The Modulation Of Host Cell On HIV-1 Infection And Latency

Part 1: Host factor Naf1 regulates HIV-1 productionThe completion of life cycle for HIV-1 includes the followed steps: viral attachment and fusion with target cells, uncoating, reverse transcription into c DNA, nuclear import and integration of c DNA, viral m RNA transcription, splicing and nuclear export of these m RNAs, viral protein translation and transport for assembly, viral budding and maturation. HIV-1 highly depends on host-cell-encoded factors to complete its life cycle. A comprehensive understanding of how HIV-1 manipulates host machineries during viral infection can facilitate the identification of host targets for antiviral drugs or gene therapy. By using genome-wide screening, we screened Naf1(HIV-1 Nef-associated factor) as a host factor candidate for regulating HIV-1 infection. Naf1 is identified as a CRM1(Chromosome region maintenance 1)-dependent nucleo-cytoplasmic shuttling protein. In this study, we found that Naf1 could promote nuclear export of unspliced HIV-1 gag m RNA and viral production. The Naf1-CRM1 association was required for this function; additionally, the mutation of the nuclear export signals and nuclear localization signal of Naf1 diminished its ability to promote HIV-1 production, suggesting that the shuttling property of Naf1 was required for this function. This study reveals a novel role of host factor Naf1 in enhancing HIV-1 production, providing a potential therapeutic target for controlling HIV-1 infection.Part 2: Dendritic cell induces HIV-1 reactivation from latencyAlthough the combination antiretroviral therapy effectively reduces HIV-1 replication and viral load below the limit of detection in most infected individuals, a reservoir of infected cells persists. Persistence of HIV-1 infection due to viral latency is the major barrier to eradication of AIDS. The mechanisms underlying HIV-1 latency establishment, maintenance and reactivation remain poorly understood. Dendritic cells(DCs) is an important antigen presenting cell and can activate T cells for anti-pathogen immunities, while DC has been proposed to act as a double-edged sword during HIV-1 infection. In this study, we investigated the necessity of DCs in driving HIV-1 reactivation from latency, and found that DCs could reactivate HIV-1 latency in CD4+ T cell and the secreted TNF-α accounted for this event. Co-culture with HIV-1 latently infected CD4+ T cells triggered DC maturation in CD40-CD40L-dependent and promoted TNF-α induction; notably, the treatments with AIDS-associated pathogens matured DCs and promoted CD40 expression, which might contribute to the enhanced ability for reactivating HIV-1 from latency. Understanding of DC-mediated HIV-1 reactivation would facilitate elucidating host modulation on viral latency, and benefit for the development of alternative strategies to eradicate HIV-1 reservoirs.