Project 1. Maturation and Assembly

Project 1 – HIV-1 Maturation and Assembly The overall goal of this project is to identify and exploit key, potentially druggable complexes and interactions that are present during HIV-1 assembly and maturation, including Gag and its maturation intermediates, the viral ribonucleoprotein (vRNP) complex, and the matrix (MA)-glycoprotein 41 (gp41) cytoplasmic tail interaction. The proposed studies are an integrated effort from 11 PCHPI investigators and four cores (NMR, CryoEM/ET, Computational, and HIV Virology). The specific aims are designed to i) understand the molecular, biochemical, and structural basis for maturation inhibitor (MI) and allosteric integrase inhibitor (ALLINI) activity and resistance pathways; ii) define the organization of RNA and proteins in the viral ribonucleoprotein complex (vRNPs) and at specific stages of maturation; and iii) characterize the interaction between the MA domain of Gag and the cytoplasmic tail of gp41. The structural and mechanistic knowledge gained through the proposed work will inform the development of novel MIs and ALLINIs with improved antiviral potency and potentially guide approaches to inhibit protein interactions in HIV-1 vRNPs and in MA-gp41 complexes.