Rahm Gummuluru, Ph.D.
Professor and Vice Chair of Microbiology
72 East Concord Street
Office: R512; 617-358-1774
Lab: R509; 617-358-1773
We are using genetic, immunological and biochemical approaches to identify the molecular mechanisms of human immunodeficiency virus (HIV) – dendritic cell (DC) interactions, and the putative contributions of viral accessory genes to HIV-1 replication in DC- T cell co-cultures.
The research in my laboratory is broadly focused on the role of dendritic cells (DC) in the initiation and propagation of HIV-1 replication, and the mechanism of subversion of DC program by the virus. Since dendritic cells are believed to be the first immune competent cells to encounter virus in the genital mucosa, a thorough understanding of HIV-DC interactions is of paramount importance. DC can capture virus particles independently of CD4 and co-receptor complexes, and retain them in an infectious state for an extended period of time. These virus-bearing DC may then facilitate a more efficient spread of virus to replication-permissive CD4+ T cells. DC-SIGN, a mannose binding C-type lectin receptor, is one virus-attachment factor that captures infectious virus particles, and facilitates trans-infection of CD4+ T cells. Our previous work has identified DC-SIGN independent mechanisms of virus attachment by DC. Hence, we are utilizing novel genetic screens to identify virus-capture mechanisms displayed by dendritic cells. The fate of the virus particle post-attachment, be it via DC-SIGN, or other molecules, in DC also remains unclear. Virion trafficking within DC also seems to bypass conventional endocytic organelles, i.e., endosomes and lysosomes. Virus localization within this novel vesicular compartment not only has the potential to protect the invading HIV from being degraded, but also creates a latent reservoir of virus that could present a major challenge for eradication by antiretroviral therapy. Furthermore, the mechanism of subsequent return of infectious virus particles to the cell surface and the method of virus transmission to T cells remains unclear. Current studies utilizing biochemical and microscopic approaches to delineate molecular pathways are underway to monitor HIV-1 trafficking and localization in the DC and its subsequent transfer to T cells. These studies will aid in our understanding of the mechanism of HIV transmission to the naïve host and might lead to the identification of novel therapies that prevent establishment of virus infection.
- Kijewski, S.D. and Gummuluru, S. 2015. A Mechanistic Overview of Dendritic Cell-Mediated HIV-1 Trans Infection; the Story so far. Future Virol. 10:257-269. PMID 26213560
- Yu, X., Xu, F., Ramirez, N.G., Kijewski, S.D., Akiyama, H, Gummuluru, S.*, and Reinhard, B.M.* 2015. Dressing up Nanoparticles: A Membrane Wrap to Induce Formation of the Virological Synapse. ACS Nano. 9:4182-4192. PMID 25853367 (*co-corresponding authors).
- Akiyama, H., Ramirez, N.G., Gudheti, M.V., and Gummuluru, S. 2015. CD-169-Mediated Trafficking of HIV to Plasma Membrane Invaginations in Dendritic Cells Attenuates Efficacy fo Anti-gp120 Broadly Neutralizing Antibodies. PLoS Pathog. 11:e1004751. PMID 25760631
- Feizpour, A., Yu, X., Akiyama, H., Miller, C.M., Edmans, E., Gummuluru, S., and Reinhard, B.M. 2015. Quantifying Lipid Contents in Enveloped Virus Particles with Plasmonic Nanoparticles. Small 11:1592-1602. PMID 25382201
- Yu, X., Feizpour, A., Wu, L., Akiyama, H., Ramirez, N, Gummuluru, S.*, and Reinhard, B.* 2014. Glycosphingolipid-functionalized nanoparticles recapitulate CD169-dependent HIV-1 uptake and trafficking in dendritic cells. Nat. Comm. 5: 4136. (*co-corresponding authors) PMID: 24947940
- Gummuluru, S., Ramirez, N., and Akiyama, H. 2014. CD169-Dependent Cell-Associated HIV-1 Transmission: A Driver of Virus Dissemination. J. Infect. Dis. 210:S641-S647. PMID 25414418
- Akiyama, H., Miller, C., Patel, H., Hatch, S.C., Archer, J., Ramirez, N., and Gummuluru, S. 2014. Virus Particle Release from Glycosphingolipid-enriched Microdomains is Essential for Dendritic cell-mediated Capture and Transfer of HIV-1 and Henipaviruses. J. Virol. 88:8813-8825. PMID 24872578
- Puryear, W.B., Akiyama, H., Geer, S.D., Ramirez, N., Yu, X., Reinhard, B., and Gummuluru, S. 2013. Interferon-inducible Mechanism of Dendritic Cell-mediated HIV-1 Dissemination is Dependent on Siglec-1/CD169. PLoS Pathog. 9(4):e1003291. PMID 23593001
- Schiralli-Lester, G.M., Akiyama, H., Evans, E., Singh, J., Gummuluru, S., and Henderson, A. J. 2013. Interleukin 2-inducible T cell kinase (ITK) facilitates efficient egress of HIV-1 by coordinating Gag distribution and actin organization. Virol. 436: 235-43. PMID 23260110
- Puryear, W.B. and Gummuluru, S. 2013. Role of glycosphingolipids in dendritic cell mediated HIV-1 trans infection. Invited review. “HIV interactions with dendritic cells: infection and immunity.” Adv Exp Med Biol. 762:131-53. PMID: 22975874
- Waheed A.A., Brass A.L., Gummuluru S., Tachedjian G. 2012. Host-pathogen interactions of retroviruses. Mol Biol Int. 2012: 648512. PMID: 23150826
- Sagar, M., Akiyama, H., Etemad, B., Ramirez, N., Freitas, I., and Gummuluru, S. 2012. Transmembrane domain membrane proximal external region but not surface unit directed broadly neutralizing HIV-1 antibodies can restrict dendritic cell mediated HIV-1 trans infection. J. Infect. Dis. 205(8):1248-1257. PMID: 22396600
- Puryear, W.B., Yu, X., Ramirez, N.P., Reinhard, B.M. and Gummuluru, S. 2012. HIV-1 Incorporation of Host Cell Derived Glycosphingolipid GM3 Allