Neonatal HIV-1 infection is associated with rapidly progressive and frequently fatal immune deficiency if left untreated. Immediate institution of antiretroviral therapy (ART), ideally within hours after birth, may restrict irreversible damage to the developing neonatal immune system and possibly provide opportunities for facilitating drug-free viral control during subsequent treatment interruptions. However, the virological and immunological effects of ART initiation within hours after delivery have not been systematically investigated. We examined a unique cohort of neonates with HIV-1 infection from Botswana who started ART shortly after birth and were followed longitudinally for about 2 years in comparison to control infants started on treatment during the first year after birth. We demonstrate multiple clear benefits of rapid antiretroviral initiation, including an extremely small reservoir of intact proviral sequences, a reduction in abnormal T cell immune activation, a more polyfunctional HIV-1–specific T cell response, and an innate immune profile that displays distinct features of improved antiviral activity and is associated with intact proviral reservoir size. Together, these data offer rare insight into the evolutionary dynamics of viral reservoir establishment in neonates and provide strong empirical evidence supporting the immediate initiation of ART for neonates with HIV-1 infection.

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Significant progress has been made in recent years in our abilities to simultaneously detect proteome and posttranslational modifications (PTMs), including phosphorylation responsible for regulating protein functions. We have an incomplete understanding of the role of phosphorylation in host-pathogen interaction. The objective of this study was to fine-map phosphorylation of HIV-1 proteins and subsequently study the consequences of these PTMs. Using mass-spectrometry, we identified over 30 unique phosphorylated sites on HIV-1 proteins detected in infected primary CD4+ T cells and in cell-free virus, with the majority being present on the viral proteins Gag, Pol, and Rev proteins. Interestingly, many of these phosphorylated sites were within previously identified optimal CTL epitopes. While CTL responses to phospho-neoepitopes is subject to recent research in cancer immunology, we lack any understanding of how phosphorylation of virus affects antiviral immune responses. We stimulated PBMCs from HIV-1 infected patients ex vivo in the presence of HIV-1 epitopes with or without phosphorylation, followed by assessment of IFN-γ, TNF-α, MIP1β, and CD107a expressions by flowcytometry. Two Gag-derived phospho-epitopes were able to elicit immune responses in CTLs, potentially indicating the genesis and functional responses to such modified epitopes in vivo in HIV-1 infected patients. Moreover, CTL clones of HLA B*5701 background responded with significantly more cytotoxic marker without any effector cytokine expression, suggesting that phospho-epitopes can modulate the quality of CTL responses. Taken together, our studies shed light on a new way of evaluating host-pathogen interaction with potential for vaccine research.

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