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Project B3: Nina Böhmer, doctoral researcher (PhD)

Development of strategies to counteract Vpu- and Nef-mediated immune evasion of HIV-1

Cure of HIV infection implies the eradication of viral reservoirs emerging from HIV latency. Since CTLs are the most effective cells for the elimination of viral infections, induction of strong HIV-1 -specific CTL responses has to be considered for HIV-1 eradication strategies. However, HIV-1 developed varying mechanisms to evade the hosts CTL immune response such as the regulatory viral molecules Vpu and Nef. Nef downregulates HLA-A/B from the cell surface, thereby decreasing the presentation of viral peptides to CTLs. Since HLA-C molecules are important inhibitory ligands for NK-cells, HLA-C is not downregulated by Nef to avoid NK-cell mediated killing of infected cells. Nevertheless, as a subgroup of patients also exhibit strong HLA-C – restricted CTL responses, HIV-1 has developed a Vpu-mediated mechanism for HLA-C downregulation from the surface of HIV-1 infected cells. Vpu and Nef-mediated immune evasion may therefore explain the failure of T-cell based vaccines in prevention of HlV-1 infection and improved viremia control.

HLA-I downregulation capacity was shown to vary depending on the Nef/Vpu genes in individual patients. We hypothesize that strong pressure by HLA-C-restricted CTLs selects HLA-C-downregulating Vpu variants, whereas a strong NK-cell response should favour Vpu variants that do not affect HLA-C-expression. Accordingly, we are evaluating the relation between Vpu sequence mutations, NK cell activity and CTL responses. Furthermore, we assume that there are HLA-C-restricted peptides that are still recognized by CTL despite the presence of HLA-C-downregulating Vpu variants. For that reason, we will investigate whether the recognition of “resistant” epitopes by CTLs negatively affects HIV-1 replication and course. The induction of Vpu-and Nef-“resistant” CTLs, characterized by high affinity binding and efficient peptide processing, and the pharmacological inhibition of Nef and Vpu should improve the elimination of HIV-infected cells by CTL.