Identifying correlates of protection from HIV acquisition and pathogenesis in humans is key to optimizing vaccine and prevention approaches. We studied the setting of breastfeeding mother to child transmission (MTCT) to determine whether passively-transferred antibodies (Abs) to specific Envelope (Env) epitopes are associated with HIV MTCT or pathogenesis.
Phage display of 1772 Env peptides from four HIV strains representing dominant clades in the cohort (3 subtype A and 1 subtype C) was used to map the epitope profile of passively-acquired Abs in plasma collected in the first week of life from 72 anti-retroviral naïve, breastfeeding infants from Nairobi, Kenya. We identified targeted Env regions using principal component analysis (PCA). To quantify the strength of Ab response to each region, we summed the enrichments of the corresponding peptides for each strain. Binomial logistic regression of enrichment and maternal viral load was used to determine whether regional responses were associated with HIV acquisition. Cox-proportional hazards models of infant survival were used to determine whether regional responses correlated with survival of infants that acquired HIV. A p-value less than 0.05 was considered significant.
Responses to the V1/V2, V3, and C5 regions of gp120, as well as the immunodominant epitope (IDE) and post-IDE region for gp41 contributed high variance in PCA. Post-IDE enrichment was associated with reduced MTCT risk for the subtype C strain (p = 0.020), and there was also a trend for two subtype A strains (p = 0.062, p = 0.060), but not for the third (p = 0.19). Among the 21 infants that acquired HIV during the study (HIV+), responses to V3 and the IDE were associated with decreased survival in Cox-proportional hazards models (Figure 1). Conversely, responses to C5 were associated with increased survival of HIV+ infants.
Passively-acquired antibody responses targeting a post-IDE epitope were associated with reduced MTCT risk. For HIV+ infants, antibody responses to V3 loop or IDE were associated with decreased survival, whereas binding to the C5 region correlated with improved clinical outcome. The distinct contribution to disease outcome of Abs targeting different Env epitopes suggests that the pre-existing antibody repertoire can be both beneficial and detrimental to disease outcomes, depending on the epitope specificity of plasma Abs.