Immune activation
HIV can induce both of these processes in the immune system, by high level activation and turnover of cells. Active immune cells are cells which are ‘turned on’ and are intent to divide and expand the immune response.
It is the activation and turnover of CD4 cells that is central to the pathogenesis of CD4 cell loss in chronic HIV infection. Research can measure this increased level of immune activation by using markers like Ki67. Ki67 is a nuclear antigen which is expressed only by cells within cell cycle mode.
HIV can lead to immune activation in several ways. T-cells do not have to be activated by a viral antigen (via a T-cell receptor) in order to divide, they can be activated by a bystander mechanism. Research has shown that the vast majority of the cells in cycle during chronic immune activation are central memory cells being driven by a bystander mechanism.
Recent research by Angélique Biancotto of the National Institute of Child Health and Human Development, US, addressed one possible mechanism for this type of immune activation.
The lymph nodes of someone with HIV have been shown to be enriched with a large number of effector T cells, which make cytokines. By looking at lymph nodes from 12 HIV-positive patients and 10 HIV-negative controls, she was able to demonstrate that levels of cytokines were higher in the lymph nodes of HIV-positive patients. Of particular interest were interleukin-2 and interleukin-15 which are both capable of bystander activation and driving T cells into cycle.
Immune activation may also be caused by damage to the wall of the gut. During acute HIV infection there is a dramatic destruction of the CD4-positive T-cell population in the gut-associated lymphoid tissue. Microbial products can then leak into systemic circulation and ultimately result in broad chronic immune activation. This has been demonstrated by elevated levels of lipopolysaccharide (LPS), which is a major constituent of the cell wall of gram-negative bacteria, in those with HIV compared to those who were uninfected.
As a result of this immune activation, HIV replication is enhanced (an activated T cell is much more capable of supporting HIV replication than is a resting T cell) and progressive CD4 T cell loss is driven that fails to constrain viral replication.
Another process of aging, oxidative stress, exacerbates problems further. Oxidative stress is increased in those with HIV and the normal antioxidant defence system is compromised. Excess free radicals create a breeding ground for HIV as it uses free radicals to replicate.
These mechanisms produce considerable strain on the immune system and Prof Gazzardhighlighted the extent to which the immune disorder induced by HIV resembles the immunological decline seen in the elderly.
With improved antiretroviral therapy (ART) bringing decades of extra life to the developed world, the impact of HIV on the aging process is beginning to become a pressing concern as researchers attempt to determine whether the giants of geriatric medicine - dementia, heart disease and cancer – will occur sooner or more frequently in HIV-positive people as they age.
Professor Brian Gazzard of the Chelsea and Westminster Hospital, London, explored these new challenges in a plenary presentation at the Fourth IAS Conference on HIV Pathogenesis, Treatment and Prevention, in Sydney last week.
Prevalence of HIV is increasing in older age groups. In the United Kingdom nearly a third of all adults who are HIV-positive are 45 years or over. Life expectancy is improving year by year, thanks to improved ART, but in addition to longer life there is also the input of new seroconversions into older age groups.
Analysis of HIV-positive diagnoses in the UK shows that a growing number of people are being diagnosed with HIV at ages over 50 – up from around 5% of all new diagnoses in 1995 to just under 10% of gay men and heterosexual men in 2005. Data from CASCADE, the UK national HIV cohort, show that just over half of all HIV infections are estimated to have occurred after the age of 30.
But while these factors increase the number of people with HIV who are reaching old age, the expected life span is still short of that of the general population. The international Antiretroviral Cohort Collaboration estimated in 2005 that a person diagnosed with HIV at the age of 20 had a life expectancy of 33 years, compared to 58 years for an equivalent individual in the HIV-negative population.
The interrelationships between aging, HIV and the potential effects of ART are complex . Diseases of aging can be more common in those with HIV infection, have a worse prognosis and ultimately decease life expectancy. While noting that some groups at risk of HIV may already have a greater risk of early death (giving the ‘dispossessed’ as an example), Prof. Gazzard went on to explain how the effects of HIV were strongly related to aging.
HIV can affect molecular mechanisms which are linked to the aging process, such as senescence and apoptosis. Apoptosis is a type of programmed cell death orchestrated to remove cell ‘corpses’ from the body.
Senescence is the capacity of cells to become redundant or ‘die’ after many divisions. With every cellular division, the terminal DNA repeats of their chromosomes become shorter, a phenomenon known as telomere shortening. Eventually, this telomere length is reduced to a point where division is no longer possible.
The aging immune system
The immune characteristics of old age, and HIV infection can be very similar. Both groups show inverted CD4/CD8 cell ratios, CD4 lymphopaenia, reduced thymic output, shorter telomeres of CD8 cells, and accumulation of late-differentiated CD4 and CD8 cells, for example.
Dr Gazzard explained the consequences of this by stating that the risk of death in the elderly, if you have a collection of late-differentiated CD4 and CD8 cells and were CMV positive, was very high,
Immune function can often decrease with age, as well as HIV infection. When people who were HIV suppressed with CD4 counts greater than 200 cells/mm3 were given hepatitis A vaccine, the immune responses can be seen to be very closely correlated with age. It’s also true that interleukin-2 doesn’t work very well in the elderly, as proven by the ESPRIT study group.
