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 mutations
D.A. Dilernia,1 D.C. Monaco,1 L.R. Jones,2 G.D. Damilano,1 S. Rodriguez,3 H. Salomon1
1Argentinean Reference Center for AIDS, Capital Federal, Argentina;
2División de Biología Molecular, Estación de Fotobiología, Playa Unión, Rawson, Chubut, Argentina;
3INTA, Castelar, Buenos Aires, Argentina

Background: 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 to
evaluate 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 gag
gene 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.