HIV transmission from infected to uninfected cells is known to be more efficient than infection with cell-free virus. In vitro, cell-cell contact stimulates HIV replication 100-10,000 fold. The ability of HIV to utilize and manipulate cell-cell contact for the purpose of efficient transmission critically contributes to the spreading of infection throughout the body and the progression to AIDS. Cell-associated HIV is also thought to play an important role during sexual as well as mother to child transmissions. Despite its importance, very little is known about the molecular mechanisms that govern contact-dependent cell to cell spread and no antiviral therapy has been directed against this step. Here we propose a team science approach to develop antiviral therapies that specifically prevent HIV cell-to-cell transmission. We will take advantage of the first robust cell-to-cell transmission assay allowing the quantitative measurement of virus spreading from cell to cell. We will apply this assay to isolate host factors required for contact-dependent cell-to-cell transmission. Our comprehensive approach will provide the scientific community with novel candidate genes that have the potential to transform research on the prevention of HIV transmission. We will then use the humanized mouse model for HIV infection to directly test if our identified lead candidate genes are required for the establishment of HIV infection in vivo following mucosal delivery. Finally, a parallel and complementary approach we will identify small molecules that function as novel therapeutics specifically interfering with HIV transmission. Our combined genetic and chemical approach will allow the development of novel preventive therapies that reduce the spreading of AIDS. This research proposal will develop antiviral therapies that target the ability of HIV to efficiently spread from cell to cell. It will first focus on basic science by identifying host genes required for HIV transmission, test their physiological relevance in vivo and initiate a translational approach to isolate small molecule inhibitors that specifically interfere with HIV transmission.

Public Health Relevance

This research proposal will develop antiviral therapies that target the ability of HIV to efficiently spread from cell to cell. It will first focus on basic science by identifying host genes required for HIV transmission, test their physiological relevance in vivo and initiate a translational approach to isolate small molecule inhibitors that specifically interfere with HIV transmission.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI084096-04
Application #
8308498
Study Section
Special Emphasis Panel (ZAI1-CCH-A (M2))
Program Officer
Sharma, Opendra K
Project Start
2009-09-29
Project End
2013-12-31
Budget Start
2012-09-01
Budget End
2013-12-31
Support Year
4
Fiscal Year
2012
Total Cost
$554,946
Indirect Cost
$219,631
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Agosto, Luis M; Zhong, Peng; Munro, James et al. (2014) Highly active antiretroviral therapies are effective against HIV-1 cell-to-cell transmission. PLoS Pathog 10:e1003982
Zhong, Peng; Agosto, Luis M; Ilinskaya, Anna et al. (2013) Cell-to-cell transmission can overcome multiple donor and target cell barriers imposed on cell-free HIV. PLoS One 8:e53138
Zhong, Peng; Agosto, Luis M; Munro, James B et al. (2013) Cell-to-cell transmission of viruses. Curr Opin Virol 3:44-50
Mothes, Walther; Sherer, Nathan M; Jin, Jing et al. (2010) Virus cell-to-cell transmission. J Virol 84:8360-8