Human immunodeficiency virus (HIV-1) is the etiologic agent of acquired immunodeficiency syndrome (AIDS). The HIV-1 envelope glycoproteins, gp120 and gp41, play critical roles during virus entry into the target cell, mediating binding to CD4 and the chemokine receptors and the fusion of viral and cellular membranes. The location of the envelope glycoproteins outside of the viral membrane renders these molecules important targets for therapeutic and vaccine development, since they are the only viral components accessible to antibodies. The short half-life of HIV-1-producing cells in infected humans suggests the probable importance of viral cytopathic effect, which is mediated by the viral envelope glycoproteins, to CD4 depletion in vivo. The goal of the proposed work is to understand the structure- function relationships of the HIV-1 envelope glycoproteins important for membrane fusion, a process that contributes to virus entry and cytopathic effect.
Specific aims for the extension period of the proposal are: 1. To define precisely the structural basis for the non-covalent association of gpl 20 and gp41 in the unliganded and CD4-bound HIV-1 and SIV envelope glycoproteins; 2. To assess whether a direct relationship exists between CD4 dependency and neutralization resistance, and to define the role of CD4 in HIV-1 entry; 3. To define the structure and function of the V1/V2 variable loops in the context of the HIV-1 envelope glycoprotein trimer;and 4. To understand the role of the chemokine receptors in the virus entry process.

Public Health Relevance

Human immunodeficiency virus (HIV-1) causes acquired immunodeficiency syndrome (AIDS), a major global public health problem. HIV-1 uses its envelope glycoproteins to enter cells. Understanding the structure and function of the HIV-1 envelope glycoproteins should expedite the development of vaccines or microbicides to inhibit HIV-1 transmission and replication.

Agency
National Institute of Health (NIH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI024755-28
Application #
8696987
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Sharma, Opendra K
Project Start
Project End
Budget Start
Budget End
Support Year
28
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02215
Madani, Navid; Princiotto, Amy M; Easterhoff, David et al. (2016) Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds. J Virol 90:5031-46
Herschhorn, Alon; Ma, Xiaochu; Gu, Christopher et al. (2016) Release of gp120 Restraints Leads to an Entry-Competent Intermediate State of the HIV-1 Envelope Glycoproteins. MBio 7:
Go, Eden P; Herschhorn, Alon; Gu, Christopher et al. (2015) Comparative Analysis of the Glycosylation Profiles of Membrane-Anchored HIV-1 Envelope Glycoprotein Trimers and Soluble gp140. J Virol 89:8245-57
Alsahafi, Nirmin; Debbeche, Olfa; Sodroski, Joseph et al. (2015) Effects of the I559P gp41 change on the conformation and function of the human immunodeficiency virus (HIV-1) membrane envelope glycoprotein trimer. PLoS One 10:e0122111
Richard, Jonathan; Veillette, Maxime; Brassard, Nathalie et al. (2015) CD4 mimetics sensitize HIV-1-infected cells to ADCC. Proc Natl Acad Sci U S A 112:E2687-94
Madani, Navid; Princiotto, Amy M; Schön, Arne et al. (2014) CD4-mimetic small molecules sensitize human immunodeficiency virus to vaccine-elicited antibodies. J Virol 88:6542-55
Herschhorn, Alon; Gu, Christopher; Espy, Nicole et al. (2014) A broad HIV-1 inhibitor blocks envelope glycoprotein transitions critical for entry. Nat Chem Biol 10:845-52
McGee, Kathleen; Haim, Hillel; Korioth-Schmitz, Birgit et al. (2014) The selection of low envelope glycoprotein reactivity to soluble CD4 and cold during simian-human immunodeficiency virus infection of rhesus macaques. J Virol 88:21-40
Yen, Po-Jen; Herschhorn, Alon; Haim, Hillel et al. (2014) Loss of a conserved N-linked glycosylation site in the simian immunodeficiency virus envelope glycoprotein V2 region enhances macrophage tropism by increasing CD4-independent cell-to-cell transmission. J Virol 88:5014-28
Mao, Youdong; Castillo-Menendez, Luis R; Sodroski, Joseph G (2013) Reply to Subramaniam, van Heel, and Henderson: Validity of the cryo-electron microscopy structures of the HIV-1 envelope glycoprotein complex. Proc Natl Acad Sci U S A 110:E4178-82

Showing the most recent 10 out of 140 publications