ABSTRACT Tuberculosis continues to kill about 1 million people including children each year with 8 million new cases. Regrettably, coinfection with HIV-1 has aggravated the problem because HIV-1 depletes CD4 T cells, which are the main defense mechanism against tuberculosis. For the reason, BCG, which is a live attenuated vaccine against tuberculosis, cannot be given to people living with HIV. We recently discovered that Sirtuin type of protein and histone deacetylates play a major role in regulating the growth of both M. tuberculosis and HIV-1 in human macrophages and drug targeting Sirtuins could control both pathogens in cell culture models and in humanized mice. Therefore, we propose to investigate Sirtuin-dependent intervention to understand how TB and HIV-1 infections induce these enzymes and how we can develop novel immunochemotherapy for confections. Specifically: Aim-1: We will analyze the impact of early Mtb and HIV infection on Sirtuin gene and protein induction in macrophages and identify their epigenetic targets. We will examine the hypothesis that Mtb-induced Sirtuin-2 can augment HIV-1 replication, whereas HIV-1 induced Sirtuin-2, in turn enhances Mtb growth in MФs thereby aggravating coinfections. We will then develop an immunochemotherapy (ICT) using a combination of Sirtuin drugs, TB and HIV targeting drugs to kill and eradicate both HIV-1 and M. tuberculosis in macrophages. Aim-2: We will investigate the effect of Sirtuin drugs on early and late stages of TB-HIV-1 coinfection using humanized mice and determine whether ICT can eradicate confections. Aim-3: Tuberculosis granulomas can restrict growth of M. tuberculosis pathogen, although prior infection with HIV-1 can deplete CD4 T cells and affect granuloma formation. We will use a TB-HIV coinfection model of humanized mice to determine if Sirtuin-drug therapy can activate macrophages of granulomas and increase host-defense against tuberculosis. Our overall goal is to develop innovative immune defense-based intervention methods to eradicate TB-HIV coinfections.