Efficiency of bridging-sheet recruitment explains HIV-1 R5 envelope glycoprotein sensitivity to soluble CD4 and macrophage tropism
Authors
O'Connell, Olivia J.Repik, Alexander
Reeves, Jacqueline D.
Gonzalez-Perez, Maria Paz
Quitadamo, Briana
Anton, Elizabeth D.
Duenas-Decamp, Maria J.
Peters, Paul J.
Lin, Rongheng
Zolla-Pazner, Susan
Corti, Davide
Wallace, Aaron
Wang, Shixia
Kong, Xiang-Peng
Lu, Shan
Clapham, Paul R.
UMass Chan Affiliations
Department of Microbiology and Physiological SystemsProgram in Molecular Medicine
Department of Medicine, Division of Infectious Diseases and Immunology
Document Type
Journal ArticlePublication Date
2013-01-01Keywords
Antibodies, MonoclonalAntibodies, Neutralizing
Antigens, CD4
HIV Antibodies
HIV Envelope Protein gp120
HIV-1
Humans
Macrophages
Models, Biological
Receptors, HIV
Recombinant Proteins
*Viral Tropism
*Virus Attachment
Amino Acids, Peptides, and Proteins
Carbohydrates
Cells
Cellular and Molecular Physiology
Immunology and Infectious Disease
Microbiology
Virology
Viruses
Metadata
Show full item recordAbstract
HIV-1 R5 viruses vary extensively in their capacity to infect macrophages. R5 viruses that confer efficient infection of macrophages are able to exploit low levels of CD4 for infection and predominate in brain tissue, where macrophages are a major target for infection. HIV-1 R5 founder viruses that are transmitted were reported to be non-macrophage-tropic. Here, we investigated the sensitivities of macrophage-tropic and non-macrophage-tropic R5 envelopes to neutralizing antibodies. We observed striking differences in the sensitivities of Env(+) pseudovirions to soluble CD4 (sCD4) and to neutralizing monoclonal antibodies (MAbs) that target the CD4 binding site. Macrophage-tropic R5 Envs were sensitive to sCD4, while non-macrophage-tropic Envs were significantly more resistant. In contrast, all Envs were sensitive to VRC01 regardless of tropism, while MAb b12 conferred an intermediate neutralization pattern where all the macrophage-tropic and about half of the non-macrophage-tropic Envs were sensitive. CD4, b12, and VRC01 share binding specificities on the outer domain of gp120. However, these antibodies differ in their ability to induce conformational changes on the trimeric envelope and in specificity for residues on the V1V2 loop stem and beta20-21 junction that are targets for CD4 in recruiting the bridging sheet. These distinct specificities of CD4, b12, and VRC01 likely explain the observed differences in Env sensitivity to inhibition by these reagents and provide an insight into the envelope mechanisms that control macrophage tropism. We present a model where the efficiency of bridging-sheet recruitment by CD4 is a major determinant of HIV-1 R5 envelope sensitivity to soluble CD4 and macrophage tropism.Source
J Virol. 2013 Jan;87(1):187-98. doi: 10.1128/JVI.01834-12. Epub 2012 Oct 10. Link to article on publisher's site
DOI
10.1128/JVI.01834-12Permanent Link to this Item
http://hdl.handle.net/20.500.14038/29997PubMed ID
23055568Related Resources
Rights
Publisher PDF posted as allowed by the publisher's author rights policy at http://journals.asm.org/site/misc/ASM_Author_Statement.xhtml.ae974a485f413a2113503eed53cd6c53
10.1128/JVI.01834-12