*Purpose: mTOR is a key regulatory kinase that controls cell-cycle progression. mTOR inhibitors have been shown to reduce expression of CCR5 and promote viral transcriptional silencing. Retrospective analysis by our group has shown that HIV-infected renal transplant recipients who received sirolimus, an mTOR complex 1 (mTORC1) inhibitor, had lower cell-associated HIV DNA levels, but prospective data are lacking. Therefore, we conducted a single-arm study of the impact of everolimus, an mTORC1/2 inhibitor, on HIV persistence and immune function in ART-suppressed liver and kidney transplant recipients.

*Methods: Ten HIV-infected transplant recipients on stable, suppressive antiretroviral therapy had everolimus added to their immunosuppressive regimen for 6 months, then removed for 6 months and prior to repeat analysis. Cellular and plasma HIV burden, lymphocyte immune phenotype and function, and gene expression/transcriptomic profiles were evaluated before, during, and following everolimus treatment. Target everolimus trough levels were maintained between 5-8 ng/mL.

*Results: Overall, everolimus was safe and well-tolerated. No significant bulk changes in CD4+ T cell HIV DNA or unspliced RNA were observed. mTOR pathway gene expression was analyzed by RNAseq transcriptome profiling, and revealed downregulation in mTOR signaling pathway gene expression in individuals while on therapy. Decreased MTORC1 signaling was noted in individuals with sustained decreases in CD4+ T cell associated HIV-1 DNA. A significant decrease in PD-1 expression from months 0 to 6 was observed in CD4+ T_EMRA cells (Wilcoxon signed-rank test p < 0.01). No differences were observed in CD4+ or CD8+ T-cell intracellular cytokine responses to HIV or CMV peptide stimulations. Surface expression of CCR5 was decreased amongst several CD4+ T cell subsets, but was not significant.

*Conclusions: The impact of mTOR inhibition on viral persistence was dependent on effective mTOR blockade, which varied between the ten subjects. Sustained cytokine responses to HIV/CMV peptide stimulations suggest no negative impact of everolimus on immune control of opportunistic infections. Despite similar trough levels of everolimus, the differential inhibition of the mTOR pathway suggests unique pharmacodynamics impacting the effectiveness of mTOR inhibition on HIV viral persistence.

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