Journal article
Induction of a Tier-1-Like Phenotype in Diverse Tier-2 Isolates by Agents That Guide HIV-1 Env to Perturbation-Sensitive, Nonnative States
Journal of virology, Vol.91(15), e00174-17
08/01/2017
DOI: 10.1128/JVI.00174-17
PMCID: PMC5512248
PMID: 28490588
Abstract
The envelope glycoproteins (Envs) on the surfaces of HIV-1 particles are targeted by host antibodies. Primary HIV-1 isolates demonstrate different global sensitivities to antibody neutralization; tier-1 isolates are sensitive, whereas tier-2 isolates are more resistant. Single-site mutations in Env can convert tier-2 into tier-1-like viruses. We hypothesized that such global change in neutralization sensitivity results from weakening of intramolecular interactions that maintain Env integrity. Three strategies commonly applied to perturb protein structure were tested for their effects on global neutralization sensitivity: exposure to low temperature, Env-activating ligands, and a chaotropic agent. A large panel of diverse tier-2 isolates from clades B and C was analyzed. Incubation at 0°C, which globally weakens hydrophobic interactions, causes gradual and reversible exposure of the coreceptor-binding site. In the cold-induced state, Envs progress at isolate-specific rates to unstable forms that are sensitive to antibody neutralization and then gradually lose function. Agents that mimic the effects of CD4 (CD4Ms) also induce reversible structural changes to states that exhibit isolate-specific stabilities. The chaotropic agent urea (at low concentrations) does not affect the structure or function of native Env. However, urea efficiently perturbs metastable states induced by cold and CD4Ms and increases their sensitivity to antibody neutralization and their inactivation rates Therefore, chemical and physical agents can guide Env from the stable native state to perturbation-sensitive forms and modulate their stability to bestow tier-1-like properties on primary tier-2 strains. These concepts can be applied to enhance the potency of vaccine-elicited antibodies and microbicides at mucosal sites of HIV-1 transmission.
An effective vaccine to prevent transmission of HIV-1 is a primary goal of the scientific and health care communities. Vaccine-elicited antibodies target the viral envelope glycoproteins (Envs) and can potentially inhibit infection. However, the potency of such antibodies is generally low. Single-site mutations in Env can enhance the global sensitivity of HIV-1 to neutralization by antibodies. We found that such a hypersensitivity phenotype can also be induced by agents that destabilize protein structure. Exposure to 0°C or low concentrations of Env-activating ligands gradually guides Env to metastable forms that expose cryptic epitopes and that are highly sensitive to neutralization. Low concentrations of the chaotropic agent urea do not affect native Env but destabilize perturbed states induced by cold or CD4Ms and increase their neutralization. The concept of enhancing antibody sensitivity by chemical agents that affect the structural stability of proteins can be applied to increase the potency of topical microbicides and vaccine-elicited antibodies.
Details
- Title: Subtitle
- Induction of a Tier-1-Like Phenotype in Diverse Tier-2 Isolates by Agents That Guide HIV-1 Env to Perturbation-Sensitive, Nonnative States
- Creators
- Jacklyn Johnson - Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAYunxia O'Malley - Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAHillel Haim - Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA Hillel-haim@uiowa.eduYinjie Zhai - Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAHamid Salimi - Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USANicole Espy - Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USANoah Eichelberger - Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAOrlando DeLeon - Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAJoel Courter - Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, USAAmos B Smith III - Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, USANavid Madani - Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USAJoseph Sodroski - Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA
- Resource Type
- Journal article
- Publication Details
- Journal of virology, Vol.91(15), e00174-17
- DOI
- 10.1128/JVI.00174-17
- PMID
- 28490588
- PMCID
- PMC5512248
- ISSN
- 0022-538X
- eISSN
- 1098-5514
- Grant note
- P01 GM056550 / NIGMS NIH HHS R37 AI024755 / NIAID NIH HHS UM1 AI100645 / NIAID NIH HHS T32 AI007533 / NIAID NIH HHS
- Language
- English
- Date published
- 08/01/2017
- Academic Unit
- Microbiology and Immunology; Stead Family Department of Pediatrics; Gastroenterology, Hepatology, Pancreatology, and Nutrition
- Record Identifier
- 9984083875402771
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