New approach to HIV vaccine development
One strategy being pursued for HIV vaccine development is to induce virus-specific CD8 T cell responses to mediate control of HIV replication. HIV can evade T cell control by mutating, so it may be advantageous for vaccines to induce responses from which little escape occurs. However T cell escape mutations can also limit HIV’s replication capacity (termed viral fitness), so responses that drive mutations with high fitness costs may also be beneficial. The EU-funded project UNFITHIV (Understanding the importance of viral fitness impairment after transmission of HIV: Implication on HIV vaccine design) explored how the fitness of the infecting virus and reductions in viral fitness caused by T cell escape mutations affect the outcome of HIV infection. Nine acutely-infected individuals controlling infection either well or poorly were studied to allow analysis of the relationship between T cell responses, viral fitness and disease prognosis. UNFITHIV found that there was a trend for individuals controlling infection well to be infected with viruses of lower fitness. Further results suggested that induction of a broad primary HIV-specific T cell response, escape from which occurred slowly and/or incurred high costs to viral fitness, was also associated with good viral control. This emphasises the need for vaccines to elicit a breadth of T cell responses to conserved viral epitopes, any escape from which will reduce viral replication capacity. The project partners also tested the hypothesis that CD8 T cells recognise novel epitopes derived from the terminal regions of the HIV genome. While these regions were previously considered to be untranslated, the founder virus sequence was found to be rapidly mutating there over time, and some of these mutations were shown to be driven by T cell responses. The project thus identified the terminal regions of the HIV-1 genome as a novel source of CD8 T cell epitopes that could be targeted in vaccine design to increase response breadth and efficacy.
