One of the principal laboratory projects in the Retroviral Diseases Section is the study of HIV replication in M/M. One goal of this effort is to develop anti-retroviral strategies directed at this population. We found that although dideoxynucleosides such as azidothymidine (AZT) are poorly phosphorylated in M/M, they still have potent anti-HIV activity. This is apparently because M/M have low levels of deoxynucleoside-5'-triphosphates. We also observed that certain cytokines, including granulocyte-macrophage colony stimulating factor (GM-CSF) and macrophage colony stimulating factor (M-CSF) can enhance the replication of HIV in M/M, and that these have variable effects on the activity of dideoxynucleosides. More recent studies have explored the phenomenon of enhancement of HIV infection of M/M by anti-HIV antibodies. It had been hypothesized that this phenomenon may work by a CD4-independent mechanism. However, we have observed that enhancement of infection of M/M is blocked by anti-CD4 antibodies or by soluble CD4, indicating that it still involves CD4 as an essential viral receptor. We are now investigating the production of cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-a) by monocytes upon exposure to HIV. IL-6 producting in patients with HIV infection may be one factor leading to the development of non-Hodgkin's lymphoma (NHL). Finally, we are exploring novel strategies for inhibiting HIV replication in M/M.
