Thursday, November 21, 2024
11/21/2024
Principal Investigators (Last, first, middle): Xu, Huanbin PROJECT SUMMARY/ABSTRACT: Despite remarkable advances in prevention of vertical HIV-1 transmission, however, there is little data to guide the optimal early treatment regimens in vulnerable neonates with high risk of MTCT. Current recommended antiretroviral regimens for children are extrapolated from clinical trial in adults. Most recently, our studies show that a short-term combined ART (cART) incorporating an integrase strand transfer inhibitor (INSTI), initiated at 3 days post infection (dpi) but not one day beyond, can rapidly suppress viremia to undetectable levels in neonates, and a prolonged 9-month-early intervention of this regimen results in sustained virologic remission in 4 of 5 infants for more than 2.5 years after treatment cessation. Surprisingly, our further preliminary data showed that delaying treatment (e.g., newborn macaques inoculated with SIV/SHIV AD8 and cART initiated at 5dpi) or treating older infants (e.g., 1.5-month old infant macaques exposed to SIV with cART initiated at 3dpi) drastically altered the outcomes after interruption of the same 9-month-early intervention, as indicated by viral rebound in 4/5 and 3/3 animals, respectively. These findings suggest that outcome of pediatric sustained virologic remission appears to be very sensitive to the age of infants (e.g., newborn versus infants) and the timing (e.g., proviral reservoir seeding?) of intervention initiation, yet the exact mechanisms of viral remission remain elusive. New antivirals are also emerging and a once-monthly analog of DTG called cabotegravir (CAB) shows even greater potential for preventing HIV acquisition and replication in recent adult clinical trials, yet its efficacy and safety in pediatric HIV therapy have not been examined. Given newborn neonates lack well-organized lymphoid tissues (sanctuary sites for antiretrovirals penetration and viral reservoirs) while possessing more dynamic and regenerative capacity than an adult, prophylactic intervention in infants may be unique in that it may have more effective antiviral activity for ART-free HIV remission, resulting in more replenishment of key immune cells and normal development of the immune system. In this proposal, we hypothesize that early prevention interventions, based on appropriate initial timing, duration and INSTI combination, could effectively block viral genome integration and completely eliminate early viral reservoirs, resulting in a sustained state of ART-free virologic remission in infants exposed to or infected with HIV, and subsequently, normal immune development throughout infancy. Utilizing the pediatric NHP model of HIV, our overarching objective is address: SA1, the impact of proviral reservoirs on prophylactic intervention outcomes in infants while assessing the efficacy and safety of cabotegravir in a preclinical trial; SA2, the optimum prevention intervention strategy for achieving pediatric HIV remission, and; SA3, the pharmacokinetics and immunological alterations of ART in the unique infant primate host. Overall, these studies will provide insight into the optimal prevention intervention that achieves a sustained state of ART-free virologic remission for infants exposed to or infected with HIV at birth, which will have significant translational significance towards the treatment of HIV infection of infants in general.
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