RESUMO
The susceptibility of macrophages to HIV-1 infection is modulated during monocyte differentiation. IL-27 is an anti-HIV cytokine that also modulates monocyte activation. In this study, we present new evidence that IL-27 promotes monocyte differentiation into macrophages that are nonpermissive for HIV-1 infection. Although IL-27 treatment does not affect expression of macrophage differentiation markers or macrophage biological functions, it confers HIV resistance by down-regulating spectrin ß nonerythrocyte 1 (SPTBN1), a required host factor for HIV-1 infection. IL-27 down-regulates SPTBN1 through a TAK-1-mediated MAPK signaling pathway. Knockdown of SPTBN1 strongly inhibits HIV-1 infection of macrophages; conversely, overexpression of SPTBN1 markedly increases HIV susceptibility of IL-27-treated macrophages. Moreover, we demonstrate that SPTBN1 associates with HIV-1 gag proteins. Collectively, our results underscore the ability of IL-27 to protect macrophages from HIV-1 infection by down-regulating SPTBN1, thus indicating that SPTBN1 is an important host target to reduce HIV-1 replication in one major element of the viral reservoir.
Assuntos
Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Interleucinas/farmacologia , Macrófagos/virologia , Monócitos/citologia , Espectrina/antagonistas & inibidores , Diferenciação Celular/efeitos dos fármacos , Regulação para Baixo , Humanos , MAP Quinase Quinase Quinases/fisiologia , Macrófagos/citologia , Proteínas Monoméricas de Ligação ao GTP/fisiologia , Proteína 1 com Domínio SAM e Domínio HD , Espectrina/genética , Espectrina/fisiologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/metabolismoRESUMO
All primate lentiviruses encode Nef, an accessory protein that is important for viral pathogenicity in vivo. Lentiviral Nef proteins regulate the release of chemokines (MIP-1 alpha/beta) from infected macrophages, thereby enhancing virus dissemination (S. Swingler, A. Mann, J. Jacque, B. Brichacek, V. G. Sasseville, K. Williams, A. A. Lackner, E. N. Janoff, R. Wang, D. Fisher, and M. Stevenson, Nat. Med. 5:997-1003, 1999). In the current study, we have identified a novel domain within Nef (K(92)EK) that is required for Nef-dependent MIP-1beta production by infected macrophages. Mutations in this domain abrogated MIP-1beta induction but did not affect other Nef-ascribed activities, such as CD4 or major histocompatibility complex (MHC) class Iota downregulation. This further underscores Nef as a modular protein with genetically separable activities that may contribute to its role in viral replication and pathogenicity.