SAMHD1 restricts HIV-1 infection in resting CD4(+) T cells.

Abstract

Unlike activated CD4(+) T cells, resting CD4(+) T cells are highly resistant to productive HIV-1 infection. Early after HIV-1 entry, a major block limits reverse transcription of incoming viral genomes. Here we show that the deoxynucleoside triphosphate triphosphohydrolase SAMHD1 prevents reverse transcription of HIV-1 RNA in resting CD4(+) T cells. SAMHD1 is abundantly expressed in resting CD4(+) T cells circulating in peripheral blood and residing in lymphoid organs. The early restriction to infection in unstimulated CD4(+) T cells is overcome by HIV-1 or HIV-2 virions into which viral Vpx is artificially or naturally packaged, respectively, or by addition of exogenous deoxynucleosides. Vpx-mediated proteasomal degradation of SAMHD1 and elevation of intracellular deoxynucleotide pools precede successful infection by Vpx-carrying HIV. Resting CD4(+) T cells from healthy donors following SAMHD1 silencing or from a patient with Aicardi-Goutières syndrome homozygous for a nonsense mutation in SAMHD1 were permissive for HIV-1 infection. Thus, SAMHD1 imposes an effective restriction to HIV-1 infection in the large pool of noncycling CD4(+) T cells in vivo. Bypassing SAMHD1 was insufficient for the release of viral progeny, implicating other barriers at later stages of HIV replication. Together, these findings may unveil new ways to interfere with the immune evasion and T cell immunopathology of pandemic HIV-1.

• Authors: Hanna-Mari Baldauf, Xiaoyu Pan, Elina Erikson, Sarah Schmidt, Waaqo Daddacha, Manja Burggraf, Kristina Schenkova, Ina Ambiel, Guido Wabnitz, Thomas Gramberg, Sylvia Panitz, Egbert Flory, Nathaniel R Landau, Serkan Sertel, Frank Rutsch, Felix Lasitschka, Baek Kim, Renate König, Oliver T Fackler, Oliver T Keppler
• Journal: Nature medicine (Nat Med) Vol. 18 Issue 11 Pg. 1682-7 (Nov 2012) ISSN: 1546-170X [Electronic] United States
• PMID: 22972397 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Human Immunodeficiency Virus Proteins
• Viral Regulatory and Accessory Proteins
• vpu protein, Human immunodeficiency virus 1
• SAM Domain and HD Domain-Containing Protein 1
• SAMHD1 protein, human
• Monomeric GTP-Binding Proteins

Topics

• Autoimmune Diseases of the Nervous System (genetics, virology)
• CD4-Positive T-Lymphocytes (immunology, metabolism)
• HIV Infections
• HIV-1 (genetics, metabolism)
• HIV-2 (genetics, metabolism)
• Human Immunodeficiency Virus Proteins (genetics, metabolism)
• Humans
• Monomeric GTP-Binding Proteins (genetics, metabolism)
• Nervous System Malformations (genetics, virology)
• Reverse Transcription (genetics)
• SAM Domain and HD Domain-Containing Protein 1
• Viral Regulatory and Accessory Proteins (genetics, metabolism)
• Virion (genetics, growth & development)
• Virus Replication