RESUMEN
OBJECTIVES: Lignosulfonic acid (LA), a low-cost lignin-derived polyanionic macromolecule, was extensively studied for its anti-HIV and anti-HSV activity in various cellular assays, its mechanism of viral inhibition and safety profile as potential microbicide. RESULTS: LA demonstrated potent inhibitory activity of HIV replication against a wide range of R5 and X4 HIV strains and prevented the uptake of HIV by bystander CD4+ T cells from persistently infected T cells in vitro (IC50: 0.07 - 0.34 µM). LA also inhibited HSV-2 replication in vitro in different cell types (IC50: 0.42 - 1.1 µM) and in rodents in vivo. Furthermore, LA neutralized the HIV-1 and HSV-2 DC-SIGN-mediated viral transfer to CD4+ T cells (IC50: ~1 µM). In addition, dual HIV-1/HSV-2 infection in T cells was potently blocked by LA (IC50: 0.71 µM). No antiviral activity was observed against the non-enveloped viruses Coxsackie type B4 and Reovirus type 1. LA is defined as a HIV entry inhibitor since it interfered with gp120 binding to the cell surface of T cells. Pretreatment of PBMCs with LA neither increased expression levels of cellular activation markers (CD69, CD25 and HLA-DR), nor enhanced HIV-1 replication. Furthermore, we found that LA had non-antagonistic effects with acyclovir, PRO2000 or LabyA1 (combination index (CI): 0.46 - 1.03) in its anti-HSV-2 activity and synergized with tenofovir (CI: 0.59) in its anti-HIV-1 activity. To identify mechanisms of LA resistance, we generated in vitro a mutant HIV-1 NL4.3LAresistant virus, which acquired seven mutations in the HIV-1 envelope glycoproteins: S160N, V170N, Q280H and R389T in gp120 and K77Q, N113D and H132Y in gp41. Additionally, HIV-1 NL4.3LAresistant virus showed cross-resistance with feglymycin, enfuvirtide, PRO2000 and mAb b12, four well-described HIV binding/fusion inhibitors. Importantly, LA did not affect the growth of vaginal Lactobacilli strains. CONCLUSION: Overall, these data highlight LA as a potential and unique low-cost microbicide displaying broad anti-HIV and anti-HSV activity.
Asunto(s)
Antivirales/farmacología , Inhibidores de Fusión de VIH/farmacología , VIH-1/efectos de los fármacos , Herpesvirus Humano 2/efectos de los fármacos , Lignina/análogos & derivados , Animales , Línea Celular Tumoral , Femenino , Células HEK293 , Proteína gp120 de Envoltorio del VIH/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/transmisión , VIH-1/fisiología , Herpes Genital/tratamiento farmacológico , Herpes Genital/transmisión , Herpesvirus Humano 2/fisiología , Humanos , Técnicas In Vitro , Leucocitos Mononucleares , Lignina/farmacología , Ratones , Replicación Viral/efectos de los fármacosRESUMEN
OBJECTIVES: This study aimed to assess the antiviral properties of a unique lectin (NICTABA) produced by the tobacco plant, Nicotiana tabacum. METHODS: Cellular assays were used to investigate the antiviral activity of NICTABA and Urtica dioica agglutinin (UDA). Surface plasmon resonance (SPR) studies were performed to study the sugar specificity and the interactions of both lectins with the envelope glycoproteins of HIV-1. RESULTS: The N-acetyl-d-glucosamine (GlcNAc)-binding lectins exhibited broad-spectrum activity against several families of enveloped viruses including influenza A/B, Dengue virus type 2, herpes simplex virus types 1 and 2 and HIV-1/2. The IC50 of NICTABA for various HIV-1 strains, clinical isolates and HIV-2 assessed in PBMCs ranged from 5 to 30 nM. Furthermore, NICTABA inhibited syncytium formation between persistently HIV-1-infected T cells and uninfected CD4+ T lymphocytes and prevented DC-SIGN-mediated HIV-1 transmission to CD4+ target T lymphocytes. However, unlike many other antiviral carbohydrate-binding agents (CBAs) described so far, NICTABA did not block HIV-1 capture to DC-SIGN+ cells and it did not interfere with the binding of the human monoclonal antibody 2G12 to gp120. SPR studies with HIV-1 envelope glycoproteins showed that the affinity of NICTABA for gp120 and gp41 was in the low nanomolar range. The specific binding of NICTABA to gp120 could be prevented in the presence of a GlcNAc trimer, but not in the presence of mannose trimers. NICTABA displayed no antiviral activity against non-enveloped viruses. CONCLUSIONS: Since CBAs possess a high genetic barrier for the development of viral resistance and NICTABA shows a broad antiviral activity profile, this CBA may qualify as a potential antiviral candidate with a pleiotropic mode of action aimed at targeting the entry of enveloped viruses.
