This proposal describes a carefully supervised training program that will provide me with research skills and experience in viral pathogenesis relevant to the lung. I propose to study the biological and molecular pathogenesis of human immunodeficiency virus infection of monoytes and macrophages under the guidance of recognized leaders in basic science in order to acquire the virology and molecular biology base for an independent research career. Monocytes and macrophages are known to be infected by HIV and a central role has been proposed for them in the pathogenesis of the disease. A key to monocyte infection is the existence of monocyte-tropic strains of HIV which differ markedly from prototype T lymphocyte-tropic isolates in host range and other biological characteristics. In Phase I a firm background will be provided by a didactic program and by intensive laboratory experience in two settings. First, I will work with Dr. Neal Nathanson in the Department of Microbiology to complete studies begun last year on the biology of HIV infection of monocytes and macrophages. We will characterize the differences between monocyte and T cell infections, establish models of latent and productive infection, and study the effect of modulators of monocyte differentiation and activation on infection. Following this I will work with Dr. Premkumar Reddy at the Wistar Institute in his ongoing project studying the genetic determinants of virus cell tropism and cytopathicity. We will generate recombinants between DNA clones of HIV isolates that differ in cell tropism and cytopathic effect, and use site-directed mutagenesis to create specific deletions and mutations within the envelope gene to map the regions that are responsible for these biological differences. Dr. Alfred Fishman will serve as my clinical sponsor during this research phase. In Phase II I will return to the Cardiovascular-Pulmonary Division of the Department of Medicine to join the active immunobiology group. I will apply this foundation to studies of the lung in AIDS. This program, moreover, will provide fundamental skills which are flexible and may eventually be expanded to other lung diseases of viral etiology.
