Altered Response Pattern following AZD5582 Treatment of SIV-Infected, ART-Suppressed Rhesus Macaque Infants

• Authors: Steven Bosinger, Emory University; Ann Chahroudi, Emory University; Jennifer Wood, Emory University; Thomas Vanderford, Emory University; Maud Mavigner, Emory University; KM Bricker, Emory University; V Obregon-Perko, Emory University; B Williams, Emory University; D Oliver, Emory University; F Uddin, Emory University; M Neja, Emory University; L Hopkins, Emory University; A Dashti, Emory University; S Jean, Emory University; S Ehnert, Emory University; S Liang, Emory University; GK Tharp, Emory University; AP Schauer, University of North Carolina; ML Cottrell, University of North Carolina; D Margolis, University of North Carolina; RM Dunham, University of North Carolina
• Journal Title: JOURNAL OF VIROLOGY
• Volume: Volume 96, Number 7
• Publisher: AMER SOC MICROBIOLOGY | 2022-04-13, Pages e0169921-e0169921
• Type of Work: Article
• Publisher DOI: http://doi.org/10.1128/jvi.01699-21
• Keywords: Science & Technology; Life Sciences & Biomedicine; Virology; HIV; HIV cure; NHP; pediatric HIV; SIV; HIV-1; RESERVOIR; CHALLENGES

Abstract

The "shock and kill" strategy for HIV-1 cure incorporates latency-reversing agents (LRA) in combination with interventions that aid the host immune system in clearing virally reactivated cells. LRAs have not yet been investigated in pediatric clinical or preclinical studies. Here, we evaluated an inhibitor of apoptosis protein (IAP) inhibitor (IAPi), AZD5582, that activates the noncanonical NF-k B (ncNF-k B) signaling pathway to reverse latency. Ten weekly doses of AZD5582 were intravenously administered at 0.1 mg/kg to rhesus macaque (RM) infants orally infected with SIVmac251 at 4 weeks of age and treated with a triple ART regimen for over 1 year. During AZD5582 treatment, on-ART viremia above the limit of detection (LOD, 60 copies/mL) was observed in 5/8 infant RMs starting at 3 days post-dose 4 and peaking at 771 copies/mL. Of the 135 measurements during AZD5582 treatment in these 5 RM infants, only 8 were above the LOD (6%), lower than the 46% we have previously reported in adult RMs. Pharmacokinetic analysis of plasma AZD5582 levels revealed a lower Cmax in treated infants compared to adults (294 ng/mL versus 802 ng/mL). RNA-Sequencing of CD41 T cells comparing pre- and post-AZD5582 dosing showed many genes that were similarly upregulated in infants and adults, but the expression of key ncNF-k B genes, including NFKB2 and RELB, was significantly higher in adult RMs. Our results suggest that dosing modifications for this latency reversal approach may be necessary to maximize virus reactivation in the pediatric setting for successful "shock and kill" strategies.