Negative HIV serology in perinatally infected children after early treatment and viral suppression: an exploratory analysis of immune correlates

BackgroundUndetectable HIV-specific antibodies in early-treated children with confirmed infection correlate with low viral reservoir and may identify those eligible for future HIV remission strategies. The neonatal immune systems unique characteristics, combined with impairments resulting from exposure to maternal HIV and antiretroviral treatment (ART), may affect antibody responses to HIV. Yet immune competence remains understudied in the context of negative HIV serology. The ANRS-EP59-CLEAC study included 76 children and adolescents with HIV. We measured plasma HIV antibodies by enzyme immunoassay, other analytes by ELISA or multiplex assays, and blood cell phenotypes and functions by flow cytometry. We used Fishers and Mann-Whitneys tests and logistic regression to analyze variables associated with negative HIV serology. Nine participants tested negative for HIV-specific antibodies, eight children and one adolescent. Negative HIV serology occurred exclusively in participants who had initiated ART early and had HIV RNA < 50 copies/mL at evaluation. Among 17 early-treated children with sustained viral suppression, only 7 had negative HIV serology. In this subgroup, negative HIV serology associated with higher nadir CD4 counts, lower plasma IgM levels, higher frequencies of circulating follicular CD8 T lymphocytes, and higher expression of the costimulatory molecule CD86 on myeloid dendritic cells. We found no evidence of B or T lymphocyte deficits associated with negative HIV serology. Low antigenic exposure was necessary but insufficient to explain negative HIV serology. Beyond its association with low HIV reservoir, negative HIV serology correlated with less severe prior CD4 T-lymphocyte depletion and higher frequencies of follicular CD8 T lymphocytes. SummaryIn HIV-infected infants, starting antiretroviral therapy (ART) very early dramatically improves health outcomes. An important phenomenon observed in some of these children is that, despite being HIV-infected, they show no detectable antibodies against the virus -- a profile referred to as negative HIV serology. This feature could help identify patients most likely to benefit from future strategies aimed at achieving long-term virus control without treatment. To better understand this phenomenon, we studied HIV-infected children and adolescents enrolled in the ANRS-EP59-CLEAC trial, which compares the effects of ART initiated early (before 6 months of age) versus late (after 24 months). We showed that negative HIV serology is associated with early treatment, but also with a better-preserved immune system: less depletion of CD4 T cells, which are critical immune cells, and a higher abundance of specific T lymphocytes with potent antiviral activity. Importantly, we found no evidence of defects in the mechanisms responsible for antibody production. These findings suggest that negative HIV serology reflects a favorable immunological profile and could serve as a useful marker to select children as candidates for HIV remission trials.