A single mutation in HIV was enough to undermine the protection of an HIV vaccine that had apparently controlled HIV infection in a monkey for six months, raising fears that current vaccines which focus on orchestrating killer T-cell responses to control HIV after infection has occurred may not be enough, faced with HIV’s phenomenal mutation rate.
Eight monkeys were given a vaccine designed to elicit cytotoxic T-lymphocyte responses to specific regions of HIV’s gag gene in experiments at Harvard University. After they had developed responses, the animals were exposed to a highly pathogenic SHIV (see What animals say about vaccines for background on this study).
Infection took place in all cases, but virus levels remained low or became undetectable. However, one monkey subsequently suffered a shift in its virus population, became sick and died within six months of initial infection. The shift was enough to ensure that the main killer T-cell population produced in response to the vaccine was no longer able to control infection, and other T-cell responses were unable to make up for this.
This is a potential setback to prospects for such vaccines, although as Dr Norman Letvin of Harvard observes, "The cup is seven eighths full, not one eighth empty."
The vaccine used was a naked DNA vaccine, which means that a portion of HIV gag DNA was injected into the animals. In this case it was combined with a human growth factor chosen to stimulate immune responses.
In comparison, an approach boosting a DNA vaccine with a common cold virus vector, both including a portion of the gag gene, has proved successful in maintaining viral load at undetectable levels for more than 500 days in monkey studies carried out by Merck. Results from this study were first reported at last year’s Keystone meeting and published in this week’s edition of Nature
Some experts believe that vaccines which contain a small number of epitopes may be more prone to breakthroughs of the kind reported by the Harvard team. There is evidence from studies of people with HIV to show that the number of different epitopes recognised by their killer T cells correlates with survival. Researchers aiming at vaccines to stimulate cellular immunity are currently agreed that it is likely to need more than gag genes to get a broad enough range of response to be useful
References
Shiver, J. W. et al. Replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity. Nature 415: 331 - 335, 2002.
Barouch, D. H. et al. Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes. Nature 415: 335 - 339, 2002.