HIV-1 ENTRY INTO CELLS: A TARGET FOR ANTIVIRAL DRUGS AND THE HUMORAL IMMUNE RESPONSE
We study how HIV-1 uses its envelope glycoproteins to attach to, then fuse with, target cells, which are predominantly CD4-positive T-cells, macrophages and dendritic cells. Central to these early events in the viral life cycle is the involvement of the CCR5 and CXCR4 co-receptors. These proteins, whose natural function is G-protein coupled chemokine receptors, are targets for the development of new antiviral agents, particularly conventional small molecules. We are studying virus-CCR5 interactions and how small molecule inhibitors interfere with these events, and we are characterizing how the virus becomes resistant to these inhibitors by acquiring escape mutations. HIV-1 attachment and entry is also the stage at which the humoral immune response interferes with viral replication, albeit rather inefficiently in the context of natural infection. Inducing broadly active neutralizing antibodies by immunization would be a valuable component of a multivalent vaccine. To this end, we are using our knowledge of the structure of the HIV-1 envelope glycoproteins to develop stable, trimeric versions of these proteins, which we hope will elicit better immune responses than those presently available. We also wish to learn how best to present envelope glycoproteins to the immune system by studying how they interact with antigen-presenting cells in vitro, and how potentially adverse consequences can be overcome by the use of adjuvants and immune-stimulatory molecules (e.g., TLR activators). In collaborative studies, we are also seeking ways to crystallize envelope glycoprotein trimers for structural studies. In addition, we are part of a multi-site research group working to devise ways to use CCR5 inhibitors and other antiretroviral drugs as vaginal microbicides. Thus, we are evaluating the protective potential of vaginal ring and silicone gel formulations of these compounds, to identify user-friendly and convenient methods to protect against HIV-1 sexual transmission.