Fusion inhibitors, a new class of antiretroviral drugs, prevent new infections of cells by HIV by blocking the fusion of viral and cell membranes and denying access of the cellular replication machinery to HIV. In clinical trials, enfuvirtide, the first fusion inhibitor approved for the treatment of HIV infection, has induced a decline in plamsa HIV-1 RNA levels in highly treatment-experienced patients, raising new hopes of improved HIV treatment. Rational strategies to exploit fusion inhibitor action, however, are precluded by the poor understanding of the mechanism of HIV fusion with target cells. Here, we propose to develop a mechanistic theory of HIV fusion with target cells and a model of HIV dynamics under fusion inhibitor therapy. A reaction kinetic approach will be developed to describe protein binding across virion and target cell surfaces that leads to the formation of fusogenic protein complexes. Membrane shape evolution driven in part by fusogenic protein complexes will be described using theories from interface science, which determine interbilayer interactions, and statistical mechanics, which quantify density fluctuations, to predict the time required for the formation of a fusion pore. Comparisons of model predictions with experiments will provide a detailed understanding of fusion kinetics. Knowledge of the lifetimes of various structural intermediates will serve to identify novel drug and antibody targets and estimate fusion inhibitor efficacy. Standard models of HIV dynamics will be adapted to incorporate fusion inhibitor action and, in combination with descriptions of fusion inhibitor pharmacokinetics, to predict viral load evolution in patients undergoing fusion inhibitor therapy. The model will build a framework for analysis of patient data, provide insights into HIV pathogenesis in vivo, and establish guidelines for the optimization of fusion inhibitor-based therapy. The new strategies to combat HIV infection to be explored here are of particular importance to developing countries where affordable alternatives to current therapies are crucial in controlling HIV-related morbidity and mortality. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Research Grants (R03)
Project #
5R03AI065334-02
Application #
7192535
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Black, Paul L
Project Start
2006-03-01
Project End
2009-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
2
Fiscal Year
2007
Total Cost
$52,434
Indirect Cost
Name
Indian Institute of Science
Department
Type
DUNS #
650088487
City
Bangalore
State
Country
India
Zip Code
560 0-12
Mulampaka, Shiva Naresh; Dixit, Narendra M (2011) Estimating the threshold surface density of Gp120-CCR5 complexes necessary for HIV-1 envelope-mediated cell-cell fusion. PLoS One 6:e19941
Balagam, Rajesh; Singh, Vasantika; Sagi, Aparna Raju et al. (2011) Taking multiple infections of cells and recombination into account leads to small within-host effective-population-size estimates of HIV-1. PLoS One 6:e14531
Gadhamsetty, Saikrishna; Dixit, Narendra M (2010) Estimating frequencies of minority nevirapine-resistant strains in chronically HIV-1-infected individuals naive to nevirapine by using stochastic simulations and a mathematical model. J Virol 84:10230-40
Arora, Pankhuri; Dixit, Narendra M (2009) Timing the emergence of resistance to anti-HIV drugs with large genetic barriers. PLoS Comput Biol 5:e1000305
Vijay, N N V; Vasantika; Ajmani, Rahul et al. (2008) Recombination increases human immunodeficiency virus fitness, but not necessarily diversity. J Gen Virol 89:1467-77
Mohanty, Utkala; Dixit, Narendra M (2008) Mechanism-based model of the pharmacokinetics of enfuvirtide, an HIV fusion inhibitor. J Theor Biol 251:541-51
Suryavanshi, Gajendra W; Dixit, Narendra M (2007) Emergence of recombinant forms of HIV: dynamics and scaling. PLoS Comput Biol 3:2003-18