PMID- 35074917
OWN - NLM
STAT- MEDLINE
DCOM- 20220228
LR  - 20240405
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 119
IP  - 4
DP  - 2022 Jan 25
TI  - CHAF1A/B mediate silencing of unintegrated HIV-1 DNAs early in infection.
LID - 10.1073/pnas.2116735119 [doi]
LID - e2116735119
AB  - Early events of the retroviral life cycle are the targets of many host 
      restriction factors that have evolved to prevent establishment of infection. 
      Incoming retroviral DNAs are transcriptionally silenced before integration in 
      most cell types, and efficient viral gene expression occurs only after formation 
      of the provirus. The molecular machinery for silencing unintegrated retroviral 
      DNAs of HIV-1 remains poorly characterized. Here, we identified the histone 
      chaperones CHAF1A and CHAF1B as essential factors for silencing of unintegrated 
      HIV-1 DNAs. Using RNAi-mediated knockdown (KD) of multiple histone chaperones, we 
      found that KD of CHAF1A or CHAF1B resulted in a pronounced increase in expression 
      of incoming viral DNAs. The function of these two proteins in silencing was 
      independent of their interaction partner RBBP4. Viral DNA levels accumulated to 
      significantly higher levels in CHAF1A KD cells over controls, suggesting enhanced 
      stabilization of actively transcribed DNAs. Chromatin immunoprecipitation assays 
      revealed no major changes in histone loading onto viral DNAs in the absence of 
      CHAF1A, but levels of the H3K9 trimethylation silencing mark were reduced. KD of 
      the H3K9me3-binding protein HP1gamma accelerated the expression of unintegrated HIV-1 
      DNAs. While CHAF1A was critical for silencing HIV-1 DNAs, it showed no role in 
      silencing of unintegrated retroviral DNAs of mouse leukemia virus. Our study 
      identifies CHAF1A and CHAF1B as factors involved specifically in silencing of 
      HIV-1 DNAs early in infection. The results suggest that these factors act by 
      noncanonical pathways, distinct from their histone loading activities, to mediate 
      silencing of newly synthesized HIV-1 DNAs.
CI  - Copyright (c) 2022 the Author(s). Published by PNAS.
FAU - Geis, Franziska K
AU  - Geis FK
AD  - Department of Biochemistry and Molecular Biophysics, Columbia University Medical 
      Center, New York, NY 10032.
AD  - Department of Microbiology and Immunology, Columbia University Medical Center, 
      New York, NY 10032.
AD  - HHMI, Columbia University Medical Center, New York, NY 10032.
AD  - Aaron Diamond AIDS Research Center, Columbia University Medical Center, New York, 
      NY 10032.
FAU - Sabo, Yosef
AU  - Sabo Y
AD  - Aaron Diamond AIDS Research Center, Columbia University Medical Center, New York, 
      NY 10032.
AD  - Division of Infectious Diseases, Department of Medicine, Columbia University 
      Medical Center, New York, NY 10032.
FAU - Chen, Xiao
AU  - Chen X
AUID- ORCID: 0000-0001-5059-8846
AD  - Department of Genetics and Development, Columbia University Medical Center, New 
      York, NY 10032.
AD  - Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 
      New York, NY 10032.
FAU - Li, Yinglu
AU  - Li Y
AD  - Department of Genetics and Development, Columbia University Medical Center, New 
      York, NY 10032.
AD  - Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 
      New York, NY 10032.
FAU - Lu, Chao
AU  - Lu C
AD  - Department of Genetics and Development, Columbia University Medical Center, New 
      York, NY 10032.
AD  - Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 
      New York, NY 10032.
FAU - Goff, Stephen P
AU  - Goff SP
AUID- ORCID: 0000-0002-9679-0582
AD  - Department of Biochemistry and Molecular Biophysics, Columbia University Medical 
      Center, New York, NY 10032; spg1@cumc.columbia.edu.
AD  - Department of Microbiology and Immunology, Columbia University Medical Center, 
      New York, NY 10032.
AD  - HHMI, Columbia University Medical Center, New York, NY 10032.
AD  - Aaron Diamond AIDS Research Center, Columbia University Medical Center, New York, 
      NY 10032.
AD  - Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 
      New York, NY 10032.
LA  - eng
GR  - P30 CA013696/CA/NCI NIH HHS/United States
GR  - R01 CA030488/CA/NCI NIH HHS/United States
GR  - R35 GM138181/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (CHAF1A protein, human)
RN  - 0 (CHAF1B protein, human)
RN  - 0 (Chromatin Assembly Factor-1)
RN  - 0 (DNA, Viral)
RN  - 0 (Histones)
RN  - EC 2.3.2.27 (Tripartite Motif-Containing Protein 28)
SB  - IM
MH  - Chromatin Assembly Factor-1/*metabolism
MH  - *DNA, Viral
MH  - Gene Expression Regulation, Viral
MH  - Gene Silencing
MH  - HIV Infections/*metabolism/*virology
MH  - HIV-1/genetics/*physiology
MH  - Histones/metabolism
MH  - Host-Pathogen Interactions
MH  - Humans
MH  - Proviruses/*genetics
MH  - Transcription, Genetic
MH  - Tripartite Motif-Containing Protein 28/metabolism
MH  - *Virus Integration
PMC - PMC8795523
OTO - NOTNLM
OT  - CHAF1A
OT  - HIV-1
OT  - histone chaperones
OT  - retroviral DNAs
OT  - transcriptional silencing
COIS- The authors declare no competing interest.
EDAT- 2022/01/26 06:00
MHDA- 2022/03/01 06:00
PMCR- 2022/07/24
CRDT- 2022/01/25 05:48
PHST- 2021/12/20 00:00 [accepted]
PHST- 2022/01/25 05:48 [entrez]
PHST- 2022/01/26 06:00 [pubmed]
PHST- 2022/03/01 06:00 [medline]
PHST- 2022/07/24 00:00 [pmc-release]
AID - 2116735119 [pii]
AID - 202116735 [pii]
AID - 10.1073/pnas.2116735119 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2022 Jan 25;119(4):e2116735119. doi: 
      10.1073/pnas.2116735119.