Étude de l’évolution du tropisme et de la pression sélective exercée sur le gène de l’enveloppe du virus de l’immunodéficience humaine de type 1 au cours de la grossesse et à l’échelle de la population

Introduction. HIV-1 evolves as a function of the immune specific response of the host. The selective pressure exerted by HIV-specific immune responses lead to the evolution of the viral genes and ultimately determine the evolution of the disease. HIV evolution at the individual level also shapes the evolution of the virus the population level and determines the future of the epidemic. HIV enters the target cell via CCR5 (R5 viruses) or CXCR4 (X4 viruses) coreceptors, and switch of tropism from R5 to X4, is associated with progression disease. Indeed, R5 virus characterize earlier stages of infection while X4 emerge at later disease stages in some patients and are considered more virulent. The immune pressures exerted on the envelope gene (env) can therefore cause HIV coreceptor switch. Pregnancy is considered a particular immune state mainly characterized by a Th2 bias necessary for the establishment of materno-fetal tolerance. Tropism switch from R5 to X4 during pregnancy has never been documented, and changes in the determinants of tropism during the HIV epidemic at the population level have never been reported. Hypotheses. Immune changes associated with initiation and progression of pregnancy generate changes in the immune pressure exerted on env and may influence coreceptor tropism switch. The evolution HIV-1 coreceptor tropism can be observed at the population level as well as the evolution of the viral envelope. Objectives. Analyze the evolution of tropism and describe the selective pressure on the envelope of pregnant women infected with HIV-1. Analyze the evolution of the determinants of tropism in at the population level. Methods. We first analyzed the evolution of determinants of tropism and determined the genotype and phenotype of HIV-1 in 19 pregnant women from centre maternel et infantile sur le SIDA de l’hôpital Sainte-Justine (CMIS). We then characterized and compared the selective pressure on env, using a Bayesian method, in 31 pregnant and 29 non-pregnant women. Finally, we analyzed and compared the determinants of tropism between contemporary and early envelope sequences retrieved from the NCBI databases. Results. Our results show the presence of X4 virus in half of our cohort, and R5 to X4 tropism switch in 5/19 subjects. Higher substitution rates were found in sequences from pregnant women as compared to sequences from non-pregnant subjects. Selective pressure in the C2 region was lower in pregnant than in non-pregnant women, and differed in 4 positions between these 2 groups. This selection decreased during pregnancy in patients who received antiretroviral therapy. Finally, accumulation of X4 mutations was observed in contemporary R5 sequences compared to early R5 sequences. Conclusion. Immune changes that are associated with pregnancy appear to induce subtle changes in selective pressures in env, changes that may influence the evolution of tropism towards X4. Switch of tropism at the population level would imply an evolving epidemic towards greater virulence. Our results are of importance regarding antiretroviral prophylaxis for the health of the mother and for the prevention of mother-to-child transmission of HIV-1. These results are also important for the future of antiretroviral therapy in the context of evolving epidemic

Keyphrases: HIV-1, Pregnancy, Selective pressure, Tropism, Human immunodeficiency virus, Genetic evolution, Coreceptor tropism