Structural characterization of the HIV-2 capsid lattice

Project Summary/Abstract Human retroviral infections (i.e., human immunodeficiency virus type 1, HIV-1; and HIV type 2, HIV-2) impact a combined 38 million people worldwide and result in at least 680,000 deaths per year. Despite advancements in antiretroviral therapies (ART), there presently is no cure for these infections. Given the continued development

of antiviral drug resistance, there remains a need for basic science investigations in addressing crucial knowledge gaps in the field, such studies can inform antiretroviral target identification, and have broad applications towards therapy and cure. One of the key aspects of HIV-1 replication that has remained

underexplored has been virus particle assembly. Here in this proposal, the overarching hypothesis being tested is that differences in human retroviral capsid (CA) protein structure and CA-CA interactions can provide new insights into particle assembly and help identify conserved features that may be promising antiretroviral targets.

There are three lines of investigation being pursued. First, the differential CA interfaces among HIV-2 will be investigated to examine whether differences in Gag lattice morphologies can be attributed to differences in CA interfaces. Second, comparative analysis between the HIV-1 and HIV-2 capsid core structure will be determined

to assess whether a novel helix in the HIV-2 mature CA is present and responsible for morphogenesis of the mature CA lattice. Finally, the molecular and structural basis for differences in HIV particle assembly and viral infectivity will be investigated using site-directed mutagenesis studies. The proposed studies will provide new

insights into the structure-function relationships among CA proteins and enable new insights in human retroviral replication.