AEGiS-11IAC: Evolution of HIV-1 reverse transcriptase specific cytotoxic T cells (CTL) with disease progression and anti-retroviral therapy.

11th International AIDS Conference

Vancouver, British Columbia — July 7-12, 1996

Evolution of HIV-1 reverse transcriptase specific cytotoxic T cells (CTL) with disease progression and anti-retroviral therapy.

Int Conf AIDS 1996 Jul 7-12; 11:223 (abstract no. Tu.A.282)
Haas G, Hosmalin A, Duntze J, Samri A, Magierowska M, Katlama C, Kraas W, Jung G, Agut H, Debre P, Autran B; Laboratoire d'lmmunologie Cellulaire et Tissulaire, Paris, France. Fax: (33 1) 42 17 74 90. E-mail: ghaas@ccr.jussieu.fr.

OBJECTIVE: To determine whether CTL recognition of HIV-1 reverse transcriptase (RT) is maintained with disease progression and influenced by naturally occurring and anti-retroviral induced viral mutations

METHODS: The evolution of HIV-specific CTL responses was followed-up over three years in a cohort of 50 patients (CD4+ counts: 1050-150/mm3) after stimulation using autologous irradiated PHA blasts or specific peptides. 28 patients responding to Pol were tested on recognition of 4 truncated Pol subregions and synthetic peptides. MHC-peptide interactions were measured by standard HLA stabilisation assays and mutations occurring in the viral sequences of 3 patients were detected by selective nested PCR.

RESULTS: CTL specific for the structural proteins Pol, as well as Env and Gag of the reference strain HIV-1 LAI were detectable in 80% of the patients at all stages of the infection. The NH2-half of the RT was recognized by 79% and the COOH-half by 54% of the patients tested. Interestingly, at more advanced stages of disease, when CD4+ counts decreased less than 200/mm3 or in patients, that received antiretroviral therapy (11 patients), CTL were rather directed to the conserved COOH-half of the molecule than to the more variable NH2-half (N-term: 18% versus C-term: 72% of patients). When studying 2 progressors over a three years time period, we observed a shift of RT recognition from the N-terminal epitopes in region pol 359-383 towards C-terminal ones in region 677-710. However, using peptide-specific restimulations, CTL precursors specific for pol 359-383 could still be expanded in vitro. CTL responses and MHC-peptide interactions in epitopes located at pol 346-354, 368-376 as well as for pol 476-484, 588-596 645-653, 681-691, 695-707 and 695-716, were characterized. To investigate whether viral mutations that induce resistance to antiretroviral drugs may cause CTL inefficiency, the impact of such mutations (namely at RT 184 and RT215) on peptide recognition was studied. In some epitopes HLA binding and CTL recognition seemed to be abrogated by viral mutations, while for others specific precursors could still be detected.

CONCLUSIONS: Our data suggest that CTL recognition of HIV-1 RT is maintained with disease progression despite shifts in immunodominance, but expansion of CTL specific for viral mutants before initiation of antiretroviral therapy may avoid the emergence of drug resistance thus opening perspectives for immunotherapy.

Keywords: AEGIS, HIV-1 Reverse Transcriptase, T-Lymphocytes, Cytotoxic, Disease Progression, HIV-1, HIV Antigens, CD4 Lymphocyte Count, Epitopes, HIV Infections, HIV Protease, HIV, HIV Long-Term Survivors, Peptides, Evolution, HIV Integrase, HLA Antigens, Major Histocompatibility Complex, In Vitro, Human, immunology, genetics, ICA11

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TuA282