t-cell tango

Understanding the immune response to HIV

T cells both orchestrate and lead the host’s immune response to HIV. A better understanding of the interplay between virus and the host T cells should ultimately lead to better therapies.

The human body reacts to HIV as it does to any virus, by mounting an immune response. But while viral infections such as the common cold are cleared after a few days, HIV persists: it stays in the body, sometimes for years, often seemingly under control but occasionally breaking out in a burst of replication. At the Nuffield Department of Clinical Medicine in Oxford, Professor Rodney Phillips’s team is exploring the dynamics of the immune response to HIV, particularly which cell types are responsible for suppression of HIV replication and how the virus counters their activity. An improved understanding of the natural history of HIV infection will help researchers develop more effective drug regimens with fewer side-effects.

When a person is infected with HIV, there is an initial phase of very rapid virus proliferation. Much of the virus is then cleared, probably by cytotoxic T lymphocytes (CTL), white blood cells that specifically recognise and destroy infected cells. Different types of CTL recognise different parts of the virus – specifically, different fragments (or epitopes) of viral proteins. The virus can escape from immune control if mutations alter one or more of these epitopes so that they are no longer recognised by T cells.

Genetic variation is one way in which HIV counters the immune system. But perhaps its most insidious property is its infection of the very cells that orchestrate the body’s defence against infection – T helper cells. These T cells, which also recognise fragments of viral proteins, activate cell killing by CTL. Without drug treatment, a patient’s T helper cells are almost completely eliminated over one to two years – leaving infected individuals vulnerable to a host of opportunistic infections.

But within this broad picture much remains unclear. The exact roles of CTL and T helper cells at different stages during infection are not certain, while our understanding of variation and competition between HIV variants within the body is far from perfect. How the immune response is affected by anti-HIV drugs, and the impact of breaks in therapy, is also unclear. In a series of collaborative projects with colleagues in the UK and overseas, Professor Phillips is exploring these issues using a number of complementary approaches.

Studies of cellular responses to HIV have been greatly aided by the use of a new technique for measuring the number of virus-specific T cells in the body. The key feature of this new technique – developed at Stanford, then adapted for HIV by Professor Andrew McMichael in Oxford and adopted by Professor Phillips’s group – is that it quantifies the actual numbers of particular types of T cell present, rather than relying on indirect measures (such as secretion of particular factors). The new assays have shed light on the acute phase of infection: "The CTL are present," says Professor Phillips, "but are not working as well as they should."

Moreover, it appears that this initial interplay between virus and CTL has important consequences. "What happens in the early stage affects what happens in the long term," says Professor Phillips. "In the absence of intervention, the viral load at the point of stabilisation of the acute phase infection determines the outcome of the disease." In collaboration with Professor Philippa Easterbrook of King’s College Hospital, London, Annette Oxenius in Professor Phillips’s group discovered that high levels of virus reflect escape from T-cell control. On the positive side, even transient treatment during the earliest stages of infection can preserve functional, HIV-specific T cells. These results suggest that acute HIV infection should be treated aggressively and as early as possible, though there is still uncertainty as to how long treatment should be continued.

Unfortunately, in the vast majority of cases, the body’s fight against HIV is ultimately an unequal struggle. However, drugs are now available to even up the playing field. Yet there is still much to learn about their effects on the immunological battle between T cells and HIV. "When anti-HIV drugs were first introduced," notes Professor Phillips, "it was felt that they might make immunology boring. In fact, they are producing some interesting complex dynamics within the immune system." Current drug regimens can suppress viral replication but do not eradicate the virus completely and when the patient stops taking the drugs, HIV rebounds. Because the drugs are usually given as combination therapy, with patients taking several pills a day, and often have unpleasant side-effects, patients do abandon treatment, despite the severity of the disease.

This process is being studied in collaboration with Professor Jonathan Weber of St Mary’s Hospital in London, home to one of Europe’s largest HIV clinics. Each month, one or two patients at the clinic cease therapy. Such patients are being enrolled in a study to investigate what happens when treatment stops, HIV re-emerges and the virus re-engages with the immune system. The response is being examined in a more interventionist manner in the Swiss Intermittent Therapy Trial, which is being coordinated by Bernard Hirschel of the University Hospital in Geneva and includes Dr Oxenius. Patients are being started on a drug regimen, then deliberately taken off, then given drugs again.

All this work on the dynamics of the interaction between T cells and the virus is feeding into mathematical models being developed by Angela McLean at the Institute for Animal Health in Compton. Mathematical analysis of the selective pressures acting on HIV at particular stages of infection will lead to models of infection that can be used to test assumptions about the interaction between host and virus and to explore the impact of interventions or viral variation.

Just as different types of T cell, as well as other factors, collaborate to fight HIV infection, Professor Phillips emphasises the importance of different laboratories pooling their knowledge and resources. "We could be competing," he says, "but we are collaborating and working together."

HIV, measles and vaccination

At the London School of Hygiene and Tropical Medicine, Felicity Cutts is leading a collaborative project, funded through the Wellcome Trust-Burroughs Wellcome Fund Infectious Diseases Initiative, exploring the effects of HIV on the spread of measles in children.

In countries with high HIV prevalence, says Dr Cutts, measles may be hard to control even with effective vaccination campaigns. "Virus transmission may be sustained despite high immunisation coverage rates in HIV-infected children." There could be several reasons for this, she suggests. "One factor could be that children with HIV lose protective maternal antibody earlier than those without HIV, resulting in susceptibility to measles at a younger age - before nine months old, the age for routine vaccination." There is some preliminary evidence to support this notion but nothing definitive.

Another possible factor evident in the literature is a link between increased susceptibility and a rapid decline in measles IgG antibody levels after vaccination in HIV-infected children. "A third possibility," says Dr Cutts, "is the prolonged shedding of measles virus." Damage to the immune system of HIV-infected children may alter their ability to clear the measles virus after infection, lengthening the period during which they are infectious and encouraging the spread of disease.

There are also important safety issues to consider. Under current WHO policy, all children from developing countries receive the measles vaccine and, without routine screening for HIV status, HIV-infected children will be among those vaccinated. Little is known, however, about the effect of the vaccine on HIV viral load. Early results from researchers at Johns Hopkins University, the University Teaching Hospital, Lusaka, and the London School suggest that measles disease may increase HIV viral load, with the potential to increase immunosuppression. Might a live attenuated virus have a similar effect?

These are the kinds of questions being addressed by the collaborative project, which includes researchers from the USA and Zambia. The studies will be based on a cohort of HIV-infected Zambian children, and will aim to identify which factors are most important for sustaining measles transmission and to assess the effectiveness and safety of the measles vaccine in HIV-infected children. Mathematical models will be developed to assess the effects of HIV coinfection on measles virus transmission and measles control strategies, information with important epidemiological and health policy implications.

The results may shed light on yet another damaging aspect of the HIV epidemic, one that could have serious implications for vaccine use in HIV-endemic areas. The smallpox eradication campaign was based on the widespread use of a vaccine. If it were being attempted today, it is highly debatable whether such a strategy would be successful.

t-cell tango

Understanding the immune response to HIV

See also

Further reading