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HIV-1 and its resistance to peptidic carbohydrate-binding agents (CBAs): an overview.

ABSTRACT: The glycoproteins on the surfaces of enveloped viruses, such as HIV, can be considered as a unique target for antiviral therapy. Different carbohydrate-binding agents (CBAs) target specific glycans present on viral glycoproteins of enveloped viruses. It has been shown that long-term CBA pressure in vitro can result in mutant HIV-1 isolates with several N-linked glycan deletions on gp120. These studies demonstrated that mainly high-mannose type glycans are deleted. However, interestingly, N241, N262 and N356 on gp120 have never been found to be affected after prolonged CBA exposure. Here, we review the mutation and (cross)-resistance profiles of eleven specific generated CBA-resistant HIV-1 strains. We observed that the broad-neutralizing anti-carbohydrate binding mAb 2G12 became completely inactive against all the generated CBA-resistant HIV-1 clade B isolates. In addition, all of the CBAs discussed in this review, with the exception of NICTABA, interfered with the binding of 2G12 mAb to gp120 expressed on HIV-1-infected T cells. The cross-resistance profiles of mutant HIV-1 strains are varying from increased susceptibility to very high resistance levels, even among different classes of CBAs with dissimilar sugar specificities or binding moieties [e.g., ?(1,3), ?(1,2), ?(1,6)]. Recent studies demonstrated promising results in non-topical formulations (e.g., intranasally or subcutaneously), highlighting their potential for prevention (microbicides) and antiviral therapy.

SUBMITTER: Ferir G

PROVIDER: S-EPMC6270665 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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HIV-1 and its resistance to peptidic carbohydrate-binding agents (CBAs): an overview.

Férir Geoffrey G Gordts Stephanie C SC Schols Dominique D

Molecules (Basel, Switzerland) 20141215 12

The glycoproteins on the surfaces of enveloped viruses, such as HIV, can be considered as a unique target for antiviral therapy. Different carbohydrate-binding agents (CBAs) target specific glycans present on viral glycoproteins of enveloped viruses. It has been shown that long-term CBA pressure in vitro can result in mutant HIV-1 isolates with several N-linked glycan deletions on gp120. These studies demonstrated that mainly high-mannose type glycans are deleted. However, interestingly, N241, N ...[more]

PMID: 25517345

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Project description:BACKGROUND: Carbohydrate-binding agents (CBAs) are potent antiretroviral compounds that target the N-glycans on the HIV-1 envelope glycoproteins. The development of phenotypic resistance to CBAs by the virus is accompanied by the deletion of multiple N-linked glycans of the surface envelope glycoprotein gp120. Recently, also an N-glycan on the transmembrane envelope glycoprotein gp41 was shown to be deleted during CBA resistance development. RESULTS: We generated HIV-1 mutants lacking gp41 N-glycans and determined the influence of these glycan deletions on the viral phenotype (infectivity, CD4 binding, envelope glycoprotein incorporation in the viral particle and on the transfected cell, virus capture by DC-SIGN(+) cells and transmission of DC-SIGN-captured virions to CD4(+) T-lymphocytes) and on the phenotypic susceptibility of HIV-1 to a selection of CBAs. It was shown that some gp41 N-glycans are crucial for the infectivity of the virus. In particular, lack of an intact N616 glycosylation site was shown to result in the loss of viral infectivity of several (i.e. the X4-tropic IIIB and NL4.3 strains, and the X4/R5-tropic HE strain), but not all (i.e. the R5-tropic ADA strain) studied HIV-1 strains. In accordance, we found that the gp120 levels in the envelope of N616Q mutant gp41 strains NL4.3, IIIB and HE were severely decreased. In contrast, N616Q gp41 mutant HIV-1ADA contained gp120 levels similar to the gp120 levels in WT HIV-1ADA virus. Concomitantly deleting multiple gp41 N-glycans was often highly detrimental for viral infectivity. Using surface plasmon resonance technology we showed that CBAs have a pronounced affinity for both gp120 and gp41. However, the antiviral activity of CBAs is not dependent on the concomitant presence of all gp41 glycans. Single gp41 glycan deletions had no marked effects on CBA susceptibility, whereas some combinations of two to three gp41 glycan-deletions had a minor effect on CBA activity. CONCLUSIONS: We revealed the importance of some gp41 N-linked glycans, in particular the N616 glycan which was shown to be absolutely indispensable for the infectivity potential of several virus strains. In addition, we demonstrated that the deletion of up to three gp41 N-linked glycans only slightly affected CBA susceptibility.

Dataset Information

HIV-1 and its resistance to peptidic carbohydrate-binding agents (CBAs): an overview.

Publications

HIV-1 and its resistance to peptidic carbohydrate-binding agents (CBAs): an overview.

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