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Published on: September 5, 2016
Effect of polyanion-resistance on HIV-1 infection
Michael D Bobardt1, Mercedes Armand-Ugón, Imma Clotet
1Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Abstract:
Polyanions are potent HIV-1 entry inhibitors. Nevertheless, resistant viruses may emerge under polyanion inhibitory pressure. Specifically, a polyanion-resistant virus replicates in T cells even in the presence of high concentrations of polyanions. We found that although the polyanion-resistant virus grows in suspension CD4+ T cells efficiently, it infects nonlymphocytic adherent CD4+ cells poorly. Given that a main distinction between suspension and adherent cells is the absence or presence of cell-surface heparan sulfate proteoglycan (HSPG), we investigated if the failure of the polyanion-resistant virus to infect adherent CD4+ cells arises from its inability to bind HSPG. We found that the emergence of mutations in gp120 associated with polyanion resistance resulted in a decreased capacity of HIV-1 to bind HSPG. We also found that the polycation polybrene rescued the capacity of the polyanion-resistant virus to bind HSPG and to infect adherent CD4+ cells. The identification of this virus, unable to bind HSPG, provides a convenient probe to measure the impact of HIV-1-HSPG interactions in vivo. Altogether, these findings suggest that polyanion-resistance narrows the range of potential target cells for HIV-1 in the host. This reinforces the hypothesis that cell-free or cell-associated polyanions such as HSPG possess the capacity to modulate HIV-1 pathogenesis.
Insights
HIV-1 entry inhibitors called polyanions can lead to resistant viruses. A resistant HIV-1 strain shows reduced binding to heparan sulfate proteoglycans (HSPG), limiting its target cell range.
Area of Science:
- Virology
- Immunology
- Biochemistry
Background:
- Polyanions are effective inhibitors of Human Immunodeficiency Virus type 1 (HIV-1) entry.
- The emergence of polyanion-resistant HIV-1 strains poses a challenge to therapeutic strategies.
- Understanding the mechanisms of resistance is crucial for developing new interventions.
Purpose of the Study:
- To investigate the mechanism by which HIV-1 develops resistance to polyanion inhibitors.
- To determine the role of heparan sulfate proteoglycans (HSPG) in polyanion-resistant HIV-1 infection.
- To characterize a novel polyanion-resistant HIV-1 strain for its potential as a research tool.
Main Methods:
- Comparative analysis of HIV-1 replication in suspension and adherent CD4+ T cells.
- Assessment of viral binding to cell-surface HSPG.
- Evaluation of viral infectivity in the presence of polyanions and polycations (polybrene).
- Mutation analysis of the viral envelope glycoprotein gp120.
Main Results:
- Polyanion-resistant HIV-1 efficiently replicates in suspension CD4+ T cells but poorly infects adherent CD4+ cells.
- Mutations associated with polyanion resistance in gp120 lead to decreased binding to HSPG.
- The polycation polybrene restores HSPG binding and infectivity of the resistant virus in adherent cells.
- The resistant virus's inability to bind HSPG was confirmed.
Conclusions:
- Polyanion resistance in HIV-1 is associated with impaired HSPG binding, restricting its cellular tropism.
- HSPG plays a significant role in mediating HIV-1 infection of adherent cells.
- This HSPG-binding deficient virus serves as a valuable tool for studying HIV-1-HSPG interactions.
- Polyanion-resistance mechanisms can modulate HIV-1 pathogenesis by altering target cell accessibility.
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