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Title
Effect of combination latency reversing agents and bNAb in SHIV-infected rhesus macaques on antiretroviral therapy
Presenter
Binhua Ling
Authors
A. Solis Leal1, N. Boby1, S. Mallick1, A. Goodroe1, J. Kaur2, F. Wu1, G. De La Torre1, C. Fennessey3, Y. Cai2, J. Murry2, B. Keele3, B. Ling4
Institutions
1Texas Biomedical Resarch Institute, San Antonio, TX, United States, 2Gilead Sciences, Inc., Foster City, United States, 3Frederick National Laboratory, AIDS and Cancer Virus Program, Frederick, United States, 4Texas Biomedical Research Institute, San Antonio, TX, United States

BACKGROUND: The combination of latency reversing agents (LRA) with antiretroviral therapy (ART) has been proposed as an HIV cure strategy. However, no therapy combination has demonstrated the capacity to clear latent HIV reservoirs. This study assessed the impact of an LRA in combination with the broadly neutralizing antibody PGT121 on viral reservoirs in ART-suppressed rhesus macaques.
METHODS: Eight macaques were infected with the barcoded virus SHIVAD8E0M and underwent ART starting at 4 weeks post-infection (wpi). These ART-suppressed animals were divided into 2 groups at 49 wpi. The active arm (n=5) was dosed with AZD5582, then ciapavir prior to a 6-week ART interruption (ATI-1). At 80wpi, ART was re-initiated with a combination of AZD5582 and PGT121. The control group received daily ART only. At 87 wpi, animals from both groups entered a 2nd ATI (ATI-2) for up to 11 weeks before necropsy. Changes in cellular and tissue viral reservoirs were evaluated using deep sequencing and quantitation methods, immunofluorescence and cell sorting.
RESULTS: Plasma viral loads (pVL) were consistently <81 copies/ml while on ART in both groups. The active arm experienced viral rebound with detectable virus in plasma and cerebrospinal fluid during ATI-1; all animals showed a similar reservoir size in multiple tissues and organs at necropsy. Viral DNA was detected in multiple regions of the brain, with low intact proviral reservoirs ranging between 75 and 374 intact proviruses/106 cells in either temporal or parietal lobes, hippocampus, and/or hypothalamus in both groups. The active arm did not rebound during ATI-2, while all control animals rebounded within 6 weeks of ATI-2.
CONCLUSIONS: Sustained viral suppression after receiving AZD5582 and PGT121 suggests that PGT121 exposure prevented viral rebound. More data collection is ongoing and will provide further insights regarding cell types and anatomic sites that harbor reservoir. These preliminary data also suggest that intact viruses in certain brain regions may serve as HIV reservoirs that could be challenging for eradication. Thus, future HIV cure strategies may need to include drugs that specifically target these resilient reservoirs.

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