a moving target

HIV heterogeneity and vaccine development

HIV is a highly variable virus. Understanding this heterogeneity may help us to understand the spread of disease and develop ways of halting its transmission.

Since the early 1980s, HIV has swept around the world. Viral gene sequencing studies quickly showed that different strains prevailed in different countries, although the significance of this was not appreciated for some time. In fact, this heterogeneity has major implications for vaccine development, and may be important to the transmission efficiency of HIV and to pathogenesis. At St Mary’s Hospital, Imperial College School of Medicine, London, Professor Jonathan Weber has a keen interest in this heterogeneity and, thanks to a Wellcome Trust collaborative grant, now has a unique opportunity to monitor viral mutation and spread.

HIV in Russia

Professor Weber has been collaborating with Professor Alexei Bobkov of the Ivanovsky Institute in Moscow since before the break-up of the Soviet Union. The Ivanovsky Institute receives samples from all over the country, creating an important resource. "Until relatively recently, the incidence of AIDS in Russia was very low," says Professor Weber. "There were point outbreaks amongst homosexual men or isolated cases due to the use of dirty needles in hospitals. Since 1998, there has been an explosive epidemic in intravenous drug users and their heterosexual partners. We have gone from documented nowhere to 25 000-30 000 new cases in the last 12 months."

This epidemic has some distinguishing features. The predominant HIV subtype worldwide amongst gay men and intravenous drug users is type B (one of ten subtypes, A-J). In Russia, by contrast, the predominant subtype is type A, which was previously associated with heterosexual transmission in Africa, with a smaller number of cases of subtype B. In addition, Professors Weber and Bobkov have detected the emergence of a new subtype, a genetic cross between types A and B. "This is the first time such an event has been observed, where both the parental strains - A and B - have previously been characterised. It provides a fascinating opportunity to study the behaviour of a new recombinant both epidemiologically and virologically in comparison to the parental strains."

With support from the Trust, Professor Weber and Professor Bobkov will be collecting and analysing data on HIV subtypes and on the lifestyle, behaviour and health of infected individuals. By enhancing the existing Russian AIDS database, they hope to identify which features of the virus contribute to transmission under particular circumstances or are responsible for particular aspects of disease. The comparatively rare emergence of a new recombinant strain, with potentially novel properties, provides a valuable opportunity to explore these issues. Most importantly, is the predominance of this new recombinant a random event or do some viruses have characteristics that favour transmission among heterosexuals?

These studies will be carried out in Russia and funded through a Collaborative Research Initiative Grant, which will enable Professor Bobkov to invest in equipment and conduct experiments within the Ivanovsky Institute. There are also funds to train local staff and for joint exchanges. "It’s a fantastic opportunity to develop the considerable skills in molecular virology already present in Russia," says Professor Weber. They will look at the cellular immunology with Professor Rodney Phillips, who is examining the effects of a short pulse of early treatment on the long-term course of HIV infection. "We are extremely eager to bring this work to the Russian context," says Professor Weber.

A moving target

Appalling though the consequences may be, the Russian epidemic will also provide valuable information for Professor Weber’s quest to develop an anti-HIV vaccine. "Antigen diversity still plagues vaccine development. The question is: how many antigens will be needed to make a vaccine that will provide broad cover?" The chief culprit is the major surface glycoprotein, gp120, the product of the env gene. This structure induces neutralising antibodies, but viral strains isolated from a single individual over time may differ by up to 5 per cent in their env sequences; isolates from different continents may vary by up to 40 per cent.

These variants may have different biological properties and may be associated with different types of transmission. They also pose a problem for vaccine development, as an effective vaccine would have to stimulate immunity across a potentially broad range of structures. Because the Russian epidemic is so new, antigenic diversity is currently quite low, enabling Professor Weber to study of cross-reactivity between subtypes A and B and the recombinant.

