Samri A, Haas G, Duntze J, Bouley JM, Calvez V, Katlama C, Autran B; Conference on Retroviruses and Opportunistic Infections.

Program Abstr 8th Conf Retrovir Oppor Infect Conf Retrovir Oppor Infect 8th 2001 Chic Ill. 2001 Feb 4-8; 8: 90 (abstract no. 165).

Hosp Pitie-Salpetriere, Paris, France.

Background: Our purpose was to investigate the consequences of drug resistance mutations appearing during nucleoside and non-nucleoside reverse transcriptase (RT) inhibitor (NRTI and NNRTI) therapies on cytotoxic T lymphocyte (CTL) recognition. Methods: Two truncated RT regions (RT-1: 1-143 and RT-2: 143-293), containing sites of mutations, were tested on Pol-specific CTL lines in treated patients. Mutations were evaluated in these patients' samples. Predicted epitopes overlapping mutations induced by NRTI and NNRTI were defined by computer analysis combining the RT sequence and HLA class I molecules and were subsequently tested in an IFN- gamma assay for ex vivo CD8 cell recognition. Results: The regions RT-1 and RT-2 were more frequently recognized in mutated samples (80%) versus in unmutated samples (38%). Forty-one epitopes overlapping these mutations were defined. The HLA-binding scores were increased by these mutations in 42% and decreased in 12%, while scores remained unchanged in 46% of cases. Moreover, 12 drug resistance mutations induced by NNRTI localized in RT-1 and RT-2 were studied in the context of 33 HLA class I molecules. 192 epitopes overlapping these mutations were predicted. NNRTI-induced mutations enhanced HLA-binding scores in 24% and decreased them in 33%, while scores remained unchanged in 43% of cases. Four of five predicted epitopes around NRTI-induced mutations were recognized in an ELISPOT assay, with frequencies of IFN-gamma spot-forming cells ranged between 40 and 270 per 10(6) PBMC, similar to known CTL epitopes in RT. Frequencies of CD8 cells directed against wild-type or mutated peptides were in accordance with the HLA-binding score changes. The CTL recognition of NNRTI resistance mutations is in progress. Conclusions: The occurrence of NRTI mutations frequently increases the immunogenicity of the mutated RT, while NNRTI might have either no effect or some deleterious effect. These findings suggest that the immune control of mutated viruses should be affected differently by these two classes of RT inhibitors.

Publication Types:

• Meeting Abstracts

Keywords:

• CD8-Positive T-Lymphocytes
• Genes, pol
• HIV-1
• Humans
• Mutation
• Nucleosides
• RNA-Directed DNA Polymerase
• Reverse Transcriptase Inhibitors
• T-Lymphocytes, Cytotoxic
• genetics

Other ID:

• GWAIDS0006450

UI: 102243946

From Meeting Abstracts