Background:  Subtype C HIV-1 is responsible for an expanding epidemic in Sub-Saharan Africa and is now the most abundant HIV-1 subtype worldwide. Recent studies have suggested that changes in HIV-1 env sequences from Zambian adults correlate with transmission. These correlates have not been evaluated in children. We followed several therapy-naïve subtype-C infected mother-infant transmission pairs. For these infants, we defined the longitudinal changes in viral genotype, and have correlated these changes with alterations in viral phenotype, host immune response and disease progression. This allows us to determine whether the characteristics in Env that promote viral transmission to children are similar to those reported for transmission between adults in the same locale.

Methods:  Venous blood from 6 mother-infant transmission pairs was taken at delivery, 2, 4, and 6 months (for rapid progressors) or until 48 months (for slow progressors). The V1-V5 region of the env gene was analyzed to evaluate HIV-1 evolution through time. The biological properties of infant HIV-1 isolates and their neutralization by contemporaneous or non-contemporaneous plasma was determined.

Results:  Three rapid progressors died within the first year of life, whereas the slow progressors have been followed for > 4 years and present no notable clinic signs of HIV-1-related disease. All primary viral isolates were found to be macrophage tropic and CCR5-utilizing. A clear phylogenetic separation between maternal and infant viral sequences suggested selective transmission events regardless of the timing of transmission. The env sequences recovered from infants during the first 6 months of life exhibited relatively low levels of genetic variation. However, HIV-1 from slow progressors developed increasing levels of diversity in env past this initial period. Neutralization assays indicated that children who did not survive through the first year were unable to mount an effective humoral immune response. In contrast, slow progressors produced an effective neutralizing antibody response.

Conclusions:  Selective transmission events were evident in all the infants despite differences in disease progression. Based on our analyses, diversity correlates with time but depends on the generation of a humoral immune response in the infected infants. We do not observe length polymorphisms or changes in potential glycosylation sites in V1-V4 region of env as has been suggested to occur in heterosexual transmission.

Keywords: HIV-1 Subtype C; perinatal transmission; disease progression