# Mechanisms that determine subcellular sites of HIV-1 assembly > **NIH NIH R37** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $537,774 ## Abstract Title: Mechanisms that determine subcellular sites of HIV-1 assembly Summary/Abstract: Virus particle assembly of HIV-1, the causative agent of AIDS, takes place at the plasma membrane (PM) in most cell types including natural host T cells. This process is driven by a viral structural protein Gag. The N- terminal matrix (MA) domain of Gag determines Gag localization to and hence virus assembly at the PM. MA mediates membrane binding of Gag via N-terminal myristoyl moiety and a highly basic region (HBR) that binds acidic lipids. Binding of HBR to a PM-specific acidic phospholipid PI(4,5)P2 is critical for PM localization of Gag and efficient virus release. Notably, in vitro and cell-based studies showed that MA HBR also interacts with tRNAs, which suppress binding of Gag to non-PI(4,5)P2 acidic lipids, suggesting tRNAs as a new host factor that regulates MA-membrane interactions. However, molecular determinants for the tRNA-MA HBR interaction and its reversal by the interaction with PI(4,5)P2, combination of which regulates PM-specific Gag localization, remain to be elucidated. Moreover, how these interactions begin and what effect these interactions have on the property of progeny virions at the end are poorly understood. Binding of tRNAs to MA HBR is most likely to occur at translation sites due to limited availability of tRNAs outside of the translation machinery. However, little is known about subcellular sites of Gag translation, where Gag begins its movement to the PM. At the PM, Gag multimerization is likely to create accumulation of acidic lipids, but its impact on the ability of progeny virions to spread to uninfected cells remains unknown. Our long-term goal is to elucidate mechanisms that determine sites of HIV-1 assembly and to use the knowledge for developing antiviral strategies. Our central hypothesis in this application is that MA HBR interactions with tRNAs, which begin during translation, and with acidic lipids determine subcellular Gag localization and the properties of progeny virions. To test this hypothesis, we plan to: 1) identify molecular determinants for interaction of MA HBR with tRNAs and its reversal by PI(4,5)P2; 2) identify tRNAs that suppress PI(4,5)P2-independent membrane binding but allow PI(4,5)P2-mediated reversal; 3) examine the possibility that Gag associates with tRNA during translation; and 4) examine the effect of acidic lipid accumulation at virus assembly sites on the virion properties. The knowledge gained from experiments outlined in this proposal will likely help us develop antiviral strategies that target mechanisms regulating Gag localization to the PM, thereby inhibiting extracellular virus release and spread. ## Key facts - **NIH application ID:** 9960393 - **Project number:** 5R37AI071727-14 - **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR - **Principal Investigator:** Akira Ono - **Activity code:** R37 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $537,774 - **Award type:** 5 - **Project period:** 2007-02-01 → 2022-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/9960393 ## Citation > US National Institutes of Health, RePORTER application 9960393, Mechanisms that determine subcellular sites of HIV-1 assembly (5R37AI071727-14). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9960393. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*