Abstract
Introduction: Infant HIV-1-infection is associated with high morbidity and mortality if antiretroviral treatment (ART) is not initiated promptly. We characterized development of circulating T follicular helper cells (cTfh) and their relationship to naïve/memory B cell subsets in a cohort of neonates initiating ART within the first week of life.Methods: Infants were diagnosed within 48 hours of birth and started ART as soon as possible. The frequency and phenotype of cTfh and B cells were analyzed at enrollment (birth −19 days) and at 4, 12, and 72 weeks of age in blood of 27 HIV-1-intrauterine-infected and 25 HIV-1 exposed uninfected (HEU) infants as part of a study in Johannesburg, South Africa. cTfh cells were divided into Tfh1, Tfh2, and Tfh17 subsets. B cell phenotypes were defined as naïve, resting memory, activated memory and tissue-like memory cells.Results: HIV-1-infected infants had higher frequencies of cTfh cells than HEU infants up to 12 weeks of age and these cTfh cells were polarized toward the Tfh1 subset. Higher frequencies of Tfh1 and lower frequencies of Tfh2 and Tfh17 correlated with lower CD4+ T cell percentages. Lower frequencies of resting memory, with corresponding higher frequencies of activated memory B cells, were observed with HIV-1 infection. Importantly, dysregulations in B cell, but not cTfh cell, subsets were normalized by 72 weeks.Conclusion: Very early ART initiation in HIV-1-infected infants normalizes B cell subsets but does not fully normalize perturbations in cTfh cell subsets which remain Tfh1 polarized at 72 weeks. It remains to be determined if very early ART improves vaccine antibody responses despite the cTfh and B cell perturbations observed over the time course of this study.
Highlights
Infant HIV-1-infection is associated with high morbidity and mortality if antiretroviral treatment (ART) is not initiated promptly
One HIV-1-infected infant died at 89 days of age and one HIV-1 exposed uninfected (HEU) infant at 25 days of age, with a number of infants lost to follow-up
We investigated whether the higher frequencies of circulating Tfh (cTfh) cells in HIV-1-infected infants observed here were due to higher frequencies of CD27+CD45RA-CD4+ memory T cells in the HIV-1-infected compared to the HEU infants
Summary
Infant HIV-1-infection is associated with high morbidity and mortality if antiretroviral treatment (ART) is not initiated promptly. There is overwhelming consensus regarding the importance of starting antiretroviral therapy (ART) in HIV-1-infected infants as soon as they are diagnosed given the rapid disease progression and high mortality observed without treatment [1, 2]. T follicular helper cells (Tfh) are a specialized subset of CXCR5-expressing CD4+ T cells that are crucial in the maintenance and proliferation of B cells in the germinal centers (GC) of lymphoid tissues [9]. Tfh cells play a complex role in HIV-1 infection. They are highly permissive to HIV-1 infection and serve as a major reservoir for HIV [10, 11], while being associated with broadly-neutralizing HIV antibody responses [12, 13]. CXCR5+ CD4+ T cells found in peripheral blood, termed circulating Tfh (cTfh) cells [14,15,16], can be used as a surrogate marker for GC Tfh cells
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