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)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI024755-29
Application #
8867119
Study Section
Special Emphasis Panel (NSS)
Program Officer
Church, Elizabeth S
Project Start
1987-04-01
Project End
2016-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
29
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
Dong, Yuanchen; Chen, Shuobing; Zhang, Shijian et al. (2018) Folding DNA into a Lipid-Conjugated Nanobarrel for Controlled Reconstitution of Membrane Proteins. Angew Chem Int Ed Engl 57:2072-2076
Herschhorn, Alon; Sodroski, Joseph (2017) An entry-competent intermediate state of the HIV-1 envelope glycoproteins. Receptors Clin Investig 4:
Herschhorn, Alon; Gu, Christopher; Moraca, Francesca et al. (2017) The ?20-?21 of gp120 is a regulatory switch for HIV-1 Env conformational transitions. Nat Commun 8:1049
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:
Madani, Navid; Princiotto, Amy M; Zhao, Connie et al. (2017) Activation and Inactivation of Primary Human Immunodeficiency Virus Envelope Glycoprotein Trimers by CD4-Mimetic Compounds. J Virol 91:
Go, Eden P; Ding, Haitao; Zhang, Shijian et al. (2017) Glycosylation Benchmark Profile for HIV-1 Envelope Glycoprotein Production Based on Eleven Env Trimers. J Virol 91:
Johnson, Jacklyn; Zhai, Yinjie; Salimi, Hamid et al. (2017) Induction of a Tier-1-Like Phenotype in Diverse Tier-2 Isolates by Agents That Guide HIV-1 Env to Perturbation-Sensitive, Nonnative States. J Virol 91:
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:
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 90:5031-5046
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

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