Gag, a multidomain and multifunctional protein, is the major building block of retrovirus particles.  Targeting of Gag to the location at which virus particle formation occurs, usually the plasma membrane, is a critical early step of retrovirus particle production.  We found that the plasma membrane-specific acidic phospholipid PI(4,5)P2  plays a key role in HIV-1 Gag targeting.  PI(4,5)P2 binds the highly basic region (HBR) of Gag, thereby recruiting Gag to the plasma membrane. We further discovered that binding of a subset of tRNA to HBR prevents Gag from binding other acidic phospholipids and hence likely blocks non-specific localization of Gag.  We are currently seeking to identify specific features of the tRNA-HBR and lipid-HBR interactions, which can potentially be used as therapeutic targets. In these studies, we use multiple cell-based and in vitro RNA-Gag and lipid-Gag binding assays.

In CD4+ T cells, which is a natural host of HIV-1, virus particle assembly occurs at the cell surface. In macrophages, another natural host, assembling HIV-1 particles apparently accumulate to internal compartments. These virus-containing compartments (VCC) are likely formed as deep invagination of the plasma membrane, and their limiting membrane appears to be still connected to the plasma membrane. These compartments may serve as viral reservoirs and may release their contents upon contact with T cells. Using genetic and microscopy-based approaches, we showed that Gag multimerization plays a key role in Gag accumulation to VCC. We continue to investigate the host determinants of Gag localization in macrophages, which may also advance our understanding of virus particle release from the VCC. 

[Publications in this area]

Chukkapalli, V, et al. 2008. J. Virol. 82:2405-2417.

Chukkapalli, V., S.J. Oh and A. Ono. 2010. Proc. Natl. Acad. Sci. USA. 107:1600-1605.

Monde, K., V. Chukkapalli, and A. Ono. 2011. J Virol. 85:3584-3595.

Inlora, J., et al.2011. J Virol. 85:3584-3595.

Chukkapalli, V., J. Inlora, et al. 2013. J. Virol. 87:7155-7159.

Inlora, J., et al. 2014. MBio. 5:e02202 

Olety, B., S.L. Veatch, and A. Ono. 2015. J. Virol. 89:7861-7873. [featured on cover]

Inlora, J., V. Chukkapalli, S. Bedi, and A. Ono. 2016. J. Virol. 90:8509-8519. [featured on cover]

Todd, G.C., A.A. Duchon, J. Inlora, E.D. Olson, K. Musier-Forsyth, and A. Ono. 2017 RNA 23: 395-405.

Thornhill, D. B. Olety, and A. Ono. 2019. J. Virol. DOI: 10.1128/JVI.00756-19 

Sumner C, Kotani O, Liu S, Musier-Forsyth K, Sato H, an A. Ono A. 2022. J Mol Biol 434: 167390.