RESUMO
Maraviroc (MVC) is a new antagonist of the CCR5 coreceptor and is the first antiviral compound available that has a cell factor essential for HIV entry as a target. The information available from clinical studies with MVC suggests that the main cause of therapeutic failure is, more than the tropism change, the rapid selection of pre-existing strains with an affinity for CXCR4, not detected by the reference test. A recently developed tropism test with an improved sensitivity will help to detect the minority, but clinically significant, presence of strains that use CXCR4. Evidence of resistance to MVC has been shown in vivo in some patients. The mechanism of this resistance appears to be related to changes in gp120 and mainly in the V3 region which enables the virus to recognise the CCR5-co-receptor bound to the MVC molecule. From a practical point of view, standardised tests are currently unavailable to assess susceptibility to MVC, although in dose-response phenotype tests a maximum percentage inhibition (MPI) < 95% would be indicative of resistance to the compound. Similarly, although some mutations associated with resistance in V3, and other zones of gp120, have been described, this preliminary information suggests different resistance patterns and at the moment, we do not know the canonical mutations to be able to establish genotyping algorithms.
Assuntos
Antagonistas dos Receptores CCR5 , Cicloexanos/farmacologia , Inibidores da Fusão de HIV/farmacologia , Infecções por HIV/tratamento farmacológico , HIV/fisiologia , Fusão de Membrana/efeitos dos fármacos , Triazóis/farmacologia , Ligação Viral/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Sequência de Aminoácidos , Ensaios Clínicos como Assunto/estatística & dados numéricos , Cicloexanos/uso terapêutico , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Farmacorresistência Viral/genética , Genes env , HIV/genética , Proteína gp120 do Envelope de HIV/química , Proteína gp120 do Envelope de HIV/genética , Proteína gp120 do Envelope de HIV/fisiologia , Inibidores da Fusão de HIV/uso terapêutico , Humanos , Maraviroc , Dados de Sequência Molecular , Estudos Multicêntricos como Assunto , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/fisiologia , Receptores CXCR4/fisiologia , Seleção Genética , Falha de Tratamento , Triazóis/uso terapêutico , Produtos do Gene env do Vírus da Imunodeficiência Humana/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/fisiologiaRESUMO
Mannose-binding proteins derived from several plants (i.e. Hippeastrum hybrid and Galanthus nivalis agglutinin) or prokaryotes (i.e. cyanovirin-N) inhibit human immunodeficiency virus (HIV) replication and select for drug-resistant viruses that show profound deletion of N-glycosylation sites in the GP120 envelope (Balzarini, J., Van Laethem, K., Hatse, S., Vermeire, K., De Clercq, E., Peumans, W., Van Damme, E., Vandamme, A.-M., Bolmstedt, A., and Schols, D. (2004) J. Virol. 78, 10617-10627; Balzarini, J., Van Laethem, K., Hatse, S., Froeyen, M., Van Damme, E., Bolmstedt, A., Peumans, W., De Clercq, E., and Schols, D. (2005) Mol. Pharmacol. 67, 1556-1565). Here we demonstrated that the N-acetylglucosamine-binding protein from Urtica dioica (UDA) prevents HIV entry and eventually selects for viruses in which conserved N-glycosylation sites in GP120 were deleted. In contrast to the mannose-binding proteins, which have a 50-100-fold decreased antiviral activity against the UDA-exposed mutant viruses, UDA has decreased anti-HIV activity to a very limited extent, even against those mutant virus strains that lack at least 9 of 22 ( approximately 40%) glycosylation sites in their GP120 envelope. Therefore, UDA represents the prototype of a new conceptual class of carbohydrate-binding agents with an unusually specific and targeted drug resistance profile. It forces HIV to escape drug pressure by deleting the indispensable glycans on its GP120, thereby obligatorily exposing previously hidden immunogenic epitopes on its envelope.
Assuntos
Fármacos Anti-HIV , Proteína gp120 do Envelope de HIV/química , HIV-1/efeitos dos fármacos , Lectinas/farmacologia , Lectinas de Plantas/farmacologia , Polissacarídeos/química , Sítios de Ligação , Sequência Conservada , Farmacorresistência Viral , Genótipo , Glicosilação , Proteína gp120 do Envelope de HIV/fisiologia , HIV-1/classificação , HIV-1/genética , Lectina de Ligação a Manose/administração & dosagem , Lectina de Ligação a Manose/farmacologia , Modelos Moleculares , Mutação , Polissacarídeos/análise , Urtica dioica/química , Cultura de VírusRESUMO
HIV infection of the central nervous system leads to HIV-associated dementia (HAD) in a substantial subset of infected individuals. The pathogenesis of neuronal dysfunction in HAD is not well understood, but previous studies have demonstrated evidence for activation of apoptotic pathways. The tumor suppressor transcription factor p53 is an apical mediator of neuronal apoptosis following a variety of injurious stimuli. To determine whether p53 participates in HAD, we exposed cerebrocortical cultures from wild-type and p53 deficient mice to the neurotoxic HIV envelope protein gp120. Using neuron/microglia co-culture of mixed p53 genotype, we observed that both neurons and microglia require p53 for gp120 induced neuronal apoptosis. Additionally, accumulation of p53 protein in neurons was recently reported in post-mortem cortical tissue from a small group of HAD patients. Using a much larger cohort of HAD cases, we extend this finding and report that p53 protein also increases in non-neuronal cells, including microglia. Taken together these findings demonstrate a novel role for p53 in the microglial response to gp120. Additionally, these findings, in conjunction with a recent report that monocytes expressing HIV-Tat also secrete neurotoxins that promote p53 activation, suggest that distinct HIV proteins may converge on the p53 pathway to promote neurotoxicity.
Assuntos
Complexo AIDS Demência/metabolismo , Lobo Frontal/patologia , Proteína gp120 do Envelope de HIV/fisiologia , Microglia/patologia , Neurônios/metabolismo , Complexo AIDS Demência/patologia , Animais , Apoptose , Biomarcadores , Cálcio/análise , Células Cultivadas , Técnicas de Cocultura , Lobo Frontal/metabolismo , Genes p53 , Humanos , Camundongos , Camundongos Knockout , Microglia/metabolismo , Degeneração Neural , Neurônios/patologia , Receptores CCR5/fisiologia , Proteínas Recombinantes/farmacologia , Transdução de Sinais , Método Simples-CegoRESUMO
Baicalin (BA) is a flavonoid compound purified from medicinal plant Scutellaria baicalensis Georgi and has been shown to possess anti-inflammatory and anti-HIV-1 activities. In an effort to elucidate the mechanism of the anti-inflammatory effect of BA, we recently found that this flavonoid compound was able to form complexes with selected chemokines and attenuated their capacity to bind and activate receptors on the cell surface. These observations prompted us to investigate whether BA could inhibit HIV-1 infection by interfering with viral entry, a process known to involve interaction between HIV-1 envelope proteins and the cellular CD4 and chemokine receptors. We found that BA at the noncytotoxic concentrations, inhibited both T cell tropic (X4) and monocyte tropic (R5) HIV-1 Env protein mediated fusion with cells expressing CD4/CXCR4 or CD4/CCR5. Furthermore, presence of BA at the initial stage of HIV-1 viral adsorption blocked the replication of HIV-1 early strong stop DNA in cells. Since BA did not inhibit binding of HIV-1 gp120 to CD4, we propose that BA may interfere with the interaction of HIV-1 Env with chemokine coreceptors and block HIV-1 entry of target cells. Therefore, BA can be used as a basis for developing novel anti-HIV-1 agents.