The latency-reversing agent HODHBt synergizes with IL-15 to enhance cytotoxic function of HIV-specific T cells (ACTG) A5321 Team

被引：8

作者：

Copertino, Dennis C., Jr. ^{[1
]}

Holmberg, Carissa S. ^{[2
]}

Weiler, Jared ^{[1
]}

Ward, Adam R. ^{[1
,2
]}

Howard, J. Natalie ^{[2
]}

Levinger, Callie ^{[2
]}

Pang, Alina P. S. ^{[1
]}

Corley, Michael J. ^{[1
]}

Duendar, Friederike ^{[3
,4
,5
]}

Zumbo, Paul ^{[3
]}

Betel, Doron ^{[1
,3
,6
]}

Gandhi, Rajesh T. ^{[7
]}

McMahon, Deborah K. ^{[8
]}

Bosch, Ronald J. ^{[9
]}

Linden, Noemi ^{[1
]}

Macatangay, Bernard J. ^{[8
]}

Cyktor, Joshua C. ^{[8
]}

Eron, Joseph J. ^{[10
]}

Mellors, John W. ^{[8
]}

Kovacs, Colin ^{[11
]}

Benko, Erika ^{[11
]}

Bosque, Alberto ^{[2
]}

Jones, R. Brad ^{[1
]}

机构：

[1] Weill Cornell Med, Infect Dis Div, Dept Med, New York, NY USA

[2] George Washington Univ, Dept Microbiol Immunol & Trop Med, Washington, DC USA

[3] Weill Cornell Med, Appl Bioinformat Core, New York, NY USA

[4] Weill Cornell Med, Dept Physiol & Biophys, New York, NY USA

[5] Catenion GmbH, Berlin, Germany

[6] Weill Cornell Med, Inst Computat Biomed, New York, NY USA

[7] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA

[8] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA

[9] Harvard TH Chan Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA USA

[10] Univ N Carolina, Dept Med, Chapel Hill, NC 27515 USA

[11] Maple Leaf Med Clin, Toronto, ON, Canada

来源：

JCI INSIGHT | 2023年 / 8卷 / 18期

关键词：

EXPRESSION; RESERVOIR; VIREMIA; REPLICATION; ELIMINATION; LYMPHOCYTES; INFECTION; PERFORIN; PACKAGE; PD-1;

D O I：

10.1172/jci.insight.169028

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

IL-15 is under clinical investigation toward the goal of curing HIV infection because of its abilities to reverse HIV latency and enhance immune effector function. However, increased potency through combination with other agents may be needed. 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one (HODHBt) enhances IL-15-mediated latency reversal and NK cell function by increasing STAT5 activation. We hypothesized that HODHBt would also synergize with IL-15, via STAT5, to directly enhance HIV -specific cytotoxic T cell responses. We showed that ex vivo IL-15 + HODHBt treatment markedly enhanced HIV-specific granzyme B-releasing T cell responses in PBMCs from antiretroviral therapy- suppressed (ART-suppressed) donors. We also observed upregulation of antigen processing and presentation in CD4+ T cells and increased surface MHC-I. In ex vivo PBMCs, IL-15 + HODHBt was sufficient to reduce intact proviruses in 1 of 3 ART-suppressed donors. Our findings reveal the potential for second-generation IL-15 studies incorporating HODHBt-like therapeutics. Iterative studies layering on additional latency reversal or other agents are needed to achieve consistent ex vivo reservoir reductions.

引用

页数：16

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