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

Autor:	Bricker KM; Department of Pediatrics, Emory University School of Medicinegrid.471395.d, Atlanta, Georgia, USA., Obregon-Perko V; Department of Pediatrics, Emory University School of Medicinegrid.471395.d, Atlanta, Georgia, USA., Williams B; Department of Pediatrics, Emory University School of Medicinegrid.471395.d, Atlanta, Georgia, USA., Oliver D; Department of Pediatrics, Emory University School of Medicinegrid.471395.d, Atlanta, Georgia, USA., Uddin F; Department of Pediatrics, Emory University School of Medicinegrid.471395.d, Atlanta, Georgia, USA., Neja M; Department of Pediatrics, Emory University School of Medicinegrid.471395.d, Atlanta, Georgia, USA., Hopkins L; Department of Pediatrics, Emory University School of Medicinegrid.471395.d, Atlanta, Georgia, USA., Dashti A; Department of Pediatrics, Emory University School of Medicinegrid.471395.d, Atlanta, Georgia, USA., Jean S; Yerkes National Primate Research Center, Emory Universitygrid.471395.dgrid.189967.8grid.471395.dgrid.189967.8, Atlanta, Georgia, USA.; Department of Pathology and Laboratory Medicine, Emory University School of Medicinegrid.471395.d, Atlanta, Georgia, USA., Wood JS; Yerkes National Primate Research Center, Emory Universitygrid.471395.dgrid.189967.8grid.471395.dgrid.189967.8, Atlanta, Georgia, USA., Ehnert S; Yerkes National Primate Research Center, Emory Universitygrid.471395.dgrid.189967.8grid.471395.dgrid.189967.8, Atlanta, Georgia, USA., Liang S; Yerkes National Primate Research Center, Emory Universitygrid.471395.dgrid.189967.8grid.471395.dgrid.189967.8, Atlanta, Georgia, USA., Vanderford T; Yerkes National Primate Research Center, Emory Universitygrid.471395.dgrid.189967.8grid.471395.dgrid.189967.8, Atlanta, Georgia, USA., Tharp GK; Yerkes National Primate Research Center, Emory Universitygrid.471395.dgrid.189967.8grid.471395.dgrid.189967.8, Atlanta, Georgia, USA., Bosinger SE; Yerkes National Primate Research Center, Emory Universitygrid.471395.dgrid.189967.8grid.471395.dgrid.189967.8, Atlanta, Georgia, USA.; Department of Pathology and Laboratory Medicine, Emory University School of Medicinegrid.471395.d, Atlanta, Georgia, USA., Schauer AP; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hillgrid.10698.36, Chapel Hill, North Carolina, USA., Mavigner M; Department of Pediatrics, Emory University School of Medicinegrid.471395.d, Atlanta, Georgia, USA.; Center for Childhood Infections and Vaccines of Children's Healthcare of Atlanta and Emory Universitygrid.471395.dgrid.189967.8grid.471395.dgrid.189967.8, Atlanta, Georgia, USA., Cottrell ML; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hillgrid.10698.36, Chapel Hill, North Carolina, USA., Margolis D; Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hillgrid.10698.36, Chapel Hill, North Carolina, USA.; Center for AIDS Research, University of North Carolina at Chapel Hillgrid.10698.36, Chapel Hill, North Carolina, USA.; UNC HIV Cure Center, University of North Carolina at Chapel Hillgrid.10698.36, Chapel Hill, North Carolina, USA.; Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hillgrid.10698.36, Chapel Hill, North Carolina, USA.; Department of Epidemiology, Gillings School of Public Health, University of North Carolina at Chapel Hillgrid.10698.36, Chapel Hill, North Carolina, USA., Dunham RM; Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hillgrid.10698.36, Chapel Hill, North Carolina, USA.; UNC HIV Cure Center, University of North Carolina at Chapel Hillgrid.10698.36, Chapel Hill, North Carolina, USA.; Qura Therapeutics, Chapel Hill, Research Triangle Park, North Carolina, USA.; HIV Drug Discovery, ViiV Healthcare, Research Triangle Park, North Carolina, USA., Chahroudi A; Department of Pediatrics, Emory University School of Medicinegrid.471395.d, Atlanta, Georgia, USA.; Yerkes National Primate Research Center, Emory Universitygrid.471395.dgrid.189967.8grid.471395.dgrid.189967.8, Atlanta, Georgia, USA.; Center for Childhood Infections and Vaccines of Children's Healthcare of Atlanta and Emory Universitygrid.471395.dgrid.189967.8grid.471395.dgrid.189967.8, Atlanta, Georgia, USA.
Jazyk:	angličtina
Zdroj:	Journal of virology [J Virol] 2022 Apr 13; Vol. 96 (7), pp. e0169921. Date of Electronic Publication: 2022 Mar 16.
DOI:	10.1128/jvi.01699-21
Abstrakt:	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-κB (ncNF-κB) 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 SIV mac251 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 CD4 + 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-κB 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. IMPORTANCE While antiretroviral therapy (ART) has improved HIV-1 disease outcome and reduced transmission, interruption of ART results in rapid viral rebound due to the persistent latent reservoir. Interventions to reduce the viral reservoir are of critical importance, especially for children who must adhere to lifelong ART to prevent disease progression. Here, we used our previously established pediatric nonhuman primate model of oral SIV infection to evaluate AZD5582, identified as a potent latency-reversing agent in adult macaques, in the controlled setting of daily ART. We demonstrated the safety of the IAPi AZD5582 and evaluate the pharmacokinetics and pharmacodynamics of repeated dosing. The response to AZD5582 in macaque infants differed from what we previously showed in adult macaques with weaker latency reversal in infants, likely due to altered pharmacokinetics and less inducibility of infant CD4 + T cells. These data supported the contention that HIV-1 cure strategies for children are best evaluated using pediatric model systems.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu