HIV-1 plasma variants encoding truncated reverse transcriptase (RT) in a patient with high RT-specific CD8+ memory T-cell response.
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 in-frame 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 antigen-specific 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.
Servizio di Virologia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Stefania
S
Paolucci
Andrea
A
Foli
Roberto
R
Gulminetti
Sandra A
SA
Calarota
Renato
R
Maserati
Fausto
F
Baldanti
Giuseppe
G
Gerna
D000328:Adult; D000595:Amino Acid Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D018389:Codon, Nonsense; D015658:HIV Infections / Q000276:immunology* / Q000821:virology*; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D007156:Immunologic Memory; D008297:Male; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA
D018389:Codon, Nonsense; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase