Chronic infectious diseases, including that caused by human immunodeficiency virus (HIV), remain a major cause of morbidity and mortality throughout the world, and efficient vaccines and therapies are not accessible for the majority of individuals who need them. The mucosa, which is the port of entry for HIV, comprises many layers of defense, one of which is the complement system. During the initial HIV-1 sexual transmission events, the vast majority of virions in the bodily fluids are opsonized, and this will influence the outcome of infection. In addition, pre-existing infections, e.g., with Herpes simplex virus-2 (HSV-2), significantly increase the risk of becoming infected with HIV. Important immune cells, such as the T cells and dendritic cells (DCs), in HIV-1-infected individuals are dysfunctional on many levels and contribute to HIV pathogenesis. Our overall objective is to attain comprehensive knowledge of the interplay between immune cells and immune factors, i.e. DCs, T cells, and complement to decipher mechanisms involved in the induction of HIV pathogenesis. The focus is on the interactions that occur between complement-opsonized virions and the immune system of the infected person. This new knowledge will form the basis of novel strategies to combat HIV infection and stop transmission.