Latency reversal plus natural killer cells diminish HIV reservoir in vivo

Jocelyn T Kim; Tian-Hao Zhang; Camille Carmona; Bryanna Lee; Christopher S Seet; Matthew Kostelny; Nisarg Shah; Hongying Chen; Kylie Farrell; Mohamed S A Soliman; Melanie Dimapasoc; Michelle Sinani; Kenia Yazmin Reyna Blanco; David Bojorquez; Hong Jiang; Yuan Shi; Yushen Du; Natalia L Komarova; Dominik Wodarz; Paul A Wender; Matthew D Marsden; Ren Sun; Jerome A Zack

doi:10.1038/s41467-021-27647-0

Latency reversal plus natural killer cells diminish HIV reservoir in vivo

Nat Commun. 2022 Jan 10;13(1):121. doi: 10.1038/s41467-021-27647-0.

Authors

Jocelyn T Kim^#¹, Tian-Hao Zhang^#², Camille Carmona³, Bryanna Lee⁴, Christopher S Seet⁵, Matthew Kostelny³, Nisarg Shah³, Hongying Chen³, Kylie Farrell³, Mohamed S A Soliman³, Melanie Dimapasoc³, Michelle Sinani⁴, Kenia Yazmin Reyna Blanco⁴, David Bojorquez³, Hong Jiang⁶, Yuan Shi⁶, Yushen Du⁶, Natalia L Komarova⁷, Dominik Wodarz⁸, Paul A Wender⁹, Matthew D Marsden¹⁰, Ren Sun^{6

11}, Jerome A Zack^{3

5}

Affiliations

¹ Department of Medicine, Division of Infectious Diseases, University of California Los Angeles, Los Angeles, CA, 90095, USA. [email protected].
² Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, 90095, USA.
³ Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, 90095, USA.
⁴ Department of Medicine, Division of Infectious Diseases, University of California Los Angeles, Los Angeles, CA, 90095, USA.
⁵ Department of Medicine, Division of Hematology and Oncology, University of California Los Angeles, Los Angeles, CA, 90095, USA.
⁶ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, 90095, USA.
⁷ Department of Mathematics, University of California, Irvine, Irvine, CA, 92697, USA.
⁸ Department of Population Health and Disease Prevention, Program in Public Health Susan and Henry Samueli College of Health Sciences, University of California, Irvine, Irvine, CA, 92697, USA.
⁹ Department of Chemistry and Department of Chemical and Systems Biology, Stanford University, Stanford, CA, 94305, USA.
¹⁰ Department of Microbiology and Molecular Genetics and Department of Medicine, Division of Infectious Diseases, School of Medicine, University of California, Irvine, Irvine, CA, 92697, USA.
¹¹ School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

^# Contributed equally.

Abstract

HIV is difficult to eradicate due to the persistence of a long-lived reservoir of latently infected cells. Previous studies have shown that natural killer cells are important to inhibiting HIV infection, but it is unclear whether the administration of natural killer cells can reduce rebound viremia when anti-retroviral therapy is discontinued. Here we show the administration of allogeneic human peripheral blood natural killer cells delays viral rebound following interruption of anti-retroviral therapy in humanized mice infected with HIV-1. Utilizing genetically barcoded virus technology, we show these natural killer cells efficiently reduced viral clones rebounding from latency. Moreover, a kick and kill strategy comprised of the protein kinase C modulator and latency reversing agent SUW133 and allogeneic human peripheral blood natural killer cells during anti-retroviral therapy eliminated the viral reservoir in a subset of mice. Therefore, combinations utilizing latency reversal agents with targeted cellular killing agents may be an effective approach to eradicating the viral reservoir.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Anti-HIV Agents / pharmacology*
Bone Marrow / drug effects
Bone Marrow / immunology
Bone Marrow / virology
CD4-Positive T-Lymphocytes / drug effects
CD4-Positive T-Lymphocytes / immunology*
CD4-Positive T-Lymphocytes / virology
Coculture Techniques
Female
HIV Infections / genetics
HIV Infections / immunology
HIV Infections / therapy*
HIV Infections / virology
HIV-1 / drug effects*
HIV-1 / genetics
HIV-1 / immunology
Host-Pathogen Interactions / drug effects
Host-Pathogen Interactions / genetics
Host-Pathogen Interactions / immunology
Humans
Killer Cells, Natural / immunology*
Killer Cells, Natural / transplantation
Male
Mice
Mice, Transgenic
Protein Kinase C / genetics
Protein Kinase C / immunology
Protein Kinase Inhibitors / pharmacology*
Spleen / drug effects
Spleen / immunology
Spleen / virology
Viral Load / drug effects
Viremia / genetics
Viremia / immunology
Viremia / therapy*
Viremia / virology
Virus Latency / drug effects
Virus Replication / drug effects

Substances

Anti-HIV Agents
Protein Kinase Inhibitors
Protein Kinase C

Abstract

Publication types

MeSH terms

Substances

Grants and funding