In which the redoubtable Dorian reports further on the doings at CROI 2011.
Michel Nussenzweig (Rockefeller, USA) gave everyone an immunology lesson in order to explain what makes broadly neutralizing anti-HIV antibodies so special. So carrying on with the immunology lesson theme, I should just point out that neutralizing antibodies are those that not only stick to the surface of a virus, but actually prevent it from infecting a susceptible cell. So far, all effective antiviral vaccines work because they can induce these neutralizing antibodies. So that’s what neutralization is, now where does the “broadly” part come in? HIV is of course a highly variable virus, so “narrowly” neutralizing antibodies only neutralize a small number of HIV variants, while “broadly” neutralizing antibodies can block infection from a wide range of different HIV variants.
To date, none of the HIV vaccine candidates tested has been able to induce broadly neutralizing anti-HIV antibodies effectively, and most HIV-infected people do not make this type of antibody during natural infection. However some people with HIV infection do produce broadly neutralizing antibodies (It should be stressed however, that HIV+ individuals who make broadly neutralizing antibodies are not cured of their infection). The reason for studying antibodies from such people is that if we can understand how broadly neutralizing antibodies are formed during natural infection, then perhaps we might find a way to induce the same kind of antibodies with a HIV vaccine.
Using a variety of fantastically ingenious techniques, Nussenzweig showed us that the magical processes of hypermutation and affinity maturation are essential for the potency and the breadth of broadly neutralizing anti-HIV antibodies. These processes occur in the germinal centres of lymph nodes, and he presented some amazing imagery data to show that the maturation of antibodies is controlled by the CD4+ T-cells in the germinal centre that “help” B-cells produce antibodies. So the final message, I guess, is that CD4+ T-cell responses are going to be essential for a vaccine to be able to induce a good neutralizing antibody response.
However, that still doesn’t resolve the “broad” part of the problem – how to focus the antibody response onto the sensitive parts of the virus. Indeed, as a presentation in the afternoon from Laurent Verkoczy (Duke Univ. USA) showed, this may be extremely difficult to achieve. For one broadly neutralizing epitope on HIV (the so-called MPER epitope), the antibodies that bind to this site on the virus are also auto-reactive. In a mouse model, he showed that the cells that carry these antibodies are “strangled at birth” by the mechanisms that prevent our immune system from damaging ourselves. These antibodies have therefore probably been deleted from most people’s immune repertoire, and are therefore not available to be selected and amplified by vaccination.
So I’m afraid no-one has yet found the way to induce these broadly neutralizing antibodies.
A virus that slows down HIV
GBV-C is a virus infecting humans that is transmitted by sex, blood transfusion, and from mother to child – rather like HIV. It is a flavivirus (other family members include yellow fever virus, and hepatitis C virus), and because of its mode of transmission, GBV-C is often found in HIV seropositive people. It does not seem to cause disease in people who are infected either acutely, or chronically. Now, you might expect that being infected by two different viruses at the same time would be worse than just being infected by one. But remarkably, the 20-40% of HIV+ individuals who have chronic GBV-C infection have SLOWER disease progression than those who only have HIV infection (at least in European/North American patient cohorts).
There were two talks presenting results trying to explain this intriguing observation. Molly Perkins (NIAID, USA) presented data from a study of HIV-infected patients in the Gambia. She found that GBV-C coinfection did not change T-cell activation, but reduced expression of the HIV coreceptor CCR5 on T-cells. In direct contrast to these results, Jack Stapleton (U Iowa, USA) presented data showing the exact opposite. In his study, GBV-C lowered T-cell activation, but had no effect on CCR5 expression.
How can two groups looking at the same question get such discordant results? Jack Stapleton noted that the different studies on this topic have been conducted in different regions of the world. Both HIV and GBV-C show geographical variation – that is to say, the HIV that infects people in Iowa is not the same as the HIV that infects people in the Gambia, and the same goes for GBV-C. So one plausible explanation may be that different types of GBV-C have different biological effects.
Not wanting to send the room into an uproar, I didn’t ask the question that immediately sprung to my mind – when are we going to test GBV-C infection as a therapeutic intervention?
Lecturer in Microbiology, University of Nantes