Journal article
Contribution of intrinsic reactivity of the HIV-1 envelope glycoproteins to CD4-independent infection and global inhibitor sensitivity
PLoS pathogens, Vol.7(6), pp.e1002101-e1002101
06/2011
DOI: 10.1371/journal.ppat.1002101
PMCID: PMC3121797
PMID: 21731494
Abstract
Human immunodeficiency virus (HIV-1) enters cells following sequential activation of the high-potential-energy viral envelope glycoprotein trimer by target cell CD4 and coreceptor. HIV-1 variants differ in their requirements for CD4; viruses that can infect coreceptor-expressing cells that lack CD4 have been generated in the laboratory. These CD4-independent HIV-1 variants are sensitive to neutralization by multiple antibodies that recognize different envelope glycoprotein epitopes. The mechanisms underlying CD4 independence, global sensitivity to neutralization and the association between them are still unclear. By studying HIV-1 variants that differ in requirements for CD4, we investigated the contribution of CD4 binding to virus entry. CD4 engagement exposes the coreceptor-binding site and increases the "intrinsic reactivity" of the envelope glycoproteins; intrinsic reactivity describes the propensity of the envelope glycoproteins to negotiate transitions to lower-energy states upon stimulation. Coreceptor-binding site exposure and increased intrinsic reactivity promote formation/exposure of the HR1 coiled coil on the gp41 transmembrane glycoprotein and allow virus entry upon coreceptor binding. Intrinsic reactivity also dictates the global sensitivity of HIV-1 to perturbations such as exposure to cold and the binding of antibodies and small molecules. Accordingly, CD4 independence of HIV-1 was accompanied by increased susceptibility to inactivation by these factors. We investigated the role of intrinsic reactivity in determining the sensitivity of primary HIV-1 isolates to inhibition. Relative to the more common neutralization-resistant ("Tier 2-like") viruses, globally sensitive ("Tier 1") viruses exhibited increased intrinsic reactivity, i.e., were inactivated more efficiently by cold exposure or by a given level of antibody binding to the envelope glycoprotein trimer. Virus sensitivity to neutralization was dictated both by the efficiency of inhibitor/antibody binding to the envelope glycoprotein trimer and by envelope glycoprotein reactivity to the inhibitor/antibody binding event. Quantitative differences in intrinsic reactivity contribute to HIV-1 strain variability in global susceptibility to neutralization and explain the long-observed relationship between increased inhibitor sensitivity and decreased entry requirements for target cell CD4.
Details
- Title: Subtitle
- Contribution of intrinsic reactivity of the HIV-1 envelope glycoproteins to CD4-independent infection and global inhibitor sensitivity
- Creators
- Hillel Haim - Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Division of AIDS, Harvard Medical School, Boston, Massachusetts, United States of AmericaBettina StrackAemro KassaNavid MadaniLiping WangJoel R CourterAmy PrinciottoKathleen McGeeBeatriz PachecoMichael S SeamanAmos B Smith IIIJoseph Sodroski
- Resource Type
- Journal article
- Publication Details
- PLoS pathogens, Vol.7(6), pp.e1002101-e1002101
- DOI
- 10.1371/journal.ppat.1002101
- PMID
- 21731494
- PMCID
- PMC3121797
- NLM abbreviation
- PLoS Pathog
- ISSN
- 1553-7366
- eISSN
- 1553-7374
- Publisher
- Public Library of Science
- Grant note
- AI024755 / NIAID NIH HHS U19 AI067854 / NIAID NIH HHS R37 AI024755 / NIAID NIH HHS AI067854 / NIAID NIH HHS T32 AI007387 / NIAID NIH HHS U01 AI067854 / NIAID NIH HHS AI060354 / NIAID NIH HHS P30 AI060354 / NIAID NIH HHS
- Language
- English
- Date published
- 06/2011
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984083265502771
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