RESUMO
Adhesion molecules are known to play major roles in the initiation and stabilization of cell-to-cell contacts during the immunological response. Human immunodeficiency virus type 1 (HIV-1) exploits those interactions to facilitate infection and propagation processes. The primary objective of the present study was to investigate the ability of antagonists specific for lymphocyte function-associated antigen 1 (LFA-1) to diminish HIV-1 infection and transmission. We demonstrate here that LFA-1 antagonists can significantly reduce HIV-1 replication in primary human cells and virus propagation by affecting cell-to-cell interactions. Moreover, the inhibition of LFA-1-mediated adhesion events also potentiates the antiviral efficacy of the peptide fusion inhibitor T-20. Altogether, our data suggest that LFA-1 antagonists represent promising antiviral agents. Antiadhesion therapy could be considered a complementary strategy targeting cellular functions essential for HIV-1 spreading and against which the combined therapy currently used displays a limited efficacy.
Assuntos
Fármacos Anti-HIV/farmacologia , Proteína gp41 do Envelope de HIV/farmacologia , Inibidores da Fusão de HIV/farmacologia , HIV-1/efeitos dos fármacos , Antígeno-1 Associado à Função Linfocitária/fisiologia , Fragmentos de Peptídeos/farmacologia , Ácidos Ftálicos/farmacologia , beta-Alanina/análogos & derivados , Linhagem Celular , Células Dendríticas/fisiologia , Sinergismo Farmacológico , Enfuvirtida , Humanos , Molécula 1 de Adesão Intercelular/análise , Lovastatina/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Antígeno-1 Associado à Função Linfocitária/efeitos dos fármacos , Vírion/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , beta-Alanina/farmacologiaRESUMO
Besides interactions between the viral envelope glycoproteins with cell surface receptors, interactions between cell-derived molecules incorporated onto virions and their ligand could also modulate HIV type-1 (HIV-1) entry inside CD4(+) T lymphocytes. Although incorporation of host ICAM-1 within HIV-1 increases both virus attachment and fusion, the precise mechanism through which this phenomenon is occurring is still unclear. We demonstrate in this study that activation of primary human CD4(+) T lymphocytes increases LFA-1 affinity and avidity states, two events promoting the early events of the HIV-1 replication cycle through interactions between virus-embedded host ICAM-1 and LFA-1 clusters. Confocal analyses suggest that HIV-1 is concentrated in microdomains rich in LFA-1 clusters that also contain CD4 and CXCR4 molecules. Experiments performed with specific inhibitors revealed that entry of HIV-1 in activated CD4(+) T cells is regulated by LFA-1-dependent ZAP70, phospholipase Cgamma1, and calpain enzymatic activities. By using laboratory and clinical strains of HIV-1 produced in primary human cells, we demonstrate the importance of the LFA-1 activation state and cluster formation in the initial step of the virus life cycle. Overall, these data provide new insights into the complex molecular events involved in HIV-1 binding and entry.