During replication, HIV-1 reverse transcriptase lacks proof reading activity and is error prone. In addition APOBEC-driven hypermutation of HIV-1 Gag and Pol genes may generate replication-deficient viral variants with inframe stop codons. Virus variants with several stop codons in the RT gene were identified in a subject with residual HIV- 1 replication during antiretroviral treatment. A role for the T-cell response in the selection of replication-deficient variants was hypothesized. Clonal analysis of HIV-1 DNA and RNA sequences from three sequential blood samples was performed. Moreover, the HIV-1-specific memory CD8+ T-cell response was investigated using a peptide-based cultured ELISPOT assay. The accumulation of HIV-1 variants with stop codons in the Pol gene (from 0% to 100%) was observed in sequential plasma samples. The cultured ELISPOT showed a sustained response to a Pol region downstream from the last stop codon. A more detailed analysis of the Pol region encompassing the detected stop codons showed a strong response to a peptide at the end of the RT region containing stop codons (positions 206 to 220) and including the last stop codon (212). These results suggest a role for a peptide-specific immunologic response in the positive selection of cells expressing the truncated HIV-1 RT and the accumulation of replication-deficient viral variants in plasma. The antigenspecific CD8+ T-cell response could be exploited to redirect the response to HIV-1 infection toward in vivo selection of viral variants with reduced or abolished pathogenicity.