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Interaction between Nef and INI1/SMARCB1 augments replicability of HIV-1 in resting human peripheral blood mononuclear cells

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Abstract

A central feature of HIV-1 infection is the inability of entering virus to integrate into chromosomes of resting T lymphocytes unless they are mitogenically activated. In contrast, SIVpbj1.9 replicates in initially resting T lymphocytes by activating infected cells. Previous reports have shown that a difference in Nef-mediated T cell activation between HIV-1 and SIVpbj1.9 plays a critical role in the differing abilities of these viruses to replicate in resting lymphocytes. However, the molecular details of these differences are still unclear. Here, we show that infection with a chimeric virus, HSIVnef, which harbors the 5′ 308 nucleotides of SIVpbj1.9 nef in place of the 5′ 221 nucleotides of HIV-1 nef in the HIV-1 proviral backbone, resulted in integration of the provirus into host chromosomes without mitogenic activation and thereby replication in resting human PBMCs (hPBMCs). These results indicate that Nef is an essential viral determinant for the integration of provirus into host chromosomes in resting T cells. Using the yeast two-hybrid system, we identified integrase interactor-1 (INI1/SMARCB1) as a cellular factor that is involved in the integration process via interaction with Nef. Although INI1 interacted with both SIVpbj1.9 and HIV-1 Nefs, SIVpbj1.9 Nef, but not HIV-1 Nef, enhanced proviral integration into host DNA. Furthermore, mutational analysis revealed that the basic-amino-acid-rich amino-terminal domain in SIVpbj1.9 Nef is crucial for interaction with INI1 and virus replication in resting hPBMCs. Taken together, these data indicate that Nef is a critical viral protein for incorporating nascent proviral DNA into host chromosomes in resting PBMCs and that this occurs through interaction with INI1. This elucidates the basis for replication of the integrated provirus when the host cell is in a resting state.

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Acknowledgments

We thank Drs. Ganjam V. Kalpana (Albert Einstein College of Medicine), Alan Engelman (Dana Farber Cancer Institute), and John A. A. Ladias (Harvard Medical School) for experimental materials and advice. This work was supported by the David Geffen Research Fellowship for AIDS Research (D. P.) and NIH/NIDDK R01 DK099055 (I.-W. P).

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Authors and Affiliations

  1. Departments of Immunology and Microbiology, and Medicine, University of Colorado School of Medicine, 12800 E. 19th Ave. MS 8333, Aurora, CO, 80045, USA

    Dohun Pyeon

  2. Department of Cell Biology and Anatomy, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, CBH-316, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA

    In-Woo Park

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Pyeon, D., Park, IW. Interaction between Nef and INI1/SMARCB1 augments replicability of HIV-1 in resting human peripheral blood mononuclear cells. Arch Virol 160, 727–737 (2015). https://doi.org/10.1007/s00705-014-2315-9

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  • DOI: https://doi.org/10.1007/s00705-014-2315-9

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