The effects of chronic infections, such as Human immunodeficiency virus (HIV), give major health problems for the individuals infected and are also very costly for the society/health care system. Today, even with antiviral therapy (ART), HIV continues to be a leading cause of morbidity and mortality around the world seeing that not all infected have access to this treatment and the exhaustion/aging of the immune system even in individuals receiving ART. The mucosa is the port of entry for HIV, and at this site are there many layers of defense, one of which is the complement system. Complement is present in bodily fluids, including cervical secretions and seminal plasma. We and others have found that the levels of complement influence the risk of acquiring HIV, as well as the severity of infection. Several pathogens take advantage of the complement system, exploiting its different components to avoid destruction and to modulate the immune responses raised against them. We have shown that opsonization of both HIV and HSV-2 enhance their infectivity. Nevertheless, there remains a gap in the knowledge as to how complement gives rise to more intense viral infections and the effects that it exerts on the innate and subsequent adaptive immune responses. Our working model and Hypothesis: We propose that complement promotes the establishment of primary HIV-1 infection and the quality of the host adaptive responses by modulating the innate immune system. The initial in vivo interactions between HIV, which is coated with complement, antibodies, and/or other factors, and the mucosa involve multiple receptors on the mucosal surface followed by the uptake/infection of DCs and T cells. We discovered that complement-opsonized HIV-1 (CHIV) target more effectively and induce a stronger infection of the human mucosa DCs and mucosal tissues, as compared to free HIV. We have shown that this is true for both the cervical and colorectal mucosa. Considering our recent findings, it is of importance to further determine the programming of the mucosal innate defense leading to enhanced infection by opsonized HIV and determine receptors, factors, and/or pathways that can be targeted to stop infection and improve the immune functions. By using e.g., scRNA seq and scATAC seq will the initial interactions and infections caused by free and complement-opsonized HIV-1 be assessed in primary colorectal and cervical mucosa tissues and isolated mucosal immune cells from healthy individuals and individuals with known inflammation and/or being HSV-2-positive. These experiments should help resolve the molecular mechanisms underlying the observed enhanced infectivity of opsonized HIV for the human mucosa and in the setting of pre-existing infection/inflammation, which will help in designing new anti-HIV treatments.