4.6 Article

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

期刊

JOURNAL OF VIROLOGY
卷 96, 期 7, 页码 -

出版社

AMER SOC MICROBIOLOGY
DOI: 10.1128/jvi.01699-21

关键词

HIV; HIV cure; NHP; pediatric HIV; SIV

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资金

  1. U.S. National Institutes of Health [R01 AI133706, UM1 AI164566]
  2. Emory CFAR Virology Core [P30 AI050409]
  3. University of North Carolina at Chapel Hill CFAR [P30 AI050410]
  4. Pediatrics/Winship Flow Cytometry Core of Winship Cancer Institute of Emory University, Children's Healthcare of Atlanta [P30 CA138292]
  5. Yerkes NPRC through the National Institutes of Health's Office of the Director, Office of Research Infrastructure Programs, [P51 OD011132, U42 OD011023]

向作者/读者索取更多资源

Antiretroviral therapy (ART) has improved HIV-1 disease outcome and reduced transmission, but viral rebound is rapid upon interruption of treatment. Intervention to reduce viral reservoir is critical, especially for children who need lifelong ART. In this study, an inhibitor of apoptosis protein (IAP) inhibitor AZD5582 was evaluated in infant macaques infected with SIV. The response to AZD5582 was weaker in infants, likely due to altered pharmacokinetics and less inducibility of infant CD4(+) T cells.
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. 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-kappa B (ncNF-kappa 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 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-kappa 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. 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.

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