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HIV-1 antibodies and vaccine antigen selectively interact with lipid domains.

ABSTRACT: The rare, broadly neutralizing antibodies, 4E10 and 2F5, that target the HIV-1 membrane proximal external region also associate with HIV-1 membrane lipids as part of a required first-step in HIV-1 neutralization. HIV-1 virions have high concentration of cholesterol and sphingomyelin, which are able to organize into liquid-ordered domains (i.e., lipid rafts), and could influence the interaction of neutralizing antibodies with epitopes proximal to the membrane. The objective of this research is to understand how these lipid domains contribute to 2F5/4E10 membrane interactions and to antigen presentation in liposomal form of HIV-1 vaccines. To this end we have engineered biomimetic supported lipid bilayers and are able to use atomic force microscopy to visualize membrane domains, antigen clustering, and antibody-membrane interactions. Our results demonstrate that 2F5/4E10 do not interact with highly ordered gel and liquid-ordered domains and exclusively bind to a liquid-disordered lipid phase. This suggests that vaccine liposomes that contain key viral membrane components, such as high cholesterol content, may not be advantageous for 2F5/4E10 vaccine strategies. Rather, vaccine liposomes that primarily contain a liquid-disordered phase may be more likely to elicit production of lipid reactive, 2F5- and 4E10-like antibodies.

SUBMITTER: Hardy GJ

PROVIDER: S-EPMC4136754 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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HIV-1 antibodies and vaccine antigen selectively interact with lipid domains.

Hardy Gregory J GJ Wong Gene C GC Nayak Rahul R Anasti Kara K Hirtz Michael M Shapter Joseph G JG Alam S Munir SM Zauscher Stefan S

Biochimica et biophysica acta 20140711 10

The rare, broadly neutralizing antibodies, 4E10 and 2F5, that target the HIV-1 membrane proximal external region also associate with HIV-1 membrane lipids as part of a required first-step in HIV-1 neutralization. HIV-1 virions have high concentration of cholesterol and sphingomyelin, which are able to organize into liquid-ordered domains (i.e., lipid rafts), and could influence the interaction of neutralizing antibodies with epitopes proximal to the membrane. The objective of this research is to ...[more]

PMID: 25019685

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Project description:Purpose of reviewTo summarize the in-vivo efficacy of neutralizing human monoclonal antibodies against HIV-1, to discuss the recent finding that an engineered human antibody VH domain, domain antibody (dAb), exhibits exceptionally potent and broadly cross-reactive neutralizing activity against HIV-1 primary isolates by targeting a hidden conserved epitope that is not accessible by larger antibodies and to suggest the possibility of developing a novel class of potent HIV-1 inhibitors based on human dAbs.Recent findingsHIV-1 has evolved a number of strategies to evade humoral immunity, including protecting highly conserved and important structures from the access of antibodies generated by the immune system. We have recently demonstrated that a human dAb (size approximately 15 kDa), m36, targets a highly protected structure on the HIV-1 envelope glycoprotein (Env), gp120, and exhibits exceptionally potent neutralizing activity against HIV-1 primary isolates, with potency on average higher than those of the broadly cross-reactive neutralizing human monoclonal antibody, scFv m9, and the inhibitory peptide, C34.SummaryThe efficacy of the anti-HIV-1 therapy is significantly compromised by resistance to the currently used US Food and Drug Administration-approved antiretroviral drugs, which suggests an urgent need to develop novel classes of potent inhibitors. Several broadly cross-reactive neutralizing human monoclonal antibodies are highly effective against HIV-1 infection in vitro, but their administration to HIV-1-infected humans has only resulted in modest antiviral effects. Engineered human antibody fragments, dAbs, could be more potent because of their small size (about 10-fold smaller than that of an IgG), which allows targeting of highly conserved structures on the HIV-1 envelope glycoprotein that are not accessible by full-size antibodies and relatively efficient penetration into the densely packed lymphoid environment in which HIV-1 mostly replicates and spreads.

Dataset Information

HIV-1 antibodies and vaccine antigen selectively interact with lipid domains.

Publications

HIV-1 antibodies and vaccine antigen selectively interact with lipid domains.

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