Singh, V. K.; Mishra, A.; Troung, K.; Bohorquez, A.; Sharma, S.; Khan, A.; Bracher, F.; Zhang, K.; Endsley, J.; Endsley, M.; Rice, A. P.; Kimata, J.; Yi, G.; JAGANNATH, C.

Coinfections with Mycobacterium tuberculosis (Mtb) and HIV-1 present a critical health challenge 38 and require treatment for survival. We found that human M1 macrophages inhibit Mtb growth, 39 while M2 macrophages, characterized by elevated Sirt2 expression, permit Mtb growth. Further, 40 we found that HIV-1 augmented Sirt2 gene expression in M[FE]s. Therefore, we explored the 41 therapeutic potential of sirtuin-modulating drugs in M[FE]s. Sirtinol, a Sirt2 inhibitor, significantly 42 reduced HIV-1 growth in M0, M1, and M2-M[FE]s by >1 log10 over 7 days. Conversely, individual 43 doses of resveratrol and SRT1460, which activate Sirt1, did not affect HIV-1. However, their 44 combination showed a strong synergistic inhibition of HIV-1. The combination of sirtinol with 45 resveratrol was neither synergistic nor antagonistic. Sirtinol upregulated iNOS and ATG5 mRNA 46 in HIV-1 infected M[FE]s in a phenotype-dependent manner. In a humanized mouse model (Hu-47 NSG-SGM3) co-infected with Mtb H37Rv and the HIV-1 BAL strain, treatment with sirtinol alone, 48 or in combination with combination antiretroviral therapy (cART), showed promising results; 49 Sirtinol alone reduced Mtb growth, while its combination with cART effectively inhibited HIV-1 50 replication in the organs. We propose that Sirt2 blockade and Sirt1-activation represent a novel 51 dual therapeutic strategy for treating HIV-1 and Mtb coinfections.