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Apobec3A maintains HIV-1 latency through recruitment of epigenetic silencing machinery to the long terminal repeat

Manabu Taura, Eric Song, Ya-Chi Ho, and Akiko Iwasaki
PNAS February 5, 2019 116 (6) 2282-2289; published ahead of print February 5, 2019 https://doi.org/10.1073/pnas.1819386116
Manabu Taura
aDepartment of Immunobiology, Yale University School of Medicine, New Haven, CT 06520;
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Eric Song
aDepartment of Immunobiology, Yale University School of Medicine, New Haven, CT 06520;
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Ya-Chi Ho
bDepartment of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06520;
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Akiko Iwasaki
aDepartment of Immunobiology, Yale University School of Medicine, New Haven, CT 06520;cHoward Hughes Medical Institute, Chevy Chase, MD 20815
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  • ORCID record for Akiko Iwasaki
  • For correspondence: akiko.iwasaki@yale.edu
  1. Contributed by Akiko Iwasaki, December 13, 2018 (sent for review November 12, 2018; reviewed by Jeremy Luban and Daniel B. Stetson)

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Significance

Human immunodeficiency virus 1 (HIV-1) infection causes a life-long disease, due to the ability of the virus to integrate into the host genome and establish latent infection. While research has revealed a number of host restriction factors that block primary infection, much less is understood with regard to the host factors that promote or block reactivation of the integrated proviral HIV-1. In this study, we show that a member of the Apobec3A (apolipoprotein B MRNA editing enzyme catalytic subunit 3A) family, A3A, suppresses HIV-1 reactivation by recruiting chromatin-modifying enzymes to impose repressive marks around the long terminal repeat promoter region. Identification of host factors that control HIV-1 latency may provide clues for therapeutic interventions needed to remove the viral reservoir from the infected individual.

Abstract

HIV-1 integrates into the genome of target cells and establishes latency indefinitely. Understanding the molecular mechanism of HIV-1 latency maintenance is needed for therapeutic strategies to combat existing infection. In this study, we found an unexpected role for Apobec3A (apolipoprotein B MRNA editing enzyme catalytic subunit 3A, abbreviated “A3A”) in maintaining the latency state within HIV-1–infected cells. Overexpression of A3A in latently infected cell lines led to lower reactivation, while knockdown or knockout of A3A led to increased spontaneous and inducible HIV-1 reactivation. A3A maintains HIV-1 latency by associating with proviral DNA at the 5′ long terminal repeat region, recruiting KAP1 and HP1, and imposing repressive histone marks. We show that knockdown of A3A in latently infected human primary CD4 T cells enhanced HIV-1 reactivation. Collectively, we provide evidence and a mechanism by which A3A reinforces HIV-1 latency in infected CD4 T cells.

  • epigenetic regulation
  • TRIM28
  • reactivation
  • viral latency
  • T cells

Footnotes

  • ↵1To whom correspondence should be addressed. Email: akiko.iwasaki{at}yale.edu.
  • Author contributions: M.T., E.S., Y.-C.H., and A.I. designed research; M.T. and E.S. performed research; M.T., E.S., and Y.-C.H. contributed new reagents/analytic tools; M.T., E.S., and A.I. analyzed data; and M.T. and A.I. wrote the paper.

  • Reviewers: J.L., University of Massachusetts Medical School; and D.B.S., University of Washington.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1819386116/-/DCSupplemental.

Published under the PNAS license.

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Apobec3A maintains HIV-1 latency through recruitment of epigenetic silencing machinery to the long terminal repeat
Manabu Taura, Eric Song, Ya-Chi Ho, Akiko Iwasaki
Proceedings of the National Academy of Sciences Feb 2019, 116 (6) 2282-2289; DOI: 10.1073/pnas.1819386116

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Apobec3A maintains HIV-1 latency through recruitment of epigenetic silencing machinery to the long terminal repeat
Manabu Taura, Eric Song, Ya-Chi Ho, Akiko Iwasaki
Proceedings of the National Academy of Sciences Feb 2019, 116 (6) 2282-2289; DOI: 10.1073/pnas.1819386116
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