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TRIM5 and Innate Resistance to HIV-1

English title TRIM5 and Innate Resistance to HIV-1
Applicant Luban Jeremy
Number 128655
Funding scheme Project funding (Div. I-III)
Research institution Dépt Microbiologie et Médecine Moléculaire Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Experimental Microbiology
Start/End 01.10.2009 - 30.09.2012
Approved amount 560'000.00
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Keywords (6)

HIV-1; retrovirus; TRIM5; restriction; SPRY; AIDS

Lay Summary (English)

Lead
Lay summary
A major goal of research in our lab is to discover host factors that regulate HIV-1 replication. The idea is that, by identifying such factors, we hope to learn about the needs of the virus, how it works, and from this information develop new strategies for inhibiting HIV-1 infection and associated disease. Additionally, it is hoped that these studies will teach us about ourselves, that is, how our cells work. Over the years we have discovered several factors that regulate HIV-1 replication. Among such factors is a protein called TRIM5 which we identified in a screen of anti-HIV-1 factors in non-human primate cells. It turns out that TRIM5 is a protein in the cells of humans and other primates that confers resistance to infection by HIV-1 and other retroviruses. In previous work, we provided evidence that TRIM5 can be thought of as a receptor in the cell cytoplasm that recognizes the complex retroviral core structure encasing the viral genomic RNA. Along with another anti-retrovirus factor called Fv1, it establishes a paradigm of innate immunity in which an invading multiprotein complex, rather than double-stranded RNA or lipopolysaccharide, is recognized by a specific receptor. Here, using a combination of complementary approaches, the mechanism by which TRIM5 inhibits retroviral infection will be deciphered. In the first specific aim the genetic requirements for recognition of the retrovirus capsid by human TRIM5? will be determined. These studies will exploit novel biochemical assays for specific recognition of mature virion cores by human TRIM5?, and in collaboration with the Gruetter lab at the University of Zurich, we will atttempt to determine the stucture of TRIM5. In the second specific aim screens for host factors essential to retroviral restriction by TRIM5? will be conducted using cell clones in which TRIM5? is not sufficient for restriction, biochemical assays for TRIM5-binding proteins, and functional screens disrupting given cellular factors. Finally, in a directed set of experiments the importance for retroviral restriction of ubiquitin and TRIM5-associated E3 ubiquitin ligase activity will be tested, as well as the contribution of TRIM5 to innate immune signal transduction. These experiments will extend knowledge concerning the mechanisms of innate immunity to HIV-1. By doing so it is expected that these studies will contribute to the development of novel approaches for preventing HIV-1 infection and for blocking progression to AIDS in those individuals already infected with this lethal virus.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Innate Immune Sensing of HIV-1 by Dendritic Cells
Luban Jeremy (2012), Innate Immune Sensing of HIV-1 by Dendritic Cells, in Cell Host and Microbe, 12(4), 408-418.
The Carboxyl-Terminus of Human Immunodeficiency Virus Type 2 Circulating Recombinant form 01_AB Capsid Protein Affects Sensitivity to Human TRIM5a
Miyamoto Tadashi (2012), The Carboxyl-Terminus of Human Immunodeficiency Virus Type 2 Circulating Recombinant form 01_AB Capsid Protein Affects Sensitivity to Human TRIM5a, in PLoS One, 7(10), e47757.
TRIM5 and the Regulation of HIV-1 Infectivity
Luban Jeremy (2012), TRIM5 and the Regulation of HIV-1 Infectivity, in Mol Biol Int, 2012, 426840.
TRIM5 structure, HIV-1 capsid recognition, and innate immune signaling
Gruetter Markus, Luban Jeremy (2012), TRIM5 structure, HIV-1 capsid recognition, and innate immune signaling, in Current Opinion in Virology, 2(2), 142-150.
Vpx rescues HIV-1 transduction of dendritic cells from the antiviral state established by type 1 interferon.
Pertel Thomas, Reinhard Christian, Luban Jeremy (2011), Vpx rescues HIV-1 transduction of dendritic cells from the antiviral state established by type 1 interferon., in Retrovirology, 8, 49.
Nef decreases HIV-1 sensitivity to neutralizing antibodies that target the membrane-proximal external region of TMgp41.
Lai Rachel (2011), Nef decreases HIV-1 sensitivity to neutralizing antibodies that target the membrane-proximal external region of TMgp41., in PLoS Pathogens, 7(12), e1002442.
TRIM5alpha associates with proteasomal subunits in cells while in complex with HIV-1 virions.
Lukic Zana, Hausmann Stephane, Sebastian Sarah, Rucci Justin, Sastri Jaya, Robia Seth L, Luban Jeremy, Campbell Edward M (2011), TRIM5alpha associates with proteasomal subunits in cells while in complex with HIV-1 virions., in Retrovirology, 8(1), 93.
Inhibition of HIV-1 infection by TNPO3 depletion is determined by capsid and detectable after viral cDNA enters the nucleus.