Asunto(s)
Acetilglucosamina/metabolismo , Aglutininas/farmacología , Antivirales/farmacología , Lectinas/farmacología , Virus/efectos de los fármacos , Productos del Gen env del Virus de la Inmunodeficiencia Humana/metabolismo , Aglutininas/aislamiento & purificación , Antivirales/aislamiento & purificación , Humanos , Concentración 50 Inhibidora , Lectinas/aislamiento & purificación , Unión Proteica , Resonancia por Plasmón de Superficie , Nicotiana/química , Urtica dioica/químicaRESUMEN
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., α(1,3), α(1,2), α(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.
Asunto(s)
Farmacorresistencia Viral , Inhibidores de Fusión de VIH/farmacología , VIH-1/efectos de los fármacos , Animales , Glicosilación , Proteína gp120 de Envoltorio del VIH/antagonistas & inhibidores , Proteína gp120 de Envoltorio del VIH/genética , Proteína gp120 de Envoltorio del VIH/metabolismo , Inhibidores de Fusión de VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/genética , Humanos , Mutación , Unión ProteicaRESUMEN
OBJECTIVES: Oscillatoria agardhii agglutinin homologue (OAAH) proteins belong to a recently discovered lectin family. The founding member OAA and a designed hybrid OAAH (OPA) recognize similar but unique carbohydrate structures of Man-9, compared with other antiviral carbohydrate-binding agents (CBAs). These two newly described CBAs were evaluated for their inactivating properties on HIV replication and transmission and for their potential as microbicides. METHODS: Various cellular assays were used to determine antiviral activity against wild-type and certain CBA-resistant HIV-1 strains: (i) free HIV virion infection in human T lymphoma cell lines and PBMCs; (ii) syncytium formation assay using persistently HIV-infected T cells and non-infected CD4+ T cells; (iii) DC-SIGN-mediated viral capture; and (iv) transmission to uninfected CD4+ T cells. OAA and OPA were also evaluated for their mitogenic properties and potential synergistic effects using other CBAs. RESULTS: OAA and OPA inhibit HIV replication, syncytium formation between HIV-1-infected and uninfected T cells, DC-SIGN-mediated HIV-1 capture and transmission to CD4+ target T cells, thereby rendering a variety of HIV-1 and HIV-2 clinical isolates non-infectious, independent of their coreceptor use. Both CBAs competitively inhibit the binding of the Manα(1-2)Man-specific 2G12 monoclonal antibody (mAb) as shown by flow cytometry and surface plasmon resonance analysis. The HIV-1 NL4.3(2G12res), NL4.3(MVNres) and IIIB(GRFTres) strains were equally inhibited as the wild-type HIV-1 strains by these CBAs. Combination studies indicate that OAA and OPA act synergistically with Hippeastrum hybrid agglutinin, 2G12 mAb and griffithsin (GRFT), with the exception of OPA/GRFT. CONCLUSIONS: OAA and OPA are unique CBAs with broad-spectrum anti-HIV activity; however, further optimization will be necessary for microbicidal application.
Asunto(s)
Aglutininas/farmacología , Fármacos Anti-VIH/farmacología , VIH-1/efectos de los fármacos , Lectinas/farmacología , Oscillatoria/metabolismo , Aglutininas/metabolismo , Fármacos Anti-VIH/metabolismo , Proteínas Bacterianas/farmacología , Línea Celular , Farmacorresistencia Viral , Células Gigantes/efectos de los fármacos , Células Gigantes/virología , Proteína gp120 de Envoltorio del VIH/metabolismo , Humanos , Concentración 50 Inhibidora , Cinética , Lectinas/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/virología , Pruebas de Sensibilidad Microbiana , Unión ProteicaRESUMEN
Lantibiotics are peptides, produced by bacteria, that contain the noncanonical amino acid lanthionine and many of them exhibit antibacterial activities. The labyrinthopeptin A1 (LabyA1) is a prototype peptide of a novel class of carbacyclic lantibiotics. Here, we extensively evaluated its broad-spectrum activity against HIV and HSV in vitro, studied its mechanism of action and evaluated potential microbicidal applications. LabyA1 exhibited a consistent and broad anti-HIV activity (EC50s: 0.70-3.3 µM) and anti-HSV activity (EC50s: 0.29-2.8 µM) in cell cultures. LabyA1 also inhibited viral cell-cell transmission between persistently HIV-infected T cells and uninfected CD4(+) T cells (EC50â¶2.5 µM) and inhibited the transmission of HIV captured by DC-SIGN(+)-cells to uninfected CD4(+) T cells (EC50â¶4.1 µM). Time-of-drug addition studies revealed that LabyA1 acts as an entry inhibitor against HIV and HSV. Cellular and virus binding studies combined with SPR/FLIPR technology showed that LabyA1 interacted with the HIV envelope protein gp120, but not with the HIV cellular receptors. LabyA1 also demonstrated additive to synergistic effects in its anti-HIV-1 and anti-HSV-2 activity with anti(retro)viral drugs in dual combinations such as tenofovir, acyclovir, saquinavir, raltegravir and enfuvirtide. LabyA1 can be considered as a novel lead peptide as it had profound antiviral activity against HIV and HSV. Pre-treatment of PBMCs with LabyA1 neither increased the expression of the activation markers CD69 and CD25, nor enhanced HIV replication, nor significantly induced various inflammatory cytokines/chemokines. LabyA1 also did not affect the growth of vaginal Lactobacilli populations. Based on the lack of toxicity on the vaginal Lactobacillus strains and its synergistic/additive profile in combination with clinically approved anti(retro)virals, it deserves further attention as a potential microbicide candidate in the prevention of sexual transmitted diseases.
Asunto(s)
Fármacos Anti-VIH/farmacología , Bacteriocinas/farmacología , VIH-1/efectos de los fármacos , Lactobacillus/efectos de los fármacos , Simplexvirus/efectos de los fármacos , Bacteriocinas/química , Antígenos CD4/metabolismo , Moléculas de Adhesión Celular/metabolismo , Farmacorresistencia Viral/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/microbiología , Células Epiteliales/patología , Femenino , Células Gigantes/efectos de los fármacos , Proteína gp120 de Envoltorio del VIH/metabolismo , Infecciones por VIH/patología , Infecciones por VIH/virología , VIH-1/aislamiento & purificación , VIH-1/fisiología , Humanos , Cinética , Lactobacillus/crecimiento & desarrollo , Lectinas Tipo C/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/patología , Leucocitos Mononucleares/virología , Nisina/metabolismo , Nisina/farmacología , Unión Proteica/efectos de los fármacos , Receptores CXCR4/metabolismo , Receptores CXCR5/metabolismo , Receptores de Superficie Celular/metabolismo , Simplexvirus/fisiología , Vagina/microbiología , Vagina/patología , Internalización del Virus/efectos de los fármacos , Replicación Viral/efectos de los fármacosRESUMEN
Feglymycin (FGM), a natural Streptomyces-derived 13mer peptide, consistently inhibits HIV replication in the lower µM range. FGM also inhibits HIV cell-to-cell transfer between HIV-infected T cells and uninfected CD4(+) T cells and the DC-SIGN-mediated viral transfer to CD4(+) T cells. FGM potently interacts with gp120 (X4 and R5) as determined by SPR analysis and shown to act as a gp120/CD4 binding inhibitor. Alanine-scan analysis showed an important role for l-aspartic acid at position 13 for its anti-HIV activity. In vitro generated FGM-resistant HIV-1 IIIB virus (HIV-1 IIIB(FGMres)) showed two unique mutations in gp120 at positions I153L and K457I. HIV-1 IIIB(FGMres) virus was equally susceptible to other viral binding/adsorption inhibitors with the exception of dextran sulfate (9-fold resistance) and cyclotriazadisulfonamide (>15-fold), two well-described compounds that interfere with HIV entry. In conclusion, FGM is a unique prototype lead peptide with potential for further development of more potent anti-HIV derivatives.
