Estimating the Timing of Mother-to-Child Transmission of the Human Immunodeficiency Virus Type 1 Using a Viral Molecular Evolution Model

Background: Mother-to-child transmission (MTCT) is responsible for most pediatric HIV-1 infections worldwide. It can occur during pregnancy, labor, or breastfeeding. Numerous studies have used coalescent and molecular clock methods to understand the epidemic history of HIV-1, but the timing of vertical transmission has not been studied using these methods. Taking advantage of the constant accumulation of HIV genetic variation over time and using longitudinally sampled viral sequences, we used a coalescent approach to investigate the timing of MTCT. Materials and Methods Six-hundred and twenty-two clonal env sequences from the RNA and DNA viral population were longitudinally sampled from nine HIV-1 infected mother-and-child pairs [range: 277–1034 days]. For each transmission pair, timing of MTCT was determined using a coalescent-based model within a Bayesian statistical framework. Results were compared with available estimates of MTCT timing obtained with the classic biomedical approach based on serial HIV DNA detection by PCR assays. Results: Four children were infected during pregnancy, whereas the remaining five children were infected at time of delivery. For eight out of nine pairs, results were consistent with the transmission periods assessed by standard PCR-based assay. The discordance in the remaining case was likely confused by co-infection, with simultaneous introduction of multiple maternal viral variants at the time of delivery. Conclusions: The study provided the opportunity to validate the Bayesian coalescent approach that determines the timing of MTCT of HIV-1. It illustrates the power of population genetics approaches to reliably estimate the timing of transmission events and deepens our knowledge about the dynamics of viral evolution in HIV-infected children, accounting for the complexity of multiple transmission events

Mother-to-child transmission of the human immunodeficiency virus type 1 : role of neutralizing antibodies and molecular characteristics of the transmitted variants.

Ce travail a confirmé le rôle protecteur de certains anticorps neutralisants dans la TME du VIH-1, a permis de suggérer que certaines souches seraient de bons indicateurs d’anticorps neutralisants associés à la protection, et a confirmé le rôle de la région V2 de l’enveloppe virale en tant que cible des anticorps neutralisants. Les caractéristiques moléculaires des virus transmis dans le contexte de la TME confortent les données en faveur de la transmission à l’enfant d’une population virale restreinte génétiquement. Une gp 120 plus compacte et une moindre glycosylation ne sont pas des caractéristiques des virus transmis de la mère à l’enfant. Cependant, deux sites de N-glycosylation semblent être sélectionnés chez les virus transmis. L’identification de deux cas de TME liés à des variants issus de recombinaisons entre variants maternels a confirmé la présence d’un « hot spot » dans la région C2 du gène env, et a révélé pour la première fois un second « hot spot » dans la région C3.A lower risk of MTCT was associated with higher NAb titers against the CRF01_AE strain, MBA, in Thailand. The results suggest that some primary isolates may be useful indicators for identifying protective antibodies, and confirm the role of the V2 region in neutralization. We found that only viruses of a restricted subset were transmitted to the infant. We did not find that shorter gp120 or fewer PNGS were characteristics of viruses transmitted from mother to infant. However, a limited number of PNGS, particularly at positions N301 and N384, may confer an advantage on the virus to be transmitted. Moreover, we identified two cases that suggest that recombination probably contributed to adaptation of HIV-1 to its environment to be successfully transmitted from mothers to their infants. In addition, our data allow both to confirm, in natural in vivo conditions, a hot spot for recombination in the C2 region of HIV-1 envelope gene, and to suggest another hot spot in the C3 region

Mother-to-child transmission of the human immunodeficiency virus type 1 (role of neutralizing antibodies and molecular characteristics of the transmitted variants.)

Ce travail a confirmé le rôle protecteur de certains anticorps neutralisants dans la TME du VIH-1, a permis de suggérer que certaines souches seraient de bons indicateurs d anticorps neutralisants associés à la protection, et a confirmé le rôle de la région V2 de l enveloppe virale en tant que cible des anticorps neutralisants. Les caractéristiques moléculaires des virus transmis dans le contexte de la TME confortent les données en faveur de la transmission à l enfant d une population virale restreinte génétiquement. Une gp 120 plus compacte et une moindre glycosylation ne sont pas des caractéristiques des virus transmis de la mère à l enfant. Cependant, deux sites de N-glycosylation semblent être sélectionnés chez les virus transmis. L identification de deux cas de TME liés à des variants issus de recombinaisons entre variants maternels a confirmé la présence d un hot spot dans la région C2 du gène env, et a révélé pour la première fois un second hot spot dans la région C3.A lower risk of MTCT was associated with higher NAb titers against the CRF01_AE strain, MBA, in Thailand. The results suggest that some primary isolates may be useful indicators for identifying protective antibodies, and confirm the role of the V2 region in neutralization. We found that only viruses of a restricted subset were transmitted to the infant. We did not find that shorter gp120 or fewer PNGS were characteristics of viruses transmitted from mother to infant. However, a limited number of PNGS, particularly at positions N301 and N384, may confer an advantage on the virus to be transmitted. Moreover, we identified two cases that suggest that recombination probably contributed to adaptation of HIV-1 to its environment to be successfully transmitted from mothers to their infants. In addition, our data allow both to confirm, in natural in vivo conditions, a hot spot for recombination in the C2 region of HIV-1 envelope gene, and to suggest another hot spot in the C3 region.TOURS-Bibl.électronique (372610011) / SudocSudocFranceF

Naturally occurring substitutions of conserved residues in human immunodeficiency virus type 1 variants of different clades are involved in PG9 and PG16 resistance to neutralization

International audienceThe recently described anti-human immunodeficiency virus type 1 (HIV-1) human mAb PG9 and PG16 are cross-clade broadly neutralizing. Therefore, it can be postulated that the targeted epitope(s) are highly conserved among variants of the entire group M. We analysed the sensitivity to PG9 and PG16 of pseudotyped viruses carrying envelope glycoproteins from the viral quasispecies of three HIV-1 clade CRF01_AE-infected patients. The broad heterogeneity in sensitivity to PG9 and PG16, despite closely genetically related envelope glycoproteins issued from single individuals, allowed us to identify two gp120 cross-clade conserved residues, a lysine at position 168 in the V2 loop and an isoleucine at position 215 in the C2 region, whose substitutions were associated with resistance to PG9 and PG16. By site-directed mutagenesis, we confirmed both in clades B and CRF01_AE that the substitutions K168E and I215M have a major impact on PG9 and PG16 neutralization sensitivity of pseudotyped viruses

Pairs sampling informations.

<p>IU: <i>in utero</i> transmission - IP: <i>intrapartum</i> transmission.</p