Despite remarkable advances in prevention of vertical HIV-1 transmission and antiretroviral drug development, pediatric HIV-1 infection remains a frequent and difficult-to-treat disease. Early initiation of antiretroviral therapy (ART) in neonates infected with HIV-1 may limit the frequency and stability of HIV-1 reservoir cells, possibly improving response to interventions aimed at viral eradication and cure. Here, we report parallel assessments of HIV-1 reservoir cells and antiviral immune responses in children infected with HIV-1 who started early ART.
37 children from the Early Infant Treatment cohort in Botswana, who started ART at a median of 2 days from birth, were included in this study. HIV-1 near full-length genome sequencing of individual proviral species were used to characterize the proviral reservoir landscape. Integration sites associated with each proviral sequence were obtained using Matched Integration site and Proviral Sequencing (MIP-Seq). Immune responses were measured using flow cytometry.
At birth, the frequency of intact proviruses was inversely associated with IL-8-secreting CD4 T cells, which represent a dominant cell subset in neonates and displayed higher levels of cell-intrinsic resistance to HIV-1 infection. After 84-96 continuous weeks of treatment, proviral DNA levels had decreased by 5-10 fold; this decrease was significantly more pronounced for intact compared with defective HIV-1 proviruses (p = 0.0209). The decline of intact proviruses was inversely associated with an expansion of CD57+ NK cells, characterized by enhanced cytotoxic activities. Conversely, proportions of NK cells expressing the inhibitory receptor NKG2A decreased over time and correlated positively with intact provirus frequency. In two study participants, intact proviruses at week 84 were frequently integrated in heterochromatin regions that represent atypical sites for proviral integration during primary infection; these same integration sites have been observed in persons with natural immune control of HIV-1.
Together, these results suggest that HIV-1 reservoir cell seeding and evolution in early-treated children is markedly influenced by innate immune responses.