Asunto(s)
Fármacos Anti-VIH/farmacología , Proteína gp120 de Envoltorio del VIH/antagonistas & inhibidores , VIH-1/efectos de los fármacos , Proteínas/farmacología , Internalización del Virus/efectos de los fármacos , Secuencia de Aminoácidos , Antibacterianos/química , Antibacterianos/farmacología , Fármacos Anti-VIH/química , Proteínas Bacterianas/química , Proteínas Bacterianas/farmacología , Antígenos CD4/efectos de los fármacos , Línea Celular , Descubrimiento de Drogas , Células Gigantes/efectos de los fármacos , VIH-1/clasificación , VIH-1/patogenicidad , VIH-1/fisiología , Humanos , Péptidos , Proteínas/químicaRESUMEN
Carbohydrate-binding agents (CBAs) are potential HIV microbicidal agents with a high genetic barrier to resistance. We wanted to evaluate whether two mannose-specific CBAs, recognizing multiple and often distinct glycan structures on the HIV envelope gp120, can interact synergistically against HIV-1, HIV-2, and HIV-1 strains that were selected for resistance against particular CBAs [i.e., 2G12 mAb and microvirin (MVN)]. Paired CBA/CBA combinations mainly showed synergistic activity against both wild-type HIV-1 and HIV-2 but also 2G12 mAb- and MVN-resistant HIV-1 strains as based on the median effect principle with combination indices (CIs) ranging between 0.29 and 0.97. Upon combination, an increase in antiviral potency of griffithsin (GRFT) up to â¼12-fold (against HIV-1), â¼8-fold (against HIV-2), and â¼6-fold (against CBA-resistant HIV-1) was observed. In contrast, HHA/GNA combinations showed additive activity against wild-type HIV-1 and HIV-2 strains, but remarkable synergy with HHA and GNA was observed against 2G12 mAb- and MVN-resistant HIV-1 strains (CI, 0.64 and 0.49, respectively). Overall, combinations of GRFT and other CBAs showed synergistic activity against HIV-1, HIV-2, and even against certain CBA-resistant HIV-1 strains. The CBAs tested appear to have distinct binding patterns on the gp120 envelope and therefore do not necessarily compete with each other's glycan binding sites on gp120. As a result, there might be no steric hindrance between two different CBAs in their competition for glycan binding (except for the HHA/GNA combination). These data are encouraging for the use of paired CBA combinations in topical microbicide applications (e.g., creams, gels, or intravaginal rings) to prevent HIV transmission.
Asunto(s)
Fármacos Anti-VIH/farmacología , Antiinfecciosos/farmacología , Metabolismo de los Hidratos de Carbono , Proteína gp120 de Envoltorio del VIH/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , VIH-2/efectos de los fármacos , Lectinas de Plantas/farmacología , Diseño de Fármacos , Farmacorresistencia Viral , Sinergismo Farmacológico , Femenino , Proteína gp120 de Envoltorio del VIH/genética , Infecciones por VIH/metabolismo , Humanos , MasculinoRESUMEN
Griffithsin (GRFT) is possibly the most potent anti-HIV peptide found in natural sources. Due to its potent and broad-spectrum antiviral activity and unique safety profile it has great potential as topical microbicide component. Here, we evaluated various combinations of GRFT against HIV-1 clade B and clade C isolates in primary peripheral blood mononuclear cells (PBMCs) and in CD4(+) MT-4 cells. In all combinations tested, GRFT showed synergistic activity profile with tenofovir, maraviroc and enfuvirtide based on the median effect principle with combination indices (CI) varying between 0.34 and 0.79 at the calculated EC(95) level. Furthermore, the different glycosylation patterns on the viral envelope of clade B and clade C gp120 had no observable effect on the synergistic interactions. Overall, we can conclude that the evaluated two-drug combination increases their antiviral potency and supports further clinical investigations in pre-exposure prophylaxis for GRFT combinations in the context of HIV-1 clade C infection.
