RESUMO
Monocyte-derived macrophages (MDM) can polarize into different subsets depending on the environment and the activation signal to which they are submitted. Differentiation into macrophages allows HIV-1 strains to infect cells of the monocytic lineage. In this study, we show that culture of monocytes with a combination of IL-12 and IL-18 led to macrophage differentiation that was resistant to HIV-1 infection. In contrast, M-CSF-derived MDM were readily infected by HIV-1. When monocytes were differentiated in the presence of M-CSF and then further treated with IL-12/IL-18, cells became resistant to infection. The restriction on HIV-1 replication was not dependent on virus entry or coreceptor expression, as vesicular stomatitis virus-pseudotyped HIV-1 replication was also blocked by IL-12/IL-18. The HIV-1 restriction factor sterile α motif and HD domain-containing protein-1 (SAMHD1) was significantly overexpressed in IL-12/IL-18 MDM compared with M-CSF MDM, and degradation of SAMHD1 by RNA interference or viral-like particles carrying the lentiviral protein Vpx restored HIV-1 infectivity of IL-12/IL-18 MDM. SAMHD1 overexpression induced by IL-12/IL-18 was not dependent on IFN-γ. Thus, we conclude that IL-12 and IL-18 may contribute to the response against HIV-1 infection through the induction of restriction factors such as SAMHD1.
Assuntos
HIV-1/fisiologia , Interleucina-12/genética , Interleucina-18/genética , Macrófagos/virologia , Proteínas Monoméricas de Ligação ao GTP/genética , Replicação Viral/genética , Diferenciação Celular/genética , HIV-1/genética , HIV-1/metabolismo , Humanos , Interleucina-12/imunologia , Interleucina-12/metabolismo , Interleucina-18/imunologia , Interleucina-18/metabolismo , Fator Estimulador de Colônias de Macrófagos/genética , Fator Estimulador de Colônias de Macrófagos/imunologia , Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Monócitos/virologia , Proteínas Monoméricas de Ligação ao GTP/imunologia , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Proteína 1 com Domínio SAM e Domínio HD , Regulação para CimaRESUMO
The alpha4beta7 integrin has been shown to serve as a coreceptor for HIV. One anti-alpha4 integrin agent (natalizumab) has been approved for the treatment of multiple sclerosis and Crohn's disease. We found that activation of CD4+ T cells with retinoic acid induced the upregulation of alpha4 and beta7 integrins. However, natalizumab failed to block the replication of HIV-1 strains in lymphoid MT-4 cells or CD4+ T cells at concentrations up to 125microg/ml. Our results suggest that alpha4 integrins are not essential cofactors for HIV replication.