Retroviruses are important viral pathogens of animals and humans, causing a variety of different diseases including cancer and AIDS. Most of these viruses including the gammaretrovirus, murine leukemia virus (MLV), can efficiently infect dividing, but not non-dividing, cell types. By contrast other retroviruses, such as the lentivirus HIV-1, can efficiently infect both dividing and non-dividing cells. We hypothesize that virus- specific interactions with intracellular host cell factors are responsible, at least in part, for this difference in target cell tropism between these retroviruses. To examine this hypothesis we are identifying and characterizing cellular factors which regulate infection by MLV, but not by HIV-1. By performing somatic cell- based mutagenesis studies, as well as the first comprehensive genome-wide siRNA screen of its type, we have made the remarkable observation that there are several hundred novel intracellular factors required for infection by MLV, but not by HIV-1. These findings demonstrate that retroviruses interact with many more cellular factors than was thought previously. The factors involved include ZASC1, a protein containing multiple zinc finger regions, as well as PAPSS1 and PAPSS2, two biosynthetic enzymes that synthesize 3' phosphoadenosine 5'phosphosulfate (PAPS), the high energy sulfate donor used in all sulfation reactions in the cell. The goals of the studies in this proposal include examining the mechanisms of action of ZASC1, and the PAPSS enzymes during MLV infection. We will also determine the steps during MLV replication that are regulated by each of the other cellular factors identified and establish whether these factors also regulate infection by other gammaretroviruses including the pig endogenous retroviruses (PERVs). This research will contribute substantially to our understanding of the roles played by cellular factors during retrovirus replication and should give new insights into why gammaretrovirus infection is restricted only to dividing cell types. Moreover, because of the risk of PERV transmission to humans, during pig to human xenotransplantations, these studies are of immediate medical relevance since they could suggest novel antiviral approaches aimed at disrupting critical gammaretrovirus-host cell factor interactions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI072645-05
Application #
8005005
Study Section
Virology - B Study Section (VIRB)
Program Officer
Park, Eun-Chung
Project Start
2007-01-01
Project End
2011-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
5
Fiscal Year
2011
Total Cost
$427,389
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Manganaro, Lara; Pache, Lars; Herrmann, Tobias et al. (2014) Tumor suppressor cylindromatosis (CYLD) controls HIV transcription in an NF-?B-dependent manner. J Virol 88:7528-40
Murry, Jeffrey P; Godoy, Joseph; Mukim, Amey et al. (2014) Sulfonation pathway inhibitors block reactivation of latent HIV-1. Virology 471-473:1-12
Bruce, James W; Hierl, Michael; Young, John A T et al. (2010) Cellular transcription factor ZASC1 regulates murine leukemia virus transcription. J Virol 84:7473-83
van der Goot, Gisou; Young, John A T (2009) Receptors of anthrax toxin and cell entry. Mol Aspects Med 30:406-12
Konig, Renate; Zhou, Yingyao; Elleder, Daniel et al. (2008) Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication. Cell 135:49-60
Bruce, James W; Ahlquist, Paul; Young, John A T (2008) The host cell sulfonation pathway contributes to retroviral infection at a step coincident with provirus establishment. PLoS Pathog 4:e1000207
Konig, Renate; Chiang, Chih-yuan; Tu, Buu P et al. (2007) A probability-based approach for the analysis of large-scale RNAi screens. Nat Methods 4:847-9
Wu, J; Schneller, S W; Seley, K L (1997) Carbocyclic oxetanocins lacking the C-3' methylene. J Med Chem 40:1401-6
Siddiqi, S M; Jacobson, K A; Esker, J L et al. (1995) Search for new purine- and ribose-modified adenosine analogues as selective agonists and antagonists at adenosine receptors. J Med Chem 38:1174-88
Siddiqi, S M; Chen, X; Rao, J et al. (1995) 3-deaza- and 7-deaza-5'-noraristeromycin and their antiviral properties. J Med Chem 38:1035-8

Showing the most recent 10 out of 17 publications