Treffer: The impact of HAART initiation on the selection and persistence of HIV-1 CTL-escape mutations

The impact of HAART initiation on the selection and persistence of HIV-1 CTL-escape mutationsD.A. Dilernia,1 D.C. Monaco,1 L.R. Jones,2 G.D. Damilano,1 S. Rodriguez,3 H. Salomon11Argentinean Reference Center for AIDS, Capital Federal, Argentina;2División de Biología Molecular, Estación de Fotobiología, Playa Unión, Rawson, Chubut, Argentina; 3INTA, Castelar, Buenos Aires, ArgentinaBackground: Immune response drives the selection of CTL escape mutations during the course of HIV infection. After initiation of HAART, antiviral drugs exert a strong selective force leading to an important limitation of viral replication. Our objective was toevaluate the impact of HAART initiation on the selection and persistence of CTL-escape mutations.Methods: Blood samples were collected from 113 newly HIV diagnosed individuals. A second sample was collected from 49 of them after 3 years. (12 of which were still drug-naı¨ve in the second sample). Dynamics of CTL-escape mutations identified in the gaggene by statistical analysis of HLA genes and viral sequences, including multiple comparison corrections (BH method) and phylogeny correction (Bayesian MCM method), were analyzed. Epitope-specific immune response was evaluated by ELISPOT against sequence-based designed peptides.Results: Immune response was evaluated on 113 individuals on an HLA-allele basis. Positive responses were detected against 6 of the 9 epitopes containing HLA-associated CTL-escape mutations.A03-restricted epitope RLRPGGKKK had the highest frequency of detection in allele-matched individuals (75%). Epitopes harboring the CTL-escape mutations identified through negative associations (i.e. escape is consensus) had lower frequency of detection: A02-restricted SLYNTVATL(25%) and A24-resctricted KYKLKHIVW(0%). Epitope sequences analysis over the second sample of 21 patients successfully sequenced showed that 38% of them did not have evidence of escape neither in the first sample nor in the second, 44% had the escape mutations in both samples and in 18%the escape mutations appeared in the second sample. Of the 7 individuals containing the epitopes of the last group, only 2 had initiated HAART (28.6%) while 64.3% (9/14) of individuals where no escape emerged, had initiated HAART.Conclusion: Accumulation of CTL-escape mutations at the population-level impaired recognition by individuals studied while initiation of HAART may prevent the selection of new escape mutations even in advanced stages of infection.