Basis of HIV resistance suggests new vaccine strategy

A few people remain HIV negative despite continuous exposure to the virus. Findings published this week reveal that this may be because their immune response involves cytotoxic T lymphocytes (CTL) against epitopes not recognised by most infected people.

“The fact that infected and protected women focus their CTL response on different HIV epitopes could be a significant finding for vaccine development”, says lead author Rupert Kaul (Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK).

Kaul’s team studied the immune responses of sex workers in a slum in Nairobi, Kenya. These women have more than 60 unprotected sexual encounters with HIV-positive men a year. Women new to the group show high rates of seroconversion in the first year, but some remain seronegative for 3 years and longer. The immune responses of 91 seronegative sex workers from the cohort were compared with those seen in 87 HIV-positive sex workers. The two groups of women both mounted HIV-1 specific CTL responses-but often against a completely different set of epitopes. A few women who remained HIV negative for several years before seroconverting showed a switch in response from one set of epitopes to the other (J Clin Invest 2001; 107: 341-49).

“Although these results are exciting, the only way to demonstrate a true causal relationship between CTL responses and HIV protection is to induce these CTL in the setting of a vaccine trial”, says Kaul. Phase I testing of a vaccine developed by Andrew McMichael of the Weatherall Institute, is underway in Oxford and Nairobi. “The vaccine in this trial does include the seronegative-specific epitopes, as well as epitopes known to induce a strong CTL response in HIV-positive workers.”

“This paper breaks new ground by identifying immune responses to specific CTL epitopes that may actually be involved in protection against HIV infection. Previous attempts to develop CTL-inducing vaccines basically assumed that any CTL response could be protective”, says Jose Esparza, coordinator of the WHO-UNAIDS HIV Vaccine Initiative. Kaul stresses that any future vaccine effort that attempts to elicit protective CTL responses should take into account the clade of HIV prevalent in the area to be targeted, and also should include epitopes tailored to the distribution of HLA types in the population. “The HLA types in Kenya have not been extensively studied but we are finding them to be quite different to those mapped elsewhere”, says Kaul. Esparza agrees but cautions that “this would be particularly challenging in Africa, where both the genetic variability of the virus and of the host population is the largest”.

Within 1-2 years, Esparza expects interim results from the first HIV-vaccine phase III efficacy trial-the rgp120 HIV vaccine is being tested in the USA and Thailand. “We do not know how effective that vaccine will be, or whether it will be effective at all. It may be prudent to prepare for the worst and to consider the use of a low efficacy vaccine while research continues to develop more effective products”, he says.