The convergence of HIV-1, Mycobacterium tuberculosis, and SARS-CoV-2 infections presents a formidable challenge characterized by heightened immune suppression and persistent viral replication. Understanding the shared molecular mechanisms underlying these co-infections is essential, providing a foundation for future translational research and therapeutic discovery. We analyzed differentially expressed genes from HIV-1/TB co-infection datasets across multiple tissues, including lung, spleen, liver, and whole blood. This was followed by PPI network analysis and single-cell multi-gene expression analysis. Gene set enrichment and pathways enrichment analysis were carried out to reveal the immune regulatory pathways that are altered during HIV-1/TB infection and SARS-CoV-2 infection. Gene expression profiling pointed out critical genes, including CXCR4, TAP1, TSC22D3 and FGR, associated with immune suppression, antigen processing, and viral attachment. TSC22D3 and CXCR4 were found to be crucial immune cell regulators in lung tissue using single-cell analysis. Apart from this, PPI network analysis revealed that TAP1, TAP2, and CXCR4 are essential hub genes, whereas the intersectional analysis with the SARS-CoV-2 gene datasets highlighted 27 genes associated with the immune response and viral persistence. Pathway enrichment analyses noted several processes, such as protein phosphorylation, apoptosis, and immune evasion, pointing out common mechanisms across these infections. Our findings suggest shared molecular signatures in HIV-1/TB and SARS-CoV-2 infections, with central genes offering potential therapeutic relevance. Future work will validate these targets through wet lab experiments to better understand their roles in immune regulation and develop novel therapies to enhance viral clearance in co-infected patients.