Mentored Scientist Award

Human Immunodeficiency Virus (HIV) remains a global health challenge despite the success of antiretroviral therapy (ART) in controlling viral replication. However, ART cannot cure HIV due to the persistence of latent viral reservoirs, which fuel viral rebound upon treatment interruption. Eliminating viral reservoirs remains a critical barrier to an HIV cure. Type I interferons (IFN-I) play a critical role in the antiviral response against HIV by inducing a range of effectors that restrict viral replication. In response, HIV has evolved mechanisms to evade IFN-I-mediated antiviral factors, facilitating persistent infection. The dynamic interaction between IFN-I signaling and HIV influences disease progression and viral persistence. Deeper understanding of the relationship is essential for developing new therapeutic approaches. Our previous studies identified miR-422a as a key regulator of IFN-mediated HIV suppression. miR-422a downregulation correlates with reduced viral load in vivo. Our preliminary data revealed that miR-422a enhances HIV infection and counteracts the antiviral activity of IFN. RNA-seq analysis further revealed HELZ2 as the sole gene significantly regulated by both miR-422a and IFN. Notably, HELZ2 knockdown increases HIV replication in primary CD4+ T cells, validating its antiviral role in HIV. Currently, few studies have explored the role of HELZ2 in HIV replication and pathogenesis. However, our preliminary findings, combined with its known biological functions, suggest that HELZ2 could be a critical player in HIV persistence. HELZ2 has been shown to degrade structured RNA through the coordination of its RNA helicase activity and 3’-5’ ribonucleolytic action. It exhibits inhibition activity against LINE-1 retrotransposition by destabilizing LINE-1 RNA and has antiviral activity against Dengue and hepatitis C virus (HCV). Additionally, HELZ2 acts as a transcriptional coactivator for peroxisome proliferator activated receptors (PPARs), which are known to repress HIV LTR promoter transcription and transrepress NF-kappaB. PPAR agonists have been demonstrated to protect against HIV-induced neuroinflammation. Given the pleiotropic functions of HELZ2, we hypothesize that HELZ2 could suppress active viral replication and reinforce viral latency. Modulating HELZ2 could provide a novel strategy to reinforce viral latency, reducing the risk of viral rebound and advancing HIV cure efforts. This approach could complement existing latency-promoting agents or inform the development of combination therapies.