HIV-1 and other lentiviruses encode accessory proteins, each of which plays a role in facilitating virus replication and causing pathogenesis. Several of the accessory proteins exert their effect by counteracting antiviral cell proteins. This project focuses on understanding how the two HIV-related accessory proteins, Vpr and Vpx, facilitate virus replication. These proteins are 50% similar in amino acid sequence, are packaged in the virion, localize to the nucleus and bind a specific E3 ubiquitin ligase. Vpx, which is encoded in HIV-2 and SIVmac but not HIV-1, targets the cellular enzyme SAMHD1 for degradation. The target of Vpr has not yet been identified. The mechanism by which SAMHD1 inhibits viruses is not clear. It is a phosphohydrolase that when expressed in myeloid cells, removes the phosphates from the deoxynucleotide triphosphates, depleting the pool of intracellular dNTPs. SAMHD1 is also an exonuclease and which of these activities restricts virus replication is not clear. SAMHD1 does not block the replication of SIVmac or HIV-2 as these viruses encode Vpx. This project seeks to understand (i) the mechanism by which SAMHD1 restricts HIV-1;(ii) how Vpx binds and targets SAMHD1 for degradation;(iii) how Vpx is released from the virus following infection;(iv) how the enzymatic activity of the protein is regulated by post-translational modifications or by associating with regulatory proteins;(v) which amino acid residues of Vpx and SAMHD1 allow the proteins to interact;(vi) how Vpx is imported into the nucleus and (vii) the role of SAMHD1 in the innate immune response to HIV-1 infection. Lastly, an inducible expression system for Vpr will be established to identify the targeted host factor. The findings will shed light on a new mechanism by which the innate immune system restricts HIV-1 and other human pathogens and how viruses have evolved to escape the restriction. Understanding this may provide strategies to therapeutically enhance the effectiveness of the innate immune response for the treatment of infectious diseases.

Public Health Relevance

The project will investigate two proteins encoded by HIV, Vpr and Vpx, that are thought to counteract the antiviral abilities of the innate immune system. The project will determine how Vpr and Vpx allow HIV to replicate in white blood cells and the mechanisms that the cells have that act to block virus replication. The studies will provide insight into how viruses evade the immune system and how to alter the immune response such that it is more effective at fighting infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI067059-05A1
Application #
8659871
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Sharma, Opendra K
Project Start
2005-07-01
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
New York University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10016
Hofmann, Henning; Vanwalscappel, Bénédicte; Bloch, Nicolin et al. (2016) TLR7/8 agonist induces a post-entry SAMHD1-independent block to HIV-1 infection of monocytes. Retrovirology 13:83
Tam, Kayan; Schultz, Megan; Reyes-Robles, Tamara et al. (2016) Staphylococcus aureus Leukocidin LukED and HIV-1 gp120 Target Different Sequence Determinants on CCR5. MBio 7:
Jáuregui, Paula; Logue, Eric C; Schultz, Megan L et al. (2015) Degradation of SAMHD1 by Vpx Is Independent of Uncoating. J Virol 89:5701-13
Norton, T D; Miller, E A; Bhardwaj, N et al. (2015) Vpx-containing dendritic cell vaccine induces CTLs and reactivates latent HIV-1 in vitro. Gene Ther 22:227-36
Simon, Viviana; Bloch, Nicolin; Landau, Nathaniel R (2015) Intrinsic host restrictions to HIV-1 and mechanisms of viral escape. Nat Immunol 16:546-53
Landau, Nathaniel R (2014) The innate immune response to HIV-1: to sense or not to sense. DNA Cell Biol 33:271-4
Zhang, Ruonan; Bloch, Nicolin; Nguyen, Laura A et al. (2014) SAMHD1 restricts HIV-1 replication and regulates interferon production in mouse myeloid cells. PLoS One 9:e89558
Huber, Andrew D; Michailidis, Eleftherios; Schultz, Megan L et al. (2014) SAMHD1 has differential impact on the efficacies of HIV nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother 58:4915-9
Bloch, Nicolin; O'Brien, Meagan; Norton, Thomas D et al. (2014) HIV type 1 infection of plasmacytoid and myeloid dendritic cells is restricted by high levels of SAMHD1 and cannot be counteracted by Vpx. AIDS Res Hum Retroviruses 30:195-203
Hakata, Yoshiyuki; Miyazawa, Masaaki; Landau, Nathaniel R (2014) Interactions with DCAF1 and DDB1 in the CRL4 E3 ubiquitin ligase are required for Vpr-mediated G2 arrest. Virol J 11:108

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