How nonhuman primate infant and mother-infant models can inform pediatric HIV-1 cure research.

PURPOSE OF REVIEW: An estimated 1.4 million children live with HIV-1, yet major gaps remain in understanding neonatal pathogenesis and curative strategies. Nonhuman primate (NHP) infant and mother-infant models provide a critical platform to investigate immune development, elucidate age-specific mechanisms of infection, and evaluate treatment responses, aspects that cannot be directly studied in humans.

RECENT FINDINGS: Newborn macaques exhibit exaggerated gut and lymph nodes seeding, absent interferon-I responses, and accelerated progression compared to juveniles, while ultra-early antiretroviral treatment (ART, day 3) achieves 80% postanalytical treatment interruption (ATI) control that collapses by day 5 due to rapid reservoir fixation. Immunotherapies reveal mechanistic constraints: interleukin-15 agonists paradoxically prolong infected cell survival, whereas CD4-mimetics and BCL-2 inhibitors reduce proviral loads. Germline-targeting SOSIP vaccines elicit superior broadly neutralizing antibodies (bNAb) precursors in infants versus adults, though maternal antibody transfer remains inefficient. Neonatal AAV-delivered bNAbs exploit immune tolerance to confer multiyear protection against SHIV challenges.

SUMMARY: NHP models, via timed infections, longitudinal and multitissue sampling, and safe ATI, dissect therapeutic windows guiding clinical translation. Advancing mother-infant NHP research is therefore essential to support the development of pediatric strategies for ART-free remission, a goal that remains challenging to achieve.