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.

Grant Number: 5F31AI184673-02
NIH Institute/Center: NIH
Principal Investigator: William Arndt