Virus and Host Directed Immunotherapies for Cure in SHIV-infected Infant Macaques

In the quest to identify a widely applicable approach to cure HIV, broadly neutralizing antibodies (bNAbs) have been tested in nonhuman primates (NHPs) and humans, including newborns and children. While encouraging, these studies have not shown a consistent reduction in the size of the persistent viral reservoir compared to antiretroviral therapy (ART) alone. Whether these immunotherapies can be optimized to sufficiently limit reservoir formation and contribute to ART-free virologic control therefore remains a gap in knowledge. The Objective of this proposal is to perform a systematic analysis of immunotherapy optimization strategies. We focus on the unique setting of postnatal infection of infants, as over half of new HIV infections in children now occur through breastfeeding. The strategies to be tested leverage three different mechanisms to enhance bNAbs: i) reactivating virus expression from latently-infected cells for bNAb recognition, ii) promoting the ‘vaccinal effect’ of bNAbs through innate immune stimulation, and/or iii) improving bNAb binding to infected cells. Our Central Hypothesis is that the impact of bNAb therapy in the first weeks of perinatal infection can be enhanced through targeted virus and host directed adjunctive treatments. In Aim 1, we will define how non- canonical NF-κB pathway activation with bNAb administration during early ART impacts reservoir establishment. In Aim 2, we will evaluate if TLR7/8 stimulation with bNAb administration during early ART enhances antiviral immune responses thereby limiting reservoir formation. In Aim 3, we will determine whether bNAb immunotherapy during early ART is improved by the attachment inhibitor fostemsavir (FTR), that maintains gp120 in a ‘closed’ conformation. The bNAbs to be used in all in vivo experiments are N6-LS and PGT121, based on their distinct target sites on the HIV Env (N6: CD4-binding site; PGT-121: V3 glycan), with the goal of maximizing binding to circulating virions and virus-infected cells. Both PGT121 and N6 have potent neutralizing capacity, with N6 being exceptionally broad. We will define the impact of these approaches in an infant rhesus macaque model of postnatal infection on viral load decay, intact reservoir size, virologic control after ART interruption, and antiviral immunity. The proposed research builds on our expertise with infant NHP models to deeply interrogate immunotherapeutic approaches aimed towards cure of perinatal HIV infection. Testing three different strategies simultaneously will vastly improve our understanding of immunotherapy in infants and incorporating shared control groups makes the best use of a limited and expensive animal resource. The experiments proposed here will provide new evidence regarding the mechanisms of HIV/SIV reservoir establishment and how this process may be perturbed in a model of perinatal infection. It is our mission to turn these discoveries into clinical trials to advance research towards a cure for children with HIV. Project Number: 1R01AI192330-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Ann Chahroudi | Institution: EMORY UNIVERSITY, ATLANTA, GA | Award Amount: $1,332,155 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 IIDA-U (02)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI19233001