HIV infection is one of the major global health problems of our times and one of the main priority research areas in EU policy for the FP6 program. Although natural immune control of HIV infection can occur, vaccine development has been hindered by difficulties in identifying what immune responses need to be induced. HIV-specific cytotoxic T lymphocyte (CTL) activity plays a central role in control of HIV.
Thus, great variability exists between different CTL in their effectiveness. Recent studies have shown that MHC class I alleles (such as HLA-B57 in HIV infection) are associated with very successful control of viral replication. The dominant epitope targeted by B57-positive subjects is a peptide in p24 Gag, sequence TSTLQEQIAW (Gag residues 240-249), and in the great majority of cases the virus escapes recognition by CTL as a result of a mutation at residue 242 from ThrAsn (T242N).
However, control of HIV is still maintained well. Subsequent works of Dr. Prado has shown that a contributing factor to this sustained control of HIV by B57-positive subjects is the fact that this T242N mutation inflicts a cost to viral replicative capacity. Thus, immune control of a now attenuated HIV is achieved more readily by remaining B57-restricted CTL responses.
These studies together with further preliminary work indicate the importance of this mechanism of immune control. The main objectives of the proposal will be: to define further the CTL responses that are effective in control of HIV, and to explore the escape mutation s that inflict a significant cost to viral replicative capacity.
These objectives will be achieved with the incorporation of Dr Prado to the host institution to integrate her previous knowledge into a new research field. This information will be of direct relevance to vaccine design, and these data will indicate which CTL responses need to be induced by a vaccine.
Call for proposal
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