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Association Between Plymorphisms in HIV-1 C POL and Particular Host MHC Alleles. Impace on Antiretroviral Therapy Efficacy F. Doualla-Bell1-3, S. Gaseitsiwe3, T. Ndung’u3, T. Peter3, V. Novitsky4, , W. Wester 3, H. Bussman 3, A. Avalos3, N. Ndwapi2, T. Gaolathe 2, H. Moffat2, R. Marlink4, M. A. Wainberg1 and M. Essex4. 3Botswana-Harvard Partnership for HIV Research and Education, 2Infectious Disease Care Clinic; Princess Marina Hospital, Gaborone, Botswana. 4Harvard School of Public Health, Boston, Massachusetts. 1McGill University-AIDS Centre, Lady Davis Institute for Medical Research -Jewish General Hospital-SMD, Montreal, Quebec, Canada Background Since January 2002, HIV-1 infected Batswana have had access to highly active antiretroviral therapy (HAART) within the public health system. To evaluate the performance of therapy in this unique African situation, where HIV-1 subtype C is predominant, we have started this study whose main objectives are 1) the study of polymorphisms prior to therapy and the patterns of mutations under drug treatment in RT gene 2) the determination of any association existing between RT polymorphisms and mutations and the absence or presence of specific major histocompatibility complex (MHC) alleles. Methods We retrospectively analyzed 17 patients (six ARV-naïve and eleven treated patients) followed at the Infectious Disease Care Clinic (IDCC) of Princess Marina Hospital (Botswana) between May 2001 and January 2003. Among the eleven ARV-treated patients, 5 started a highly active antiretroviral therapy (HAART) regimen containing ddI/d4T/NVP (4/5 failed) while the 6 others started a CBV/EFV regimen (1/6 failed). At first sign of viral rebound the pol gene of HIV was sequenced and analyzed for the presence of resistance mutations (Viroseq, Applied Biosystems). Sequence-specific primer technique was used to determine the HLA class II specificities using sequencing-based typing kit (Applied Biosystems, SA) Results Among the 11 treated patients, only one was non adherent and 5 failed their first line regimen (4 under ddI/d4T/NVP and 1 under CBV/NVP). A lot of polymorphisms including E291D, L214F, R211K, V245Q and V292I were detected in both groups while primary mutations associated to NNRTI and NRTI resistance: K103N (2/5), Y181C (4/5), K65R (2/5), T69D (1/5), M184V (2/5), V106M (1/5), T215Y and M230L (1/5), were only observed in the 5 treated patients presenting with clinical failure. The absence of the I135V polymorphism in RT has also been noticed in the 5 failing patients while it was present on the RT gene of unfailed patient taking CBV/NVP since 1 year. Finally, the V106M mutation (specifically associated with EFV resistance in HIV-1C), has been found in two patients taking EFV and was co-present with the P272X polymorphism. Three of the 5 failing patients taking ddI/d4T/NVP expressed DRB13 and DRB3*02 HLA alleles. Interestingly, these 3 patients did not experience a recovery of CD4 count above 101+69.8 cells/ml after one year treatment. For two of them the presence of these HLA alleles was associated with the presence of the K166R polymorphism. Conclusion These results taken together with recent published data indicate possible correlation between specific HLA alleles, and the presence of certain polymorphisms in pol including drug resistance mutations. Although these data are preliminary, further studies may lead to optimization of ARV therapy management in countries such as Botswana with little prior experience with HAART. |