Combining Spironolactone to Antiretroviral Therapy Accelerates HIV Decay in Humanized Mice

Spironolactone (SP), a clinically used aldosterone antagonist, has been explored as an anti-HIV agent in models of HIV-1 latency for inducing transcriptional silencing of the viral reservoir. SP promotes the degradation of xeroderma pigmentosum group B (XPB) protein, a crucial component of transcription factor II H (TFIIH) required for RNA polymerase II transcriptional initiation. This study evaluated the impact of a long-acting formulation of SP on HIV replication within the context of antiretroviral therapy (ART) in the humanized mice model of HIV infection. The findings demonstrate that adding SP to ART accelerates viral decline and reduces expression of inflammation-related genes in human immune cells - genes often upregulated in chronic viral infections. Although SP treatment did not alter levels of cell-associated viral DNA, it led to a significant 4.4-fold decrease in systemic cell-associated viral RNA. This supports the role of XPB in HIV transcriptional regulation and advocates for incorporating transcriptional inhibitors like SP into primary HIV therapy. Additionally, SP treatment diminished markers of immune activation and inflammation, critical factors contributing to morbidity and mortality in individuals with chronic HIV infection. These results highlight SP's potential to enhance HIV treatment by mitigating key aspects of viral persistence and associated immune challenges. Overall design: A comparative RNA-seq analysis of mononuclear cells (MNCs) isolated from the liver, lung, spleen and lymph nodes of BLT humanized mice that were infected with HIV and then treated with ART or ART + Spironolactone (200 mg long-acting subcutaneous pellets) for 35 days. We compared gene expression of samples treated with ART alone or with the combination of ART + SP.