The complete cellular sensor pathway and effector involved in innate immune signaling pathways that response to HIV-1 infection is not clearly understand yet. The focus of global innate immune responses to HIV-1 infection program is to apply a comprehensive system-level understanding of these essential immediate virus-host responses is significantly interfere with the initial establishment of HIV infection. Our study is to understand the role of HIV restriction factors with the TLR9 stimulation. We hypothesized that the responsiveness of HIV-infected cells towards TLR9 stimulation is a requirement for HIV replication, and innate immune signaling pathway involve via TLR9 mediate pathway. From the study, we identified CUL1, RNF31, and ARL8A act as positive regulators of innate immune signaling pathway via TLR9 receptors. By knowing the correlation between TLR9 and restriction factors, we switched the gear toward other TLR family member, TLR3. Interestingly, additional experiment conducted in our lab shows a significant number of the putative HIV restriction factors acted as strong negative regulators of TLR3 signaling, suggesting that additional evidence of a strong correlation between HIV replication and TLR families