RESUMEN
Restriction of HIV-1 in myeloid-lineage cells is attributed in part to the nucleotidase activity of the SAM-domain and HD-domain containing protein (SAMHD1), which depletes free nucleotides, blocking reverse transcription. In the same cells, the Vpx protein of HIV-2 and most SIVs counteracts SAMHD1. Both Type I and II interferons may stimulate SAMHD1 transcription. The contributions of SAMHD1 to retroviral restriction in the central nervous system (CNS) have been the subject of limited study. We hypothesized that SAMHD1 would respond to interferon in the SIV-infected CNS but would not control virus due to SIV Vpx. Accordingly, we investigated SAMHD1 transcript abundance and association with the Type I interferon response in an SIV model. SAMHD1 transcript levels were IFN responsive, increasing during acute phase infection and decreasing during a more quiescent phase, but generally remaining elevated at all post-infection time points. In vitro, SAMHD1 transcript was abundant in macaque astrocytes and further induced by Type I interferon, while IFN produced a weaker response in the more permissive environment of the macrophage. We cannot rule out a contribution of SAMHD1 to retroviral restriction in relatively non-permissive CNS cell types. We encourage additional research in this area, particularly in the context of HIV-1 infection.
Asunto(s)
Enfermedades Virales del Sistema Nervioso Central/metabolismo , Macrófagos/metabolismo , Proteínas de Unión al GTP Monoméricas/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/metabolismo , Regulación hacia Arriba/inmunología , Carga Viral/inmunología , Animales , Enfermedades Virales del Sistema Nervioso Central/inmunología , Enfermedades Virales del Sistema Nervioso Central/virología , Femenino , Interferón Tipo I/biosíntesis , Interferón Tipo I/inmunología , Macaca nemestrina , Macrófagos/inmunología , Macrófagos/virología , Masculino , Proteínas de Unión al GTP Monoméricas/biosíntesis , Síndrome de Inmunodeficiencia Adquirida del Simio/metabolismo , Virus de la Inmunodeficiencia de los Simios/inmunologíaRESUMEN
Pilakka-Kanthikeel et al. recently reported higher levels of the retroviral restriction factor sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1) in astrocytes than in microglia, suggesting that SAMHD1 levels might explain in part the relatively refractory nature of astrocytes to retroviral replication. These findings are consistent with our studies of simian and human immunodeficiency virus infection of astrocytes and macrophages. Similarly, a role for two host microRNAs in post-transcriptional regulation of SAMHD1 agrees with our in vitro results and those of others. However, data from an animal model of HIV neurologic disorders may not be consistent with robust miRNA-mediated regulation of SAMHD1 in vivo.