Characterization of HIV excape mutants and T cell responses in elite suppressors

Johns Hopkins University, Baltimore MD

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Abstract

Elite suppresors are HIV-1 infected patients who mantain viral loads of <50 copies/ml without antiretroviral therapy. We have recently shown for the first time that replication competent virus can be isolated from some of these individuals suggesting that immunologic control of replication competent HIV-1 is possible. Interestingly, we have also shown for the first time that low levels of virus are present in the plasma of these individuals. We demonstrated a striking discordance between the sequence of gag in plasma versus resting CD4+ T cells. Substitutions in T cell epitopes were found in all clones amplified from the plasma, but were rare in clones amplified from the resting CD4+ T cells. Immunologic analyses has confirmed that these substitutions are escape mutations which develop as a response to the strong selective pressure exerted by HIV-1 specific CD8+ T cells. In spite of these escape mutations, the virus does not replicate at a high enough level for the viral load to exceed more than 50 copies/ml. The objective of this proposal is to determine the mechanisms by which immunolgic control of this replication competent virus is achieved. The complete HIV-1 proteome will be analyzed for T cell epitopes and the sequences of these epitopes in plasma and resting CD4 T cells will be analyed to help determine whether some critical epitopes remain unmutated. This could potentially explain why immune control is achieved even though escape mutations occurs at some epitopes. An alternative hypothesis is that viral fitness is greatly reduced by the presence of escape mutations. This will be tested by the construction of recombinant HIV-1 containing sequences from isolates obtained from plasma. The replication capacity of these isolates will be compared to that of wild type virus. Finally we will compare the ability of peptides representing wild type epitopes and escape mutants to induce several aspects of T cell activation including cytokine secretion, proliferation and gene transcription. This well help define the immune correlates of protection in HIV-1 disease. This work will be important for the development of vaccines that can be used to improve the HIV specific immune responses in HIV-1 infected individuals. This may allow some patients to control the virus without antiretroviral therapy for prolonged periods of time.