De Iaco Alberto (2011), Inhibition of HIV-1 infection by TNPO3 depletion is determined by capsid and detectable after viral cDNA enters the nucleus., in Retrovirology, 8, 98.
TRIM22 inhibits HIV-1 transcription independently of its E3 ubiquitin ligase activity, Tat, and NF-kappaB-responsive long terminal repeat elements.
Kajaste-Rudnitski Anna, Marelli Sara S, Pultrone Cinzia, Pertel Thomas, Uchil Pradeep D, Mechti Nadir, Mothes Walther, Poli Guido, Luban Jeremy, Vicenzi Elisa (2011), TRIM22 inhibits HIV-1 transcription independently of its E3 ubiquitin ligase activity, Tat, and NF-kappaB-responsive long terminal repeat elements., in Journal of virology, 85(10), 5183-96.
TRIM5 is an innate immune sensor for the retrovirus capsid lattice.
Pertel Thomas, Hausmann Stéphane, Morger Damien, Züger Sara, Guerra Jessica, Lascano Josefina, Reinhard Christian, Santoni Federico A, Uchil Pradeep D, Chatel Laurence, Bisiaux Aurélie, Albert Matthew L, Strambio-De-Castillia Caterina, Mothes Walther, Pizzato Massimo, Grütter Markus G, Luban Jeremy (2011), TRIM5 is an innate immune sensor for the retrovirus capsid lattice., in Nature, 472(7343), 361-5.
Association of TRIM22 with the type 1 interferon response and viral control during primary HIV-1 infection.
Singh Ravesh, Gaiha Gaurav, Werner Lise, McKim Kevin, Mlisana Koleka, Luban Jeremy, Walker Bruce D, Karim Salim S Abdool, Brass Abraham L, Ndung'u Thumbi, CAPRISA Acute Infection Study Team (2011), Association of TRIM22 with the type 1 interferon response and viral control during primary HIV-1 infection., in Journal of virology, 85(1), 208-16.
Cyclophilin B interacts with sodium-potassium ATPase and is required for pump activity in proximal tubule cells of the kidney.
Suñé Guillermo, Sarró Eduard, Puigmulé Marta, López-Hellín Joan, Zufferey Madeleine, Pertel Thomas, Luban Jeremy, Meseguer Anna (2010), Cyclophilin B interacts with sodium-potassium ATPase and is required for pump activity in proximal tubule cells of the kidney., in PloS one, 5(11), e13930.
Cyclosporine A-sensitive, cyclophilin B-dependent endoplasmic reticulum-associated degradation.
Bernasconi Riccardo, Soldà Tatiana, Galli Carmela, Pertel Thomas, Luban Jeremy, Molinari Maurizio (2010), Cyclosporine A-sensitive, cyclophilin B-dependent endoplasmic reticulum-associated degradation., in PloS one, 5(9), e13008.
Deciphering the code for retroviral integration target site selection.
Santoni Federico Andrea, Hartley Oliver, Luban Jeremy (2010), Deciphering the code for retroviral integration target site selection., in PLoS computational biology, 6(11), e1001008.
p62/sequestosome-1 associates with and sustains the expression of retroviral restriction factor TRIM5alpha.
O'Connor Christopher, Pertel Thomas, Gray Seth, Robia Seth L, Bakowska Joanna C, Luban Jeremy, Campbell Edward M (2010), p62/sequestosome-1 associates with and sustains the expression of retroviral restriction factor TRIM5alpha., in Journal of virology, 84(12), 5997-6006.
Cyclosporine blocks incorporation of HIV-1 envelope glycoprotein into virions.
Sokolskaja Elena, Olivari Silvia, Zufferey Madeleine, Strambio-De-Castillia Caterina, Pizzato Massimo, Luban Jeremy (2010), Cyclosporine blocks incorporation of HIV-1 envelope glycoprotein into virions., in Journal of virology, 84(9), 4851-5.
Human cellular restriction factors that target HIV-1 replication.
Strebel Klaus, Luban Jeremy, Jeang Kuan-Teh (2009), Human cellular restriction factors that target HIV-1 replication., in BMC medicine, 7, 48.
Potent inhibition of HIV-1 by TRIM5-cyclophilin fusion proteins engineered from human components.
Neagu Martha R, Ziegler Patrick, Pertel Thomas, Strambio-De-Castillia Caterina, Grütter Christian, Martinetti Gladys, Mazzucchelli Luca, Grütter Markus, Manz Markus G, Luban Jeremy (2009), Potent inhibition of HIV-1 by TRIM5-cyclophilin fusion proteins engineered from human components., in The Journal of clinical investigation, 119(10), 3035-47.
Efficient IgM assembly and secretion require the plasma cell induced endoplasmic reticulum protein pERp1.
van Anken Eelco, Pena Florentina, Hafkemeijer Nicole, Christis Chantal, Romijn Edwin P, Grauschopf Ulla, Oorschot Viola M J, Pertel Thomas, Engels Sander, Ora Ari, Lástun Viorica, Glockshuber Rudi, Klumperman Judith, Heck Albert J R, Luban Jeremy, Braakman Ineke (2009), Efficient IgM assembly and secretion require the plasma cell induced endoplasmic reticulum protein pERp1., in Proceedings of the National Academy of Sciences of the United States of America, 106(40), 17019-24.

Collaboration

Group / person Country
Types of collaboration
University of Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events



Self-organised

Title Date Place
Retroviruses 24.05.2010 Cold Spring Harbor

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Keystone 20.03.2011 Vancouver


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media SIDA Immune Discovery Tribune de Geneve Western Switzerland 21.04.2011

Associated projects

Number Title Start Funding scheme
113558 TRIM5 and Innate Resistance to HIV-1 01.10.2006 Project funding (Div. I-III)

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