Glycan deletions in the HIV-1 gp120 V1/V2 domain compromise viral infectivity, sensitize the mutant virus strains to carbohydrate-binding agents and represent a specific target for therapeutic intervention

ABSTRACT Alcian Blue (AB), a phthalocyanine derivative, is able to prevent infection by a wide spectrum of human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus strains in various cell types [T cells, (co)receptor-transfected cells, and peripheral blood mononuclear cells]. With the exception of herpes simplex virus, AB is inactive against a broad variety of other (DNA and RNA) viruses. Time-of-addition studies show that AB prevents HIV-1 infection at the virus entry stage, exactly at the same time as carbohydrate-binding agents do. AB also efficiently prevents fusion between persistently HIV-1-infected HUT-78 cells and uninfected (CD4+) lymphocytes, DC-SIGN-directed HIV-1 capture, and subsequent transmission to uninfected (CD4+) T lymphocytes. Prolonged passaging of HIV-1 at dose-escalating concentrations of AB resulted in the selection of mutant virus strains in which several N-glycans of the HIV-1 gp120 envelope were deleted and in which positively charged amino acid mutations in both gp120 and gp41 appeared. A mutant virus strain in which four N-glycans were deleted showed a 10-fold decrease in sensitivity to the inhibitory effect of AB. These data suggest that AB is likely endowed with carbohydrate-binding properties and can be considered an important lead compound in the development of novel synthetic nonpeptidic antiviral drugs targeting the glycans of the envelope of HIV.

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Exposure of HIV-1 to a combination of two carbohydrate-binding agents markedly delays drug resistance development and selects for virus strains with compromised fitness

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkt414 ◽

2013 ◽

Vol 69 (3) ◽

pp. 582-593 ◽

Cited By ~ 3

Author(s):

L. Mathys ◽

J. Balzarini

Keyword(s):

Drug Resistance ◽

Carbohydrate Binding ◽

Resistance Development ◽

Binding Agents ◽

Virus Strains ◽

Hiv 1

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Pradimicin A, a Carbohydrate-Binding Nonpeptidic Lead Compound for Treatment of Infections with Viruses with Highly Glycosylated Envelopes, Such as Human Immunodeficiency Virus

Journal of Virology ◽

10.1128/jvi.01404-06 ◽

2006 ◽

Vol 81 (1) ◽

pp. 362-373 ◽

Cited By ~ 77

Author(s):

Jan Balzarini ◽

Kristel Van Laethem ◽

Dirk Daelemans ◽

Sigrid Hatse ◽

Antonella Bugatti ◽

...

Keyword(s):

Molecular Weight ◽

Human Immunodeficiency Virus ◽

Prolonged Exposure ◽

Glycosylation Site ◽

Carbohydrate Binding ◽

Genetic Barrier ◽

Drug Pressure ◽

Immunodeficiency Virus ◽

Virus Strains ◽

Hiv 1

ABSTRACT Pradimicin A (PRM-A), an antifungal nonpeptidic benzonaphtacenequinone antibiotic, is a low-molecular-weight (molecular weight, 838) carbohydrate binding agent (CBA) endowed with a selective inhibitory activity against human immunodeficiency virus (HIV). It invariably inhibits representative virus strains of a variety of HIV-1 clades with X4 and R5 tropisms at nontoxic concentrations. Time-of-addition studies revealed that PRM-A acts as a true virus entry inhibitor. PRM-A specifically interacts with HIV-1 gp120 and efficiently prevents virus transmission in cocultures of HUT-78/HIV-1 and Sup T1 cells. Upon prolonged exposure of HIV-1-infected CEM cell cultures, PRM-A drug pressure selects for mutant HIV-1 strains containing N-glycosylation site deletions in gp120 but not gp41. A relatively long exposure time to PRM-A is required before drug-resistant virus strains emerge. PRM-A has a high genetic barrier, since more than five N-glycosylation site deletions in gp120 are required to afford moderate drug resistance. Such mutated virus strains keep full sensitivity to the other known clinically used anti-HIV drugs. PRM-A represents the first prototype compound of a nonpeptidic CBA lead and, together with peptide-based lectins, belongs to a conceptually novel type of potential therapeutics for which drug pressure results in the selection of glycan deletions in the HIV gp120 envelope.

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Inhibition of infection and transmission of HIV-1 and lack of significant impact on the vaginal commensal lactobacilli by carbohydrate-binding agents

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkt152 ◽

2013 ◽

Vol 68 (9) ◽

pp. 2026-2037 ◽

Cited By ~ 8

Author(s):

M. I. Petrova ◽

L. Mathys ◽

S. Lebeer ◽

S. Noppen ◽

E. J. M. Van Damme ◽

...

