Research updates
HIV - a global challenge   page 6
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5. The management of HIV    Link to the Medical Research Council web site
 
The cell membrane
Although at present there is no cure for HIV infection, there are drugs available which can prolong life and delay the onset of AIDS.
Antiretrovirals to inhibit onset of AIDS

Known as antiretrovirals, all these drugs target different stages of the life cycle of HIV. One group of drugs used are the nucleoside analogues, which inhibit HIV reverse transcriptase. Zidovudine, for example, was first licensed for use in the treatment of HIV infection in 1987. Protease inhibitors were developed later in the 1990s and inhibit the viral protease enzyme. HIV protease plays a crucial role in viral replication, being responsible for cleaving viral polyproteins into active structural proteins, and for the maturation of reverse transcriptase.

In 1996 there were several trials showing that the combination of two nucleoside analogue reverse transcriptase inhibitors and a protease inhibitor improved survival and slowed disease progression compared to using two nucleoside analogues alone, at least in advanced disease. Substantial reductions in mortality and morbidity have also been seen in clinical practice. Since then, three crucial issues have arisen with these drug treatments

  • the long-term side effects suffered by patients
  • the problem of adherence
  • the emergence of drug-resistant strains of HIV.

Side effects

Metabolic abnormalities have emerged in large numbers of patients treated with current multi-drug regimens, consistent with increased risk of cardivascular disease. The long term effects of these abnormalities are still unknown. Further, a number of individuals suffer from severe fat-wasting (lipoatrophy) and/or fat accumulation (lipodystrophy), which, aside from social consequences, may also be associated with increased cardiovascular risk.

Adherence

Adherence is increasingly perceived as a cornerstone of successful therapy. The majority of anti-HIV drugs are dosed twice or three times daily with food restrictions, leading to large pill counts and complex regimes for multi-drug therapy. The high mutation rate makes keeping to a strict schedule even more important to avoid escape of virus mutants. A number of studies aimed at developing simpler regimens are currently underway.

Drug resistance

Finally, as the number of patients taking therapies for long periods of time increases, drug resistance plays an increasingly prominent role. An MRC funded study recently estimated that around 20% of new infections in the UK were with HIV virus resistant to at least one antiretroviral drug. Resistance testing is now widely used to identify genotypic mutations associated with drug resistance in order to choose the most active therapeutic regimens.

Antiretrovirals are targeted to the life cycle of the virus. A recent approach is to supplement this anti-HIV therapy with immune therapy aimed at enhancing the host immune system. A large international trial, ESPRIT, comparing the addition of interleukin-2 to standard regimens is coordinated in the UK and part of Europe by the MRC Clinical Trials Unit.

Developing a vaccine
A study carried out during 1995 by scientists at the Medical Research Council’s laboratories in The Gambia, West Africa, produced results which may help the development of a vaccine against HIV infection. HIV-2, which appears to be less pathogenic and less easily transmitted than HIV-1, is the most prevalent HIV infection in The Gambia. The research showed that despite their repeated exposure to HIV over several years, the blood of a group of female prostitutes contained no detectable virus. Present in the women’s blood however, were highly active HIV-specific cytotoxic T lymphocytes (CTLs). Researchers consider that the women produced an immune response which destroyed the virus and that their CTLs could be providing protective immunity against HIV infection. Further research is investigating whether HIV-2 specific CTLs can recognise and kill HIV-1 infected cells as a possible mechanism of cross-protection.

Question 5
a) Explain how drug-resistant strains of HIV may develop.

b) How may combination therapy avoid this problem?

Look at the box about developing a vaccine.
c) The quest to develop a vaccine against HIV is being pursued worldwide. List the features of HIV which make vaccine development a considerable challenge.

d) Many successful vaccines provide long-lasting immunity through stimulation of antibody-producing cells. In the case of an HIV vaccine, two other types of immune cells may be more important. What are these? Give your reasoning.

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