T-cell responses shape infant SIV reservoirs and post-intervention control following AAV9-eCD4-Ig and latency reversal

Jairo A. Fonseca; Alexis C. King; Kaleaha S. Davis; Daniel O'Hagan; Adrian Khoei; Lucas Alves Britto Da Costa; Camryn Cockerham; Mackenzie Cottrell; Stephanie Ehnert; Jennifer S. Wood; Michael D. Alpert; Matthew R. Gardner; Jeffrey D. Lifson; Maud Mavigner; Mauricio A. Martins; Ann Chahroudi

doi:10.1172/jci.insight.208375

T-cell responses shape infant SIV reservoirs and post-intervention control following AAV9-eCD4-Ig and latency reversal

Jairo A. Fonseca,¹ Alexis C. King,¹ Kaleaha S. Davis,¹ Daniel O'Hagan,² Adrian Khoei,³ Lucas Alves Britto Da Costa,² Camryn Cockerham,¹ Mackenzie Cottrell,³ Stephanie Ehnert,⁴ Jennifer S. Wood,⁴ Michael D. Alpert,⁵ Matthew R. Gardner,² Jeffrey D. Lifson,⁶ Maud Mavigner,¹ Mauricio A. Martins,² and Ann Chahroudi¹

Published September 24, 2026 - More info

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Abstract

Early antiretroviral therapy (ART) limits viral reservoir establishment in infants but also constrains viral-specific immunity required to clear reactivated cells. In the early ART context, we evaluated whether combining adeno-associated virus serotype 9 (AAV9)–vectored eCD4-IgG1 with pharmacologic latency reversal using the second mitochondria-derived activator of caspases (SMAC) mimetic AZD5582 could promote reservoir reduction and control in simian immunodeficiency virus (SIV)–infected infant macaques. AAV9 delivery achieved sustained eCD4-IgG1 expression and AZD5582 induced on-ART viremia, but the combination did not reduce intact SIV proviral DNA relative to controls. Partial post-intervention control of viremia during Analytical Treatment Interruption (ATI) occurred in 2/6 infants receiving AAV9-eCD4-IgG1 + AZD5582 with restricted reservoir expansion during recrudescence at week 13. Intact reservoir size during ATI correlated inversely with on-ART viremia during AZD5582 treatment. Controllers did not show increased eCD4-IgG1 expression nor increased on-ART viremia during AZD5582 treatment, but harbored less pre-ART intact SIV DNA in PBMCs than non-controllers. Controllers also exhibited higher frequencies and greater polyfunctionality of virus-specific CD8⁺ T-cells prior to ATI. These findings implicate immune control of reservoir size and post-ART viral dynamics in early-treated infants and suggest that AAV9-eCD4-IgG1 + AZD5582 increases the likelihood of post-ART viral control.

T-cell responses shape infant SIV reservoirs and post-intervention control following AAV9-eCD4-Ig and latency reversal

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T-cell responses shape infant SIV reservoirs and post-intervention control following AAV9-eCD4-Ig and latency reversal

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