Keyword(s):

Carbohydrate Binding ◽

Binding Agents ◽

Hiv 1

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Identification of novel thiocarboxanilide derivatives that suppress a variety of drug-resistant mutant human immunodeficiency virus type 1 strains at a potency similar to that for wild-type virus.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.6.1454 ◽

1996 ◽

Vol 40 (6) ◽

pp. 1454-1466 ◽

Cited By ~ 31

Author(s):

J Balzarini ◽

W G Brouwer ◽

D C Dao ◽

E M Osika ◽

E De Clercq

Keyword(s):

Human Immunodeficiency Virus ◽

Reverse Transcriptase ◽

Human Immunodeficiency Virus Type ◽

Effective Concentration ◽

Mutant Virus ◽

Wild Type ◽

Immunodeficiency Virus ◽

Virus Strains ◽

Hiv 1

A large variety of carboxanilide and thiocarboxanilide derivatives in which the original oxathiin or aliphatic moieties present in the prototype compounds UC84 and UC38 were replaced by an (un) substituted furanyl, thienyl, phenyl, or pyrrole entity have been evaluated for activity against wild-type human immunodeficiency virus type 1 strain IIIB [HIV-1 (IIIB)] and a series of mutant virus strains derived thereof. The mutant viruses contained either the Leu-100-->Ile, Lys-103-->Asn, Val-106-->Ala, Glu-138-->Lys, Tyr-181-->Cys, or Tyr-188-->Leu mutation in their reverse transcriptase. Several 3-(2-methylfuranyl)- and 3-(2-methylthienyl)-thiocarboxanilide ester, (thio)ether, and oxime ether derivatives showed exquisitely potent antiviral activity against wild-type HIV-1 (50% effective concentration, 0.009 to 0.021 microM). The pentenylethers of the 2-methylfuranyl and 2-methylthienyl derivatives (i.e., 313, N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]- 2-methyl-3-furancarbothioamide or UC-781, and 314, N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl] -2-methyl-3-thiophenecarbothioamide or UC-82) proved virtually equally inhibitory for wild-type and the Ile-100, Ala-106, and Lys-138 mutant virus strains (50% effective concentration, 0.015 to 0.021 microM). Their inhibitory effect against the Asn-103 and Cys-181 reverse transcriptase mutant virus strains was decreased only four- to sevenfold compared with wildtype virus. UC-781 and UC-82 should be considered potential candidate drugs for the treatment of HIV-1-infected individuals.

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Capture and transmission of HIV-1 by the C-type lectin L-SIGN (DC-SIGNR) is inhibited by carbohydrate-binding agents and polyanions

Antiviral Research ◽

10.1016/j.antiviral.2009.03.011 ◽

2009 ◽

Vol 83 (1) ◽

pp. 61-70 ◽

Cited By ~ 7

Author(s):

Joeri Auwerx ◽

Katrien O. François ◽

Els Vanstreels ◽

Kristel Van Laethem ◽

Dirk Daelemans ◽

...

Keyword(s):

Carbohydrate Binding ◽

Binding Agents ◽

Hiv 1

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The role of N -glycans of HIV-1 gp41 in virus infectivity and susceptibility to the suppressive effects of carbohydrate-binding agents

Retrovirology ◽

10.1186/preaccept-5732415801310430 ◽

2014 ◽

Vol 11 (1) ◽

pp. 107 ◽

Cited By ~ 1

Author(s):

Leen Mathys ◽

Jan Balzarini

Keyword(s):

Carbohydrate Binding ◽

Virus Infectivity ◽

Binding Agents ◽

Hiv 1

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Sensitivity of transmitted and founder human immunodeficiency virus type 1 envelopes to carbohydrate-binding agents griffithsin, cyanovirin-N and Galanthus nivalis agglutinin

Journal of General Virology ◽

10.1099/jgv.0.000299 ◽

2015 ◽

Vol 96 (12) ◽

pp. 3660-3666 ◽

Cited By ~ 6

Author(s):

Bodan Hu ◽

Tao Du ◽

Chang Li ◽

Sukun Luo ◽

Yalan Liu ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Carbohydrate Binding ◽

Immunodeficiency Virus ◽

Binding Agents ◽

Galanthus Nivalis ◽

Hiv 1 ◽

Microbicide Candidate

Human immunodeficiency virus type 1 (HIV-1) transmission often results from infection by a single transmitted/founder (T/F) virus. Here, we investigated the sensitivity of T/F HIV-1 envelope glycoproteins (Envs) to microbicide candidate carbohydrate-binding agents (CBAs) griffithsin (GRFT), cyanovirin-N (CV-N) and Galanthus nivalis agglutinin (GNA), showing that T/F Envs demonstrated different sensitivity to CBAs, with IC50 values ranging from 0.006 ± 0.0003 to >10 nM for GRFT, from 0.6 ± 0.2 to 28.9 ± 2.9 nM for CV-N and from 1.3 ± 0.2 to >500 nM for GNA. We further revealed that deglycosylation at position 295 or 448 decreased the sensitivity of T/F Env to GRFT, and at 339 to both CV-N and GNA. Mutation of all the three glcyans rendered a CBA-sensitive T/F Env largely resistant to GRFT, indicating that the sensitivity of T/F Env to GRFT is mainly determined by glycans at 295, 339 and 448. Our study identified specific T/F Env residues associated with CBA sensitivity.

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