Host response to lentiviral infection

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Among lentiviruses, only the human immunodeficiency virus (HIV) and the feline immunodeficiency virus (FIV) utilize a combination of ubiquitous chemokine and specific T-cell receptors for viral entry, and cause immunodeficiency in their natural hosts. FIV has co-evolved with domestic and wild cats for a longer time than HIV has with humans, and disease associated with FIV infection develops more gradually in cats than immunodeficiency in HIV-infected people. Further, some cats infected with FIV do not get ill at all, while most others eventually succumb to the disease. Identifying feline host factors that modulate this response to infection is of great interest for designing prophylactic or therapeutic HIV interventions. Therefore, in this research we will investigate why some cats develop either no or only mild immunodeficiency from infection with FIV. First, we will determine differences in the make-up of viruses that cause disease and those that don't cause disease by molecular examination of the viral proteins and their modifications. Next, we will examine how these different viruses alter the function of dendritic cells (DC), which are the "master" regulators of the immune response. Finally, we will investigate how the immune system, and specifically how helper and cytotoxic lymphocytes, respond to the different viruses. These studies will give us insight into whether trying to manipulate the early phase of immunodeficiency virus infection through increasing DC function, or reducing immune activation, may improve the outcome of infection. Further, these studies will clarify whether the nature and degree of the host immune response determines the onset of immunodeficiency, and how important the composition of the particular virus is.