RESUMO
The hallmark of chronic viral infections is a progressive exhaustion of antigen-specific CD8(+) T cells that leads to persisting viral replication. It is generally believed that exhaustion is a consequence of the accumulation of multiple inhibitory receptors on CD8(+) T cells that makes them dysfunctional. Here, we show that during human chronic HIV-1 infection, a CD8(+) T-cell positive costimulatory pathway mediated by DNAX-activating molecule-1 is also disrupted. Thus, DNAX-activating molecule-1 downregulation on CD8(+) T cells aggravates the impairment of CTL effector function in chronic HIV-1 infection.
Assuntos
Antígenos de Diferenciação de Linfócitos T/imunologia , Linfócitos T CD8-Positivos/patologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Animais , Antígenos CD/fisiologia , Antígenos de Diferenciação de Linfócitos T/biossíntese , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos Virais/imunologia , Proteínas Reguladoras de Apoptose/fisiologia , Linfócitos T CD8-Positivos/imunologia , Regulação para Baixo , Glicoproteínas/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , Humanos , Ativação Linfocitária , Contagem de Linfócitos , Coriomeningite Linfocítica/imunologia , Camundongos , Fragmentos de Peptídeos/imunologia , Receptor de Morte Celular Programada 1 , Receptores Virais/imunologia , Especificidade do Receptor de Antígeno de Linfócitos T , Carga Viral , Proteínas Virais/imunologia , Replicação ViralRESUMO
A significant proportion of human immunodeficiency virus (HIV) infected patients are coinfected with hepatitis B virus (HBV). Currently available treatments for chronic hepatitis B (interferon [IFN]-alpha and lamivudine [3TC]) have limited long-term utility because of side effects or of the development of resistance. Tenofovir disoproxil fumarate (TDF) is a nucleotide analog with excellent activity in vitro against HBV, which is also active against 3TC-resistant HBV variants. In this 24-week pilot study, the anti-HBV activity of TDF was prospectively evaluated in a cohort of 6 HIV coinfected subjects for whom 3TC and IFN therapy had previously failed. At baseline, all patients were taking 3TC or FTC and were hepatitis B surface antigen and hepatitis B e antigen positive; 4 had cirrhosis. Baseline HBV load was 7.95 log(10) copies/mL. By weeks 12 and 24, HBV load had decreased by 3.1 log(10) copies/mL and 4.3 log(10) copies/mL, respectively. There was a transient increase of transaminases after the initiation of treatment. No patient developed HBe antibodies. TDF is a very promising drug for the treatment of chronic hepatitis B in HIV-infected individuals.
