Virus transmission by cells bearing virus particles on their surface is a markedly more efficient mechanism of virus spread than cell-free virus infection.  T cell-to-T cell HIV-1 transmission is thought to occur at the virological synapse (VS) formed between a virus-producing T cell and a non-infected T cell.  We observed that in a motile, polarized T cells, HIV-1 Gag, the building block of virus particles, accumulates to a rear-end protrusion known as the uropod. Such Gag-laden uropod mediates frequent contacts with other T cells.  Therefore, it is conceivable that the uropod serves as a  precursor of the VS.  On this front, we seek to understand the mechanistic basis of the polarized Gag localization to the uropod.  We also aim at understanding virus spread between T cells in the lymph-node, using 3D culture systems that mimic the lymph node environment*.

In lymph nodes and other secondary lymphoid organs, stromal cells known as fibroblastic reticular cells (FRCs) play structural and regulatory roles. We discovered that FRCs capture HIV-1 particles and transfer them to T cells that come into contact. This mode of virus transmission is known as trans-infection. Interestingly, we further found that a uropod protein, CD44, which is efficiently incorporated into nascent virus particles along with other uropod proteins, is required for virus capture by FRC.  Ongoing studies are aimed at fully understanding the mechanism promoting the efficient incorporation of these uropod proteins [see (ii)] and the impact of these virion-incorporated proteins on subsequent infection into new target cells. [See also a Michigan Medicine blog article covering this work]

In contrast to HIV-1, influenza A virus can spread efficiently in the cell-free mode.  However, it has been shown that in the presence of a commonly used anti-influenza drug Oseltamivir, it spreads primarily via the cell-to-cell mode. Despite the implications for virus resistance to the drug, very little is known about the molecular mechanisms mediating cell-to-cell spread of influenza A virus.  On this front, we seek to determine the role played by virion morphogenesis in cell-to-cell transmission within epithelial cell monolayers.

*in collaboration with Dr. Ariella Shikanov's lab in Dept. Biomedical Engineering

[Publications in this area]

Llewellyn, G.N., et al. 2010. PLoS Pathogens 6:e1001167.

Llewellyn, G.N., et al. 2013. J. Virol. 87: 6441-6454.

Grover, J.R., S.L. Veatch, and A. Ono. 2015. J. Virol. 89:454-467.

Murakami, T., et al. 2018. Nature Commun. 9: 2436.

Murakami, T., et al. 2021. Proc Natl Acad Sci U S A 117: 8055- 8063.