3. Viral pathogenesis and correlates of protection

Quality of CD8+ T cell reponses contributes to control of viral replication

Analyses performed in the past in collaboration with Dr. Harrer and Dr. Walker indicated that long-term non-progressing individuals (LNTP) display CTL activities that are primarily directed towards highly conserved epitopes. Given that these epitopes overlap protein domains, which catalyze essential steps during virus replication, one could assume that the opportunities of the virus to escape immune control by establishing single point mutations in such a domain are fairly limited. This hypothesis was largely confirmed by establishing - based on the specificities of CTL clones derived from an LTNP individual - 19 proviral mutants, in which the optimal nonameric epitope was stepwise substituted by related or non-related amino acids. Most of the generated mutants showed severe defects in their replicative capacity due to negative interference with an important step during virus assembly and disassembly process. Those variants, however, that still replicated to wildtype-levels were efficiently recognized and killed by the LTNP's CTL clones. This clearly suggests that HIV vaccines should try to focus CD8+ T cells to highly conserved epitopes while considering the frequencies of HLA haplotypes in a given cohort as defined above.

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