This HIT-IT proposal addresses the hypothesis that an agent designed to bind to HIV-1 envelope spike glycoprotein gp120 and insert into the viral membrane simultaneously can deliver a membrane-directed force to the spike, thereby causing it to porate its own membrane, resulting in outflow of viral contents and deactivation of the virus. This hypothesis is based on the vision that (i) the mature HIV virion is likely osmotically stressed, and (ii) one role of the viral spike glycoprotein gp41 is to destabilize the viral membrane. In this work, we will design, test and optimize chimerae with gp120-binding and membrane-insertion domains. The project relies on a highly interconnected simulation/experimentation approach. If successful, our results will form the basis upon which a completely new class of virucidal agents can be developed.

Public Health Relevance

We propose to develop virucides against HIV-1 based upon a novel interpretation of the viral life cycle. These molecules will be designed to hijack essential viral properties, normally used to infect cells, in such a way as to trick the virus into self-destructing in the absence of a target cell. If successful, this work will form the basis for the development of potent, cheap and easy-to-manufacture microbicides for preventing the spread of AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI084117-04
Application #
8312616
Study Section
Special Emphasis Panel (ZAI1-CCH-A (M2))
Program Officer
Lawrence, Diane M
Project Start
2009-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$338,429
Indirect Cost
$117,906
Name
Drexel University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Baker, Michelle K; Gangupomu, Vamshi K; Abrams, Cameron F (2014) Characterization of the water defect at the HIV-1 gp41 membrane spanning domain in bilayers with and without cholesterol using molecular simulations. Biochim Biophys Acta 1838:1396-405
Contarino, Mark; Bastian, Arangassery R; Sundaram, Ramalingam Venkat Kalyana et al. (2014) Chimeric Cyanovirin-MPER Recombinantly Engineered Proteins Cause Cell-Free Virolysis of HIV-1. Antimicrob Agents Chemother 58:4249
Emileh, Ali; Abrams, Cameron F (2011) A mechanism by which binding of the broadly neutralizing antibody b12 unfolds the inner domain ýý1 helix in an engineered HIV-1 gp120. Proteins 79:537-46
Gangupomu, Vamshi K; Abrams, Cameron F (2010) All-atom models of the membrane-spanning domain of HIV-1 gp41 from metadynamics. Biophys J 99:3438-44