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A point mutation in HIV-1 integrase redirects proviral integration into centromeric repeats

Author

Listed:
  • Shelby Winans

    (Columbia University Medical Center
    Columbia University Medical Center
    Columbia University)

  • Hyun Jae Yu

    (Frederick National Laboratory)

  • Kenia los Santos

    (Columbia University Medical Center
    Columbia University Medical Center
    Columbia University)

  • Gary Z. Wang

    (Columbia University Medical Center)

  • Vineet N. KewalRamani

    (National Cancer Institute)

  • Stephen P. Goff

    (Columbia University Medical Center
    Columbia University Medical Center
    Columbia University)

Abstract

Retroviruses utilize the viral integrase (IN) protein to integrate a DNA copy of their genome into host chromosomal DNA. HIV-1 integration sites are highly biased towards actively transcribed genes, likely mediated by binding of the IN protein to specific host factors, particularly LEDGF, located at these gene regions. We here report a substantial redirection of integration site distribution induced by a single point mutation in HIV-1 IN. Viruses carrying the K258R IN mutation exhibit a high frequency of integrations into centromeric alpha satellite repeat sequences, as assessed by deep sequencing, a more than 10-fold increase over wild-type. Quantitative PCR and in situ immunofluorescence assays confirm this bias of the K258R mutant virus for integration into centromeric DNA. Immunoprecipitation studies identify host factors binding to IN that may account for the observed bias for integration into centromeres. Centromeric integration events are known to be enriched in the latent reservoir of infected memory T cells, as well as in elite controllers who limit viral replication without intervention. The K258R point mutation in HIV-1 IN is also present in databases of latent proviruses found in patients, and may reflect an unappreciated aspect of the establishment of viral latency.

Suggested Citation

  • Shelby Winans & Hyun Jae Yu & Kenia los Santos & Gary Z. Wang & Vineet N. KewalRamani & Stephen P. Goff, 2022. "A point mutation in HIV-1 integrase redirects proviral integration into centromeric repeats," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29097-8
    DOI: 10.1038/s41467-022-29097-8
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    References listed on IDEAS

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    1. Chenyang Jiang & Xiaodong Lian & Ce Gao & Xiaoming Sun & Kevin B. Einkauf & Joshua M. Chevalier & Samantha M. Y. Chen & Stephane Hua & Ben Rhee & Kaylee Chang & Jane E. Blackmer & Matthew Osborn & Mic, 2020. "Distinct viral reservoirs in individuals with spontaneous control of HIV-1," Nature, Nature, vol. 585(7824), pages 261-267, September.
    2. Inês J. de Castro & James Budzak & Maria L. Di Giacinto & Lorena Ligammari & Ezgi Gokhan & Christos Spanos & Daniela Moralli & Christine Richardson & Jose I. de las Heras & Silvia Salatino & Eric C. S, 2017. "Repo-Man/PP1 regulates heterochromatin formation in interphase," Nature Communications, Nature, vol. 8(1), pages 1-16, April.
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