Person:

Ruprecht, Ruth Margrit

Background: Given the high prevalence of mother to child infection, the development of a better understanding of African subtype C HIV-1 transmission and natural evolution is of significant importance. In this study, we genotypically and phenotypically characterized subtype C viruses isolated over a 67-month follow-up period from an in utero-infected Zambian infant. Changes in genotype and phenotype were correlated to alterations of the host humoral immune response. Results: A comparison of baseline maternal and infant samples indicated that the infant sequences are monophyletic and contain a fraction of the diversity observed in the mother. This finding suggests that selective transmission occurred from mother to child. Peaks in infant HIV-1 Env genetic diversity and divergence were noted at 48 months, but were not correlated with changes in co-receptor usage or syncytia phenotype. Phylogenetic analyses revealed an accumulation of mutations over time, as well as the reappearance of ancestral lineages. In the infant C2-V4 region of Env, neither the median number of putative N-glycosylation sites or median sequence length showed consistent increases over time. The infant possessed neutralizing antibodies at birth, but these decreased in effectiveness or quantity with time. De novo humoral responses were detected in the child after 12 months, and corresponded with an increase in Env diversity. Conclusion: Our study demonstrates a correlation between HIV-1 Env evolution and the humoral immune response. There was an increase in genetic diversification in the infant viral sequences after 12 months, which coincided with increases in neutralizing antibody titers. In addition, episodes of viral growth and successive immune reactions in the first 5–6 years were observed in this slow progressor infant with delayed onset of AIDS. Whether this pattern is typical of slow progressing subtype C HIV-1 infected infant needs to be further substantiated.

Background: The causal mechanisms of differential disease progression in HIV-1 infected children remain poorly defined, and much of the accumulated knowledge comes from studies of subtype B infected individuals. The applicability of such findings to other subtypes, such as subtype C, remains to be substantiated. In this study, we longitudinally characterized the evolution of the Env V1–V5 region from seven subtype C HIV-1 perinatally infected children with different clinical outcomes. We investigated the possible influence of viral genotype and humoral immune response on disease progression in infants. Results: Genetic analyses revealed that rapid progressors (infants that died in the first year of life) received and maintained a genetically homogeneous viral population throughout the disease course. In contrast, slow progressors (infants that remained clinically asymptomatic for up to four years) also exhibited low levels variation initially, but attained higher levels of diversity over time. Genetic assessment of variation, as indicated by dN/dS, showed that particular regions of Env undergo selective changes. Nevertheless, the magnitude and distribution of these changes did not segregate slow and rapid progressors. Longitudinal trends in Env V1–V5 length and the number of potential N-glycosylation sites varied among patients but also failed to discriminate between fast and slow progressors. Viral isolates from rapid progressors and slow progressors displayed no significant growth properties differences in vitro. The neutralizing activity in maternal and infant baseline plasma also varied in its effectiveness against the initial virus from the infants but did not differentiate rapid from slow progressors. Quantification of the neutralization susceptibility of the initial infant viral isolates to maternal baseline plasma indicated that both sensitive and resistant viruses were transmitted, irrespective of disease course. We showed that humoral immunity, whether passively acquired or developed de novo in the infected children, varied but was not predictive of disease progression. Conclusion: Our data suggest that neither genetic variation in env, or initial maternal neutralizing activity, or the level of passively acquired neutralizing antibody, or the level of the de novo neutralization response appear to be linked to differences in disease progression in subtype C HIV-1 infected children.