. This is the focus of the Sydney Declaration that ‘Ten per cent of all resources dedicated to HIV programming should be used for research towards optimizing interventions utilized and health outcomes achieved.’. Although ART roll-out is progressing including in Asia and Africa global ART coverage remains at around 28% in adults and 17% in children. How to improve coverage and effectiveness?
Dr Zewdie highlighted the importance of operational research being an intermediate leveraging agent between understanding the epidemic and cost effective implementation ‘how to do things better’. Research can inform treatment programs, build individual and institution capacity through partnerships and systems development and build an evidence base. There are a number of challenges to research in the developing world (countries of the south) including a scarcity of human resources - the brain drain. For example 50% of doctors trained in Papua New Guinea work overseas. Infrastructure is often poor and only a small proportion of international funding (< 5%) is focused on research reducing the incentive for people to move into research or for talented individuals to stay or return after overseas training.
Research priorities discussed include integration of HIV into mainstream clinical practice to optimise care, TB-HIV coinfection being an example (Which to treat first?); research into understanding the needs of vulnerable people to improve access and effectiveness of treatment (e.g. the lack of treatment coverage for IDUs in Eastern Europe); integrating new therapies into clinical practice (such as 2nd line ART); developing sustainable North-South partnerships; and moving towards a shared agenda between research and programs.
Research plays a key role in effective treatment role out but there remain many challenges. Research priorities are important in order to improve our ability to achieve universal access.
Michael M. Lederman discussed the mechanisms of immunodeficiency in chronic HIV infection and the role that immune activation has in increasing HIV progression. Ultimately the question is ‘Do we given immunosuppressants to people with HIV to prevention immune activation?’ Again a difficult question which perhaps should be explored in those how have poor responses to HAART.
Brian Gazzard discussed the parallels between the aging process and HIV progression. Many of the consequences of HIV progression can be attributed to aging. Should we be looking at treating known important risk factors associated with aging or even important determinants of these such as smoking? Key points for preventing HIV progression.
|