Establishment of Human Retrovirus Particle Assembly Sites

Abstract

Human immunodeficiency virus (HIV) currently infects about 37 million people globally and has led to over 35 million deaths since its emergence in the human population by causing acquired immunodeficiency syndrome (AIDS). HIV type 1 (HIV-1) is responsible for the AIDS pandemic). HIV-1 spreads by intravenous drug use, sexual contact, blood transfusions, breastfeeding). Virus particle assembly is a foundationally important aspect in all modes of infectious spread and virus transmission. Comparative analyses with closely related human retroviruses can be particularly informative when studying areas including virus particle assembly and host-cell interactions that influence this process – which represents an important knowledge gap in the field. In preliminary studies, our collaborative research team has observed that the actin cortex can act as physical barrier for HIV-1 Gag recruitment to the plasma membrane (PM), particularly retroviral Gag-genomic RNA (gRNA) complexes. The actin cortex is functioning as a non-specific barrier that limits potential virus assembly sites on the PM. Here, in this fellowship application, experiments are proposed to gain further insights into the fundamental aspects of how virus-host cell interactions establish virus particle assembly sites. First, studies are proposed to investigate virus assembly sites in the context of the actin cortex. Multiple experimental approaches with be used to test the hypothesis that the actin cortex acts as a physical barrier for Gag-gRNA complexes, including comparative analyses in the context of cell-cell contact and using closely related human retroviruses. Second, I propose to investigate the role of the tumor suppressor adenomatous polyposis coli (APC) protein enrichment at virus particle assembly sites, testing the hypothesis that APCs interaction with the Gag protein helps to stabilize the Gag lattice and enhance the efficiency of Gag puncta biogenesis and gRNA recruitment. Comparative analyses will be leveraged to understand how APC may rely on interactions with actin filaments and play a more significant role during virus particle assembly at cell-cell contacts. Together, these studies will provide new insights into HIV-1 particle assembly, and advance knowledge in this crucial aspect of virus replication.