The overarching goal of this Program is to determine the vulnerabilities of the HIV-1 Env protein cell entry machine as a target for disease intervention by identifying Env inhibitors, defining their structural mechanisms of action, and using a structure-mechanism framework as a guide to optimize antagonist functions. Inhibition of the initial entry of HIV-1 into host cells remains a compelling, yet elusive means to prevent infection and spread of the virus. Inhibitors of HIV-1 Env that can either block cell interactions, inactivate the trimeric virus spike protein complex before receptor encounter or disrupt receptor-induced conformational changes in the Env would hold great promise of inhibiting initial HIV-1 infection. Such inhibitors would provide virus-targeted molecular weapons both to prevent AIDS transmission, a global health priority, and to treat already-infected individuals. In spite of the great potential of Env inhibitors for AIDS intervention, structural complexity and polymorphisms of the Env proteins have presented significant challenges to progress. Nonetheless, the efforts of our Program have led to the development of two classes of Env gp120 inhibitors that utilize the highly conserved CD4 binding site, but with very different modes of action. Investigation of these inhibitors has defined unique pathways to engage the virus Env trimer and cause both inactivation of the virus and blockade of virus entry into the host cell. Our Program is ideally positioned to take advantage of these new results through state-of-the-art structure- and mechanism-based approaches, achieved by the collaborative nature of our multi-institutional research team, with strong expertise in high-resolution structure determination, structural dynamics, kinetic, thermodynamic and structural mechanisms of protein-protein interactions, chemical design and synthesis, computational methods, and virology. We will apply this team approach to structure-based design and mechanistic investigations of inhibitor chemotypes that we have already developed, and new inhibitor chemotypes as they are discovered in our own and other laboratories. Overall, the Program will provide a broad-based research infrastructure to identify new paths for the discovery of preventive and therapeutic agents that block HIV-1 Env function.

Public Health Relevance

In the effort to control and ultimately eradicate the global AIDS pandemic, targeting the HIV-1 envelope (Env) remains an important means to identify preventive and therapeutic interventions. The thrust of this Program Project is to identify HIV-1 antagonists by understanding the molecular and structural mechanisms of the HIV-1 Env and the vulnerabilities of Env that can be utilized to inactivate the virus and block host cell infectin.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-AARR-E (43))
Program Officer
Sakalian, Michael
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Drexel University
United States
Zip Code
Espy, Nicole; Pacheco, Beatriz; Sodroski, Joseph (2017) Adaptation of HIV-1 to cells with low expression of the CCR5 coreceptor. Virology 508:90-107
Nguyen, Hanh T; Madani, Navid; Ding, Haitao et al. (2017) Evaluation of the contribution of the transmembrane region to the ectodomain conformation of the human immunodeficiency virus (HIV-1) envelope glycoprotein. Virol J 14:33
Afanador, Gustavo A; Guerra, Alfredo J; Swift, Russell P et al. (2017) A novel lipoate attachment enzyme is shared by Plasmodium and Chlamydia species. Mol Microbiol 106:439-451
Witt, Kristen C; Castillo-Menendez, Luis; Ding, Haitao et al. (2017) Antigenic characterization of the human immunodeficiency virus (HIV-1) envelope glycoprotein precursor incorporated into nanodiscs. PLoS One 12:e0170672
Acharya, Kriti; Rashad, Adel A; Moraca, Francesca et al. (2017) Recognition of HIV-inactivating peptide triazoles by the recombinant soluble Env trimer, BG505 SOSIP.664. Proteins 85:843-851
Pancera, Marie; Lai, Yen-Ting; Bylund, Tatsiana et al. (2017) Crystal structures of trimeric HIV envelope with entry inhibitors BMS-378806 and BMS-626529. Nat Chem Biol 13:1115-1122
Prévost, Jérémie; Zoubchenok, Daria; Richard, Jonathan et al. (2017) Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody-Dependent Cell-Mediated Cytotoxicity Responses. J Virol 91:
Pacheco, Beatriz; Alsahafi, Nirmin; Debbeche, Olfa et al. (2017) Residues in the gp41 Ectodomain Regulate HIV-1 Envelope Glycoprotein Conformational Transitions Induced by gp120-Directed Inhibitors. J Virol 91:
Herschhorn, Alon; Sodroski, Joseph (2017) An entry-competent intermediate state of the HIV-1 envelope glycoproteins. Receptors Clin Investig 4:
Ding, Shilei; Verly, Myriam M; Princiotto, Amy et al. (2017) Short Communication: Small-Molecule CD4 Mimetics Sensitize HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity by Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Nonhuman Primates. AIDS Res Hum Retroviruses 33:428-431

Showing the most recent 10 out of 139 publications