Asunto(s)
Adenina/análogos & derivados , Proteínas Algáceas/farmacología , Fármacos Anti-VIH/farmacología , Ciclohexanos/farmacología , Sinergismo Farmacológico , Proteína gp41 de Envoltorio del VIH/farmacología , VIH-1/efectos de los fármacos , Lectinas/farmacología , Organofosfonatos/farmacología , Fragmentos de Péptidos/farmacología , Triazoles/farmacología , Adenina/farmacología , Linfocitos T CD4-Positivos/virología , Células Cultivadas , Enfuvirtida , Genotipo , VIH-1/clasificación , VIH-1/genética , Humanos , Leucocitos Mononucleares/virología , Maraviroc , Pruebas de Sensibilidad Microbiana , Lectinas de Plantas , TenofovirRESUMEN
Tenofovir, a well-known and highly prescribed anti-HIV-1 drug for the treatment of HIV/AIDS infections, has recently also shown its effectiveness as a potential microbicide drug in the prevention of HIV transmission. Here, we evaluated the combination of tenofovir with various members of the class of carbohydrate-binding agents (CBAs) targeting the glycans on the viral envelope gp120 for their anti-HIV efficacy. The tenofovir/CBA combinations predominantly showed synergistic antiviral activity using the median effect principle. These findings illustrate that combination of tenofovir with CBAs may increase the antiviral potency of the individual drugs and reducing the risk on potential side-effects.
Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/farmacología , Sinergismo Farmacológico , Proteína gp120 de Envoltorio del VIH/antagonistas & inhibidores , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Organofosfonatos/farmacología , Adenina/farmacología , Línea Celular , Proteína gp120 de Envoltorio del VIH/metabolismo , Infecciones por VIH/tratamiento farmacológico , VIH-1/clasificación , VIH-1/metabolismo , Humanos , TenofovirRESUMEN
The lectin actinohivin (AH) is a monomeric carbohydrate-binding agent (CBA) with three carbohydrate-binding sites. AH strongly interacts with gp120 derived from different X4 and R5 human immunodeficiency virus (HIV) strains, simian immunodeficiency virus (SIV) gp130, and HIV type 1 (HIV-1) gp41 with affinity constants (KD) in the lower nM range. The gp120 and gp41 binding of AH is selectively reversed by (alpha1,2-mannose)3 oligosaccharide but not by alpha1,3/alpha1,6-mannose- or GlcNAc-based oligosaccharides. AH binding to gp120 prevents binding of alpha1,2-mannose-specific monoclonal antibody 2G12, and AH covers a broader epitope on gp120 than 2G12. Prolonged exposure of HIV-1-infected CEM T-cell cultures with escalating AH concentrations selects for mutant virus strains containing N-glycosylation site deletions (predominantly affecting high-mannose-type glycans) in gp120. In contrast to 2G12, AH has a high genetic barrier, since several concomitant N-glycosylation site deletions in gp120 are required to afford significant phenotypic drug resistance. AH is endowed with broadly neutralizing activity against laboratory-adapted HIV strains and a variety of X4 and/or R5 HIV-1 clinical clade isolates and blocks viral entry within a narrow concentration window of variation (approximately 5-fold). In contrast, the neutralizing activity of 2G12 varied up to 1,000-fold, depending on the virus strain. Since AH efficiently prevents syncytium formation in cocultures of persistently HIV-1-infected HuT-78 cells and uninfected CD4+ T lymphocytes, inhibits dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin-mediated capture of HIV-1 and subsequent virus transmission to CD4+ T lymphocytes, does not upregulate cellular activation markers, lacks mitogenic activity, and does not induce cytokines/chemokines in peripheral blood mononuclear cell cultures, it should be considered a potential candidate drug for microbicidal use.
