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Retrovirology. 2014 Oct 25;11:90. doi: 10.1186/s12977-014-0090-z.

Host and viral determinants for MxB restriction of HIV-1 infection.

Author information

1
Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA, 02215, USA. kmatreyek@gmail.com.
2
Present address: Department of Genome Sciences, University of Washington, Seattle, WA, 98195, USA. kmatreyek@gmail.com.
3
Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA, 02215, USA. weifeng_wang@dfci.harvard.edu.
4
Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA, 02215, USA. erik_serrao@dfci.harvard.edu.
5
Section on Eukaryotic Transposable Elements, Program in Cellular Regulation and Metabolism, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA. parmit.singh@nih.gov.
6
Section on Eukaryotic Transposable Elements, Program in Cellular Regulation and Metabolism, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA. levinh@mail.nih.gov.
7
Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA, 02215, USA. alan_engelman@dfci.harvard.edu.

Abstract

BACKGROUND:

Interferon-induced cellular proteins play important roles in the host response against viral infection. The Mx family of dynamin-like GTPases, which include MxA and MxB, target a wide variety of viruses. Despite considerable evidence demonstrating the breadth of antiviral activity of MxA, human MxB was only recently discovered to specifically inhibit lentiviruses. Here we assess both host and viral determinants that underlie MxB restriction of HIV-1 infection.

RESULTS:

Heterologous expression of MxB in human osteosarcoma cells potently inhibited HIV-1 infection (~12-fold), yet had little to no effect on divergent retroviruses. The anti-HIV effect manifested as a partial block in the formation of 2-long terminal repeat circle DNA and hence nuclear import, and we accordingly found evidence for an additional post-nuclear entry block. A large number of previously characterized capsid mutations, as well as mutations that abrogated integrase activity, counteracted MxB restriction. MxB expression suppressed integration into gene-enriched regions of chromosomes, similar to affects observed previously when cells were depleted for nuclear transport factors such as transportin 3. MxB activity did not require predicted GTPase active site residues or a series of unstructured loops within the stalk domain that confer functional oligomerization to related dynamin family proteins. In contrast, we observed an N-terminal stretch of residues in MxB to harbor key determinants. Protein localization conferred by a nuclear localization signal (NLS) within the N-terminal 25 residues, which was critical, was fully rescuable by a heterologous NLS. Consistent with this observation, a heterologous nuclear export sequence (NES) abolished full-length MxB activity. We additionally mapped sub-regions within amino acids 26-90 that contribute to MxB activity, finding sequences present within residues 27-50 particularly important.

CONCLUSIONS:

MxB inhibits HIV-1 by interfering with minimally two steps of infection, nuclear entry and post-nuclear trafficking and/or integration, without destabilizing the inherent catalytic activity of viral preintegration complexes. Putative MxB GTPase active site residues and stalk domain Loop 4 -- both previously shown to be necessary for MxA function -- were dispensable for MxB antiviral activity. Instead, we highlight subcellular localization and a yet-determined function(s) present in the unique MxB N-terminal region to be required for HIV-1 restriction.

PMID:
25348155
PMCID:
PMC4213484
DOI:
10.1186/s12977-014-0090-z
[Indexed for MEDLINE]
Free PMC Article

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