As well as immune function, response to ART is linked to aging, he explained. “You can find ten papers to show something different but most of the papers tend to show that the immune response to ART is reduced in older people, presumably because with increasing age the thymus undergoes a process of involution which results in a reduction in thymic size,” explained Prof. Gazzard.
The role of the thymus is vital for orchestration of T-cell development and maturation.
But old age does brings good news too; CPCRA analyses of adherence showed that you are more likely to have better adherence if you are over 50. This led to a greater frequency of undetectable viral load in those who were older.
When it comes to survival, many cohort studies suggest that older people with HIV survive less well. Most chronic diseases of aging occur more frequently in those with HIV. Prof. Gazzard commented on multivariate analysis from the EuroSIDA study group showing that each ten year increment of age carried a ‘very major increase’ in risk of chronic renal disease and chronic renal failure.
Prof. Gazzard went on to discuss in more detail what he termed the ‘geriatric giants - those things that will kill most of us in due course’ - such as cardiovascular disease, cancer and dementia.
Cardiovascular disease
The most important thing that will determine whether we get cardiovascular disease is our genetic makeup. The second most important thing is smoking. While there are very minor differences depending on which boosted PI is used in ART, Dr Gazzard implored those present to concentrate on smoking cessation first.
However, the DAD study showed that when you adjust for NNRTI exposure, there is a per year incremental increased risk of developing cardiovascular disease related to PI exposure. In addition, the SMART study showed some surprising results with an increased cardiovascular risk for those who stopped antiretroviral therapy.
“HIV itself is associated with a very big increase in cardiovascular risk and that is reduced enormously by antiretroviral drugs, but not necessarily back to completely normal,” explained Dr Gazzard.
Exactly how HIV influences atheroma (fat accumulation and swelling in artery walls which can lead to cardiovascular disease) is not fully understood.
Dementia
Despite ART there is evidence that gliosis (proliferation of specialist cells in areas where neurons have been damaged) may continue in the brain and this is said to correlate with proviral DNA in the central nervous system.
There are also theories to suggest that HIV itself may encourage Alzheimer’s disease by affecting the brain in similar ways to the illness. These similarities include increased brain beta-amyloid deposition and increased extracellular amyloid plaques, both affecting brain function.
In addition, neprolysin (an enzyme responsible for amyloid degradation) in the extracellular environment, is inhibited by transactivator (a regulatory gene which accelerates the production of HIV). The existence of an apolipoprotein e4 allele also correlates to both HIV-associated dementia and Alzhiemer’s.
However, when looking at cause and effect, D Gazzard said that much of the dementia in older people with HIV should perhaps be called dementia in the context of HIV rather than HIV dementia.
While ART itself may increase the risk of dementia, Dr Gazzard also noted that ART has had an effect in changing the course of HIV-related dementia, likely due to effective reduction of HIV RNA.
Cortical presentations appear to be much more common than subcortical presentations now, resulting in memory loss rather than loss of function.
PET scans (used to diagnose brain conditions) show that the temporal lobe is more likely to be involved than the basal ganglia and the strong correlations once seen between HIV-associated neurocognitive impairment and biomarkers like beta microglobin are breaking down and may no longer be present.
While these parallels between the aging process and HIV progression may cause concern for some patients, Professor Gazzard compelled us to recognise that death is inevitable for us all. There is research still to be done and while meaningful improvements in outcome for people with HIV and increasing age might not be achievable beyond a certain point, these data could inform the pathogenesis of age-related diseases in everyone.
Cancer
A study from Prof. Gazzard’s own research centre showed early on in the HAART era that a number of non-AIDS related cancers are increased in incidence in those with HIV, such as seminoma, anal cancer and head and neck cancer.
This work has now been confirmed by larger studies. The DAD study showed that fatal non-AIDS defining malignancies were now more common than classic AIDS defining cancers. It also indicated that the risk of these increases with lower CD4 cell count and with age.
Gazzard gave two possible reasons for this; it may be because the people who are at risk of HIV infection are also at risk of acquiring oncogenic viruses; or it may be because there’s a loss of immunosurveillance allowing oncogenic viruses to proliferate.
He explained that HIV could be capable of promoting cancerous growth by defining six distinct mechanisms related to all cancers:
• Self sufficiency in growth signals
• Insensitivity to antigrowth signals (such as retinoblastoma protein)
• Evasion of apoptosis
• Limitless replication potential (avoidance of senescence)
• Sustained angiogenesis (Vascular Endothelial Growth Factor or VEGF production)
• Tissue invasion and metastasis (Intercellular Adhesion Molecules(ICAM)
HIV can affect each of these mechanisms; for example antigrowth and growth signals are both interfered with by HIV and HIV infection can lead to increased levels of VEGF, which plays a key role in tumour growth. The question remains whether this alone explains the increasing cancer rates or whether loss of immunosurveillance plays a part.
A recent meta-analysis of cancer cohorts looked at increased risk of cancer in people with HIV infection as well as people immunosuppressed after an organ transplant, and found immunosuppression was associated with increased risk of certain types of cancers, particularly those caused by infectious agents. These findings suggest that even a modest deficiency in immune surveillance is enough to increase the risk of a wide range of cancers.