Diversity of the Human Immunodeficiency Virus Type 1 (HIV-1) env Sequence after Vertical Transmission in Mother-Child Pairs Infected with HIV-1 Subtype A

Document Type

Article

Department

Obstetrics and Gynaecology (East Africa)

Abstract

Although several virologic and immunologic factors associated with an increased risk of perinatal human immunodeficiency virus type 1 (HIV-1) transmission have been described, the mechanism of mother-to-child transmission is still unclear. More specifically, the question of whether selective pressures influence the transmission remains unanswered. The aim of this study was to assess the genetic diversity of the transmitted virus after in utero transmission and after peripartum transmission and to compare the viral heterogeneity in the child with the viral heterogeneity in the mother. To allow a very accurate characterization of the viral heterogeneity in a single sample, limiting-dilution sequencing of a 1,016-bp fragment of the env gene was performed. Thirteen children were tested, including 6 with in utero infections and 7 with peripartum infections. Samples were taken the day after birth and at the ages of 6 and 14 weeks. A homogeneous virus population was seen in six (46.2%) infants, of whom two were infected in utero and four were infected peripartum. A more heterogeneous virus population was detected in seven infants (53.8%), four infected in utero and three infected peripartum. The phylogenetic trees of the mother-child pairs presented a whole range of different tree topologies and showed infection of the child by one or more maternal variants. In conclusion, after HIV-1 transmission from mother to child a heterogeneous virus population was detected in approximately one-half of the children examined. Heterogeneous virus populations were found after peripartum infection as well as after in utero infection. Phylogenetic tree topologies argue against selection processes as the major mechanism driving mother-to-child transmission but support the hypothesis that virus variability is mainly driven by the inoculum level and/or exposure time. Transmission of human immunodeficiency virus type 1 (HIV-1) from an infected mother to her child can occur in utero, during birth, or postnatally through breast milk and is the main source of pediatric HIV-1 infection. Antiviral therapy during pregnancy and delivery, combined with elective caesarean section and replacement feeding, has been shown to reduce the incidence of HIV-1 transmission to less than 2% (15). Despite this success and although many factors that affect mother-to-child transmission are known, the exact mechanism remains unclear, and a thorough scientific base to further improve both therapeutic and preventive interventions is missing. Most molecular-variability studies of recently infected individuals, adults as well as children, have shown that the majority of recent infections are characterized by the presence of highly homogeneous virus (26, 31). This contrasts with the extensive genetic diversity seen in chronic infections (4, 23). These observations led to the assumption of selective transmission of HIV-1. Already in 1993 Zhu et al. (32) proposed three possible models for selective transmission: selective penetration, selective amplification, and low inoculum level; but it is still unclear which of these models is applicable. Selective transmission is definitely not the overall rule. Several cases of recent infections with a heterogeneous virus population have been described (20). One recent study of adults suggested gender-related differences in HIV-1 diversity at the time of infection, with women being more often infected with a heterogeneous population than men (14). The number of infants found to harbor a heterogeneous virus population compared to the number found to be infected with homogeneous virus varies from study to study, with heterogeneous infection/homogeneous infection ratios of 0/7 (1), 3/1 (3), 6/17 (6), 2/1 (12), 1/3 (19), 2/8 (24), 3/2 (28), and 0/3 (29). This results in an overall incidence of a heterogeneous virus population in the children of 28.8%. In most of the studies the number of mother-child pairs is small and information concerning the infection time of the infants is lacking. Moreover the ages of the infants at the time of sample collection vary considerably, and follow-up samples from the infants are seldom studied. To further study the molecular mechanisms involved in mother-to-child transmission of HIV-1, we compared proviral env sequences (V1 to V4) from 13 mothers and their infected children. We also looked for differences in virus heterogeneity between in utero-infected infants and infants infected at or around birth.

Comments

This work was published before the author joined Aga Khan University.

Publication (Name of Journal)

Journal of virology

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