The molecular epidemiology of HIV-1 envelope diversity during HIV-1 subtype C vertical transmission in Malawian mother–infant pairs

OBJECTIVES: To study the relationship between HIV-1 subtype C genetic diversity and mother-to-child transmission and to determine if transmission of HIV-1 V1/V2 env variants occurs stochastically. DESIGN: Case-case-control study of Malawian mother-infant pairs consisting of 32 nontransmitting women, 25 intrauterine transmitters, and 23 intrapartum transmitters in Blantyre, Malawi. METHODS: A heteroduplex tracking assay against the highly variable HIV-1 env V1/V2 region was used to characterize the relationship between HIV-1 diversity and mother-to-child transmission. The relative abundance of the maternal env variants was quantified and categorized as transmitted or nontransmitted based on the env variants detected in the infant plasma. The V1/V2 region was sequenced from two mother-infant pairs and a phylogenetic tree was built. RESULTS: No relationship was found between transmission and overall maternal env diversity. Infants had less diverse HIV-1 populations than their mothers, and intrauterine-infected infants had fewer V1/V2 variants and were more likely to harbor a homogeneous V1/V2 population than infants infected intrapartum. V1/V2 sequences cloned from two mother-infant transmission pairs support multiple env variant transmission when multiple variants are detected, rather than single variant transmission followed by diversification. Almost 50% of the HIV-infected infants contained V1/V2 env variants that were not detected in maternal plasma samples. Finally transmission of env variants was not related to their abundance in maternal blood. CONCLUSION: These data suggest that the predominant mechanism(s) of HIV-1 subtype C mother-to-child transmission differs by the timing of transmission and is unlikely to be explained by a simple stochastic model.