Naf1 Regulates HIV-1 Latency by Suppressing Viral Promoter-Driven Gene Expression in Primary CD4+ T Cells.

HIV-1 latency is characterized by reversible silencing of viral transcription driven by the long terminal repeat (LTR) promoter of HIV-1. Cellular and viral factors regulating the LTR activity contribute to HIV-1 latency and certain repressive cellular factors modulate viral transcription silencing. Nef-associated factor 1 (Naf1) is a host nucleo-cytoplasmic shuttling protein and regulates multiple cellular signal pathways and HIV-1 production. We have recently reported that the nucleus-located Naf1 promoted nuclear export of unspliced HIV-1 gag mRNA, leading to the accumulated Gag production. Here, we demonstrate new functions of Naf1 in regulating HIV-1 persistence. We found that Naf1 contributes to the maintenance of HIV-1 latency by inhibiting LTR-driven HIV-1 gene transcription in a nuclear factor kappa B-dependent manner. Interestingly, Naf1 knockdown significantly enhanced viral reactivation in both HIV-1 latently infected Jurkat T cells and primary central memory CD4 + T cells. Furthermore, Naf1 knockdown in resting CD4 + T cells from HIV-1-infected individuals treated with antiretroviral therapy significantly increased viral reactivation upon T-cell activation, suggesting an important role of Naf1 in modulating HIV-1 latency in vivo . Our findings provide new insights into a better understanding of HIV-1 latency, and implicate that the inhibition of Naf1 activity to activate HIV-1 latently infected cells may be a potential therapeutic strategy. IMPORTANCE HIV-1 latency is mainly characterized by a reversible silencing of long terminal repeats (LTR) promoter-driven transcription of an integrated provirus. Cellular and viral proteins regulating LTR activity contribute to the modulation of HIV-1 latency. In this study, we found that host protein Naf1 inhibited HIV-1-LTR-driven transcription of HIV genes and contributed to the maintenance of HIV-1 latency. Our findings provide new insights into a better understanding of host-modulation on HIV-1 latency, which may lead to a potential therapeutic strategy for HIV persistence by targeting Naf1 protein.