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J Virol. 2019 Sep 4. pii: JVI.01403-19. doi: 10.1128/JVI.01403-19. [Epub ahead of print]

CD4 Incorporation into HIV-1 Viral Particles Exposes Envelope Epitopes Recognized by CD4-induced Antibodies.

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Centre de Recherche du CHUM, QC, Canada.
Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC, Canada.
Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Microbiology, Harvard Medical School, Boston, MA, USA.
Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Infectious Diseases Division, Department of Medicine of Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Centre de Recherche du CHUM, QC, Canada


CD4 downregulation on infected cells is a highly conserved function of primate lentiviruses. It has been shown to positively impact viral replication by a variety of mechanisms including enhanced viral release and infectivity, decrease of cell reinfection and protection from antibody-dependent cellular cytotoxicity (ADCC), which is often mediated by antibodies that require CD4 to change envelope (Env) conformation. Here we report that incorporation of CD4 into HIV-1 viral particles affects Env conformation resulting in the exposure of occluded epitopes recognized by CD4-induced antibodies. This translates into enhanced neutralization susceptibility by these otherwise non-neutralizing antibodies but is prevented by the HIV-1 Nef accessory protein. Altogether, these findings suggest that another functional consequence of Nef-mediated CD4 downregulation is the protection of viral particles from neutralization by commonly-elicited CD4-induced antibodies.IMPORTANCE It has been well established that Env-CD4 complexes expose epitopes recognized by commonly-elicited CD4-induced antibodies at the surface of HIV-1-infected cells, rendering them vulnerable to ADCC responses. Here we show that CD4 incorporation has a profound impact on Env conformation at the surface of viral particles. Incorporated CD4 exposes CD4-induced epitopes on Env, rendering HIV-1 susceptible to neutralization by otherwise non-neutralizing antibodies.


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