Impact de la variabilité génétique sur l'antigénicité et l'immunogénicité des glycoprotéines d'enveloppe d'isolats de HTLV-1 d'origines géographiques différentes

Les glycoprotéines d'enveloppe du rétrovirus HTLV-1 (Human T-Cell Leukemia Virus type 1), essentielles dans l'étape d'infection et très immunogènes, représentent une possible cible vaccinale. L'impact de leur variabilité génétique sur leurs fonctions est analysé par l'étude génétique et sérologique d'isolats HTLV-1 de patients d'origine géographique différente. L'analyse phylogénétique de la totalité du gène env de 62 nouveaux isolats et de souches PTLV-1 permet d'individualiser de nouveaux groupes africains. Un nouveau sous-type Maroni émerge entre les sous-types majeurs cosmopolite et d'Afrique centrale. La réactivité des sérums de patients vis-à-vis de peptides synthétiques, montre que la région 273-295 est immunodominante et comporte des épitopes linéaires et conformationnels dont certains neutralisables, identifiés par l'inhibition de la formation de syncytia. L'acide aminé H ou Y en position 290 modifie la capacité neutralisante des sérums et l'immunogénicité de l'enveloppe.The highly immunogenic HTLV-1 (Human T-Cell Leukemia Virus ttype 1) envelope glycoproteins play a critical part in the initial infection step and represent a possible vaccinal target. The ffect of their genetic variability on their functions is analysed by a genetic and serologic study of HTLV-1 isolates of patients from different geographic origin. The phylogenetic analysis of the total env gene from 62 new isolates and PTLV-1 strains allowed to identify new African groups. A new "Maroni" subtype is individualized, emerging between major cosmopolitan subtypes and subtypes from Central Africa. The reactivity of patients sera was tested against synthetic peptides. This study demonstrate that the 273-295 region is immunodominant and includes linear and conformational epitopes. Some of them induce neutralizing antibodies which inhibit syncitia formation. The amino acid H or Y in 290 position modifies the sera neutralizing activity and the envelop immunogenicity.BORDEAUX2-BU Santé (330632101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Transmission of HIV-1 minority-resistant variants and response to first-line antiretroviral therapy.: Transmission of minority resistant HIV-1

International audienceBACKGROUND: The transmission of drug-resistant HIV-1 can impair the virological response to antiretroviral therapy. Minority-resistant variants have been detected in acute seroconverters. We investigated the clinical relevance of the detection of majority and minority-resistant variants in an observational study in antiretroviral therapy naive, recently infected patients. METHODS: We included patients infected between 1996 and 2005, with a plasma sample obtained less than 18 months after seroconversion and prior to antiretroviral therapy initiation. Majority-resistant variants were determined by direct population sequencing. Minority-resistant variants were searched by allele-specific PCR for the mutations K103N and M184V in reverse transcriptase and L90M in protease. The association between resistance and viroimmunological response to antiretroviral therapy was estimated by using a piecewise linear mixed model. RESULTS: Majority-resistant variants were detected in 23/172 (13.4%) patients. Patients with majority-resistant variants had a lower mean plasma viral load and higher mean CD4 cell count at baseline compared with those without resistance. The decrease in viral load between 1 and 6 months on antiretroviral therapy was significantly steeper in patients with sensitive viruses compared with those with majority-resistant variants (P = 0.029). Minority-resistant variants were detected in 21/73 (29%) patients with wild-type viruses at sequencing analysis. The presence of minority-resistant variants did not modify baseline viral load and CD4 cell count and did not affect the changes in viral load and CD4 cell count. CONCLUSION: The transmission of majority-resistant variants, but not minority-resistant variants, influenced the response to antiretroviral therapy in this prospective study. The detection of the transmission of minority-resistant variants warrants further clinical validation