HIV-1 infection is characterized by a gradual loss of CD4+ T cells and progressive immune deficiency that leads to opportunistic infections, otherwise rare malignancies and ultimately death. Extensive research over the past two decades has increased our insight into the pathogenic mechanisms underlying these features of HIV-1 infection. Here, we will give a brief overview of the most recent findings and present a model that fits most of the relevant aspects of HIV-1 infection as known. We hypothesize that HIV-1 infection depletes T cell supplies (which are not replaced because of low and static thymic function) by direct infection and killing of cells and through hyperactivation of the immune system.