Professor Weber was a founder member of the WHO Network for HIV Isolation and Characterisation, which was established in 1992 to coordinate systematic investigation of viral heterogeneity on a global scale. The Network has compiled a bank of samples, initially from four countries that are potential sites for vaccine trials - Uganda, Rwanda, Thailand and Brazil - and subsequently from a wider range of countries, including South Africa, India and China. Twelve laboratories are coordinating their studies through the WHO, gathering information on HIV subtypes, assays to detect them and the relevance of subtypes to vaccine development.

With Trust funding and as part of the WHO Network, Professor Weber’s laboratory is studying the sensitivity of these diverse isolates to neutralisation, and is developing sensitive antibody-based screening assays for detecting HIV-1 subtypes in surveys. One key finding is that there is no direct link between subtypes defined by gene sequence and vaccine or neutralisation serotypes: different subtypes may be recognised by the same neutralising antibody. "The subtypes are genetically discrete but biologically indistinguishable to neutralising antibodies," says Professor Weber.

This work is geared to practical ends. "Through the Network, we hope to learn more about the antigenicity of the virus and how it works in the real world. And through our studies of conserved neutralisation in HIV-1 subtypes of widely differing genetic sequences, we hope to identify conserved motifs likely to induce broadly cross-reactive antibodies." Even an understanding of the antibody response to HIV will not be a complete picture, however. An effective vaccine, he suggests, will have to stimulate both arms of the immune system - T cells and neutralising antibodies. The bad news is that, so far, no vaccine has managed to do that in the field. The ever-changing HIV remains as elusive a target as ever.

AIDS and pneumonia

In recent years Malawi has seen a fourfold increase in hospital admissions for pneumonia and an eightfold increase for pnemococcal meningitis. It is not difficult to identify the reason for this upsurge: "Invasive pneumococcal disease patients are 96 per cent HIV positive in our experience," says Stephen Gordon, a researcher from the University of Sheffield working at the Wellcome Trust Research Laboratories in Blantyre, Malawi.

While in Blantyre on a Wellcome Trust Training Fellowship in Clinical Tropical Medicine, Dr Gordon found that alveolar macrophages – the aggressive phagocytic cells responsible for clearing pneumococci from the alveoli of the lungs – are infected by HIV and fail to clear the bacteria. Pathogens such as Streptococcus pneumoniae end up invading the bloodstream, causing a potentially fatal septicaemia. The reason for this failure is unclear, as in vitro experiments have not shown a defect in phagocytosis, but "in vitro phagocytosis of pathogens is poor generally," points out Dr Gordon.

With a recently awarded Career Development Fellowship in Clinical Tropical Medicine, Dr Gordon aims to take the simple in vitro model much further to take into account the way in which alveolar macrophages work in the lung itself, in concert with the alveolar epithelium and alveolar lymphocytes. "There is good evidence that lung defence is independent of systemic defence," says Dr Gordon. "After all, we don’t get septicaemic every time we inhale a few pneumos. But almost nothing is known of how this works, except that the capsular polysaccharide vaccine given systemically is ineffective."

Dr Gordon quotes George Bernard Shaw, who, in The Doctor’s Dilemma, said: "Stimulate the phagocytes". "We still aim to do that," says Dr Gordon. "We now have good delivery mechanisms for inhaled therapy and trials are under way using cytokine therapy in HIV infection." Cytokines are proteins produced by T cells, a vital arm of the immune system, that act as chemical messengers, stimulating the immune response. "For Africa," Dr Gordon believes, "an inhaled vaccine is more realistic and it is exciting in this regard that non-capsulate pneumos [which have no protective outer capsule to resist antibodies and do not cause pneumonia] given nasally are both immunogenic and protective in animals, and have been shown to be immunogenic in humans."

Shaw continues, "Drugs are a delusion". Given the increasing emergence of antibiotic-resistant strains of Streptococcus pneumoniae, finding treatments that stimulate the immune system becomes of paramount importance. And with no effective vaccine against S. pneumoniae in Africa, stimulating the macrophage is certainly a strategy worth pursuing.

External links

Imperial College School of Medicine

a moving target

HIV heterogeneity and vaccine development

HIV in Russia

A moving target

See also

External links

Further reading