Antiretroviral drug resistance mutations sustain or enhance CTL recognition of common HIV-1 Pol epitopes

Antiretroviral drug resistance and escape from CTL are major obstacles to effective control of HIV replication. To investigate the possibility of combining drug and immune-based selective pressures against HIV, we studied the effects of antiretroviral drug resistance mutations on CTL recognition of five HIV-1 Pol epitopes presented by common HLA molecules. We found that these common drug resistance mutations sustain or even enhance the antigenicity and immunogenicity of HIV-1 Pol CTL epitopes. Variable patterns of cross-reactive and selective recognition of wild-type and corresponding variant epitopes demonstrate a relatively diverse population of CD8(+) T cells reactive against these epitopes. Variant peptides with multiple drug resistance mutations still sustained CTL recognition, and some HIV-infected individuals demonstrated strong CD8(+) T cell responses against multiple CTL epitopes incorporating drug resistance mutations. Selective reactivity against variant peptides with drug resistance mutations reflected ongoing or previous exposure to the indicated drug, but was not dependent upon the predominance of the mutated sequence in endogenous virus. The frequency and diversity of CTL reactivity against the variant peptides incorporating drug resistance mutations and the ability of these peptides to activate and expand CTL precursors in vitro indicate a significant functional interface between the immune system and antiretroviral therapy. Thus, drug-resistant variants of HIV are susceptible to immune selective pressure that could be applied to combat transmission or emergence of antiretroviral drug-resistant HIV strains and to enhance the immune response against HIV.