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If HIV researcher Philip Goulder (pictured left) ever feels that his work on fundamental biological questions lacks a human dimension, he just recalls his frequent visits to a prenatal clinic in Durban, South Africa, and is disabused. More than half the women attending that clinic are HIV positive. Those patients do not receive anti-retroviral therapy.

Goulder, a Wellcome Trust Senior Fellow, and his team at Oxford University are investigating why some individuals mount an effective natural immune response to HIV, while others can't. Their research probes basic scientific questions like how the immune system responds to masquerading pathogens like HIV (see insert).

But it isn't all basic science. Goulder is a part of a collaborative project, working with researchers and clinicians in Durban and in Boston, that aims to use the knowledge he gains from his basic research to treat patients with HIV. HIV, Goulder notes, "is a major global pathogen," so there is "an urgent and continual need to do something." This translational aspect to his work has been a major motivating and rewarding element in his successful research career to date.

Early Research

Goulder got his first taste of research as a zoology undergraduate at Oxford University, where his did an undergrad dissertation project on how benign butterflies mimic poisonous species in Africa. He fell in love with the continent and was inspired to study medicine with the intention of returning to Africa some day to work in tropical medicine.

After taking his medical degree at London and Cambridge, Goulder went on to train as a paediatrician. His training included work with paediatric HIV patients at Duke University, in North Carolina. When he finished his clinical speciality training, Goulder, eager to get first-hand research experience, he undertook a Ph.D. in HIV research, with Oxford's Andrew McMichael, on immune response to HIV. Since then, research has been his primary professional interest.

Toward the end of his doctoral work, Goulder published a seminal paper on how HIV mutation results in the virus escaping from previously adequate immune control. This phenomenon was accompanied by disease progression in patients who were previously asymptomatic.

Goulder moved to Harvard Medical School as a post-doc to continue investigating this immune response, now in HIV-infected children. But in the back of his mind Goulder maintained an even more pressing research ambition: to study the immune control of HIV in patients in South Africa, who, unlike those in Boston, were unlikely to receive anti-retroviral treatment.

A Global Response

Over the past 7 years, Goulder has led a large-scale collaborative study on HIV patients with the University of KwaZuluNatal in Durban, the Massachusetts General Hospital in Boston, and the Department of Paediatrics at Oxford University, among others. Their most recent results, published in the journal Nature last December, show that individuals with a certain human leukocyte antigen (HLA or "tissue type") genetic profile can mount a consistent and effective immune response against HIV and remain healthy (see insert). Understanding the mechanism--how specific HLA molecules give immune "T cells" (known as CTLs) the armoury to tackle HIV--could, in principle, be exploited to design a vaccine that can mimic this response. As Goulder explains, "We can't say what a vaccine should look like until we know what constitutes [natural] immune control of HIV." Their most recent results have given them that insight.

Immune Control of HIV and Tissue Type (HLA)

HIV can out-play the immune system by entering and eventually destroying CD4 T cells (T Helper cells) and also by evading CD8 T cells (Cytotoxic T cells - "CTLs" or "killer" cells) attack.

The chief job of the CTL is to eliminate virus infected cells. CTLs can tell the difference between virus infected and healthy cells because the human leukocyte antigen (HLA or "tissue type") molecules that are on all cells "display" the virus on the outside of the virus infected cells. It's like the HLA creates a "label" and "instruction" to the CTL: "Here is a virus infected cell--please destroy!" But only certain parts of the virus that are displayed will be recognised by the CTL: other parts will be deemed as harmless and the cells whose HLA display these "harmless" parts will not be destroyed. So if only the harmless part is displayed on a given cell, this virus infected cell will survive.

For most infections, HLA molecules do a good job at showing the "right parts" of the virus to the CTL cells. With HIV it can be problematic.

HIV is excellent at mutating (i.e. changing its identity) and thus often only harmless parts of HIV get displayed by HLA even though the cell is infected by HIV. But, according to Goulder, people who have a certain HLA type, for example people with HLA-B57, have CTL cells that manage to still mount an effective immune response to HIV despite HIV mutating. How? HLA-B57 doesn't let HIV away with hiding. In the case of the CTL B57 immune response, the virus has two unappealing choices. The first one is: it doesn't mutate but then the virus infected cell is killed by the CTL. The second one is: it does, but the mutation that HIV must make to evade the immune response is, by chance, in a critical region of the virus for its survival. Thus, the mutation itself will partially cripple the virus. So, in either scenario, HIV is in trouble.

Goulder says working on such collaborative projects is inspiring, and to him, the ultimate professional reward. The team's research goes beyond what he describes as an "intellectual exercise; there is also a capacity building element." The logistics of leading a project on three continents requires plenty of organisational skills and demands a hectic schedule; Goulder spends 25% of his time abroad. But for Goulder the rewards are great: "You meet a huge number of fantastic people," he explains, "It is a privilege to interact with them."

The Future of HIV Research

HIV is a major global public health issue, and the research field is dynamic. Does that mean it is over subscribed and difficult for the early career researcher to penetrate? Goulder admits the area is deemed "sexy," and has attracted top scientific talent. However, this high level of competition is something Goulder views as a positive force. HIV researchers, Goulder feels, still profit career-wise from a relatively robust funding scene. Goulder also believes when it comes to publishing, breakthroughs in HIV often have a higher impact in comparison to equally novel science about a less infamous pathogen.

According to Goulder, having clinical training has been helpful when dealing with clinicians and in appreciating what clinical complications HIV-positive patients may have. But the clinician-scientist path is not the only one for scientists interested in HIV research. Academic researchers without clinical degrees--molecular biologists, bioinformatics specialists, etc.--also have very important roles to play.

Goulder plans are to stay in the field long term, and in global-collaborative projects. His work and the work of his research team, he feels, demonstrate the "short, medium, and long term value of pure research for patients." As for a future HIV vaccine, Goulder believes that "a consortium-driven vaccine effort" will indeed be successful. He sees this type of approach--"enabling scientists to work together for a common goal"--as the ultimate career drive, and one he can already recommend.