Asunto(s)
Fármacos Anti-VIH/metabolismo , Proteínas Bacterianas/metabolismo , Proteína gp120 de Envoltorio del VIH/metabolismo , VIH-1/efectos de los fármacos , Manosa/metabolismo , Animales , Fármacos Anti-VIH/farmacología , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/metabolismo , Proteínas Bacterianas/inmunología , Proteínas Bacterianas/farmacología , Anticuerpos ampliamente neutralizantes , Linfocitos T CD4-Positivos/virología , Células Cultivadas , Anticuerpos Anti-VIH , Proteína gp120 de Envoltorio del VIH/química , VIH-1/metabolismo , Humanos , Lectinas/inmunología , Lectinas/metabolismo , Lectinas/farmacología , Leucocitos Mononucleares/virología , Manosa/química , Pruebas de Neutralización , Polisacáridos/química , Polisacáridos/metabolismoRESUMEN
Microvirin (MVN), a recently isolated lectin from the cyanobacterium Microcystis aeruginosa PCC7806, shares 33% identity with the potent anti-human immunodeficiency virus (HIV) protein cyanovirin-N (CV-N) isolated from Nostoc ellipsosporum, and both lectins bind to similar carbohydrate structures. MVN is able to inhibit infection by a wide variety of HIV-1 laboratory-adapted strains and clinical isolates of different tropisms and subtypes in peripheral blood mononuclear cells. MVN also inhibits syncytium formation between persistently HIV-1-infected T cells and uninfected CD4(+) T cells and inhibits DC-SIGN-mediated HIV-1 binding and transmission to CD4(+) T cells. Long term passaging of HIV-1 exposed to dose-escalating concentrations of MVN resulted in the selection of a mutant virus with four deleted high mannose-type glycans in the envelope gp120. The MVN-resistant virus was still highly sensitive to various other carbohydrate binding lectins (e.g. CV-N, HHA, GNA, and UDA) but not anymore to the carbohydrate-specific 2G12 monoclonal antibody. Importantly, MVN is more than 50-fold less cytotoxic than CV-N. Also in sharp contrast to CV-N, MVN did not increase the level of the activation markers CD25, CD69, and HLA-DR in CD4(+) T lymphocytes, and subsequently, MVN did not enhance viral replication in pretreated peripheral blood mononuclear cells. Therefore, MVN may qualify as a useful lectin for potential microbicidal use based on its broad and potent antiviral activity and virtual lack of any stimulatory properties and cellular toxicity.
Asunto(s)
Fármacos Anti-VIH/farmacología , Proteínas Bacterianas/química , Proteínas Bacterianas/farmacología , Linfocitos T CD4-Positivos/virología , Proteínas Portadoras/farmacología , VIH-1/metabolismo , Lectinas/química , Lectina de Unión a Manosa/química , Manosa/química , Microcystis/metabolismo , Antígenos CD/biosíntesis , Antígenos de Diferenciación de Linfocitos T/biosíntesis , Linfocitos T CD4-Positivos/metabolismo , Separación Celular , Química Farmacéutica/métodos , Evaluación Preclínica de Medicamentos , Citometría de Flujo , Antígenos HLA-DR/metabolismo , Humanos , Subunidad alfa del Receptor de Interleucina-2/biosíntesis , Lectinas Tipo C/biosíntesis , Lectina de Unión a Manosa/farmacologíaRESUMEN
While 25 compounds have been formally licensed for the treatment of HIV infection (AIDS), only seven licensed products are currently available for the treatment of chronic hepatitis B virus (HBV) infection: interferon-α, pegylated interferon-α, lamivudine, adefovir (dipivoxil), entecavir, telbivudine and tenofovir (disoproxil fumarate). In contrast to the treatment of HIV infections where the individual drugs are routinely used in combination, for the treatment of chronic HBV infection the individual drugs are generally used in monotherapy. In principle, combination drug therapy should allow reducing the likelihood of drug-resistant development.
RESUMEN
A decade ago, standard therapy against chronic hepatitis B virus infections only consisted of lamivudine or IFN-alpha. Treatment with lamivudine and IFN has been compounded by, respectively, the emergence of drug-resistant virus strains and the appearance of serious side effects. In the last 10 years, hepatitis B treatment has made much progress. Several treatments are now licensed for the treatment of patients with chronic hepatitis B and others are under development. Here, we provide an overview of the potential and mode of action of anti-HBV agents that are currently available, and/or may become available in the near future. Foremost among these newer compounds are adefovir dipivoxil, entecavir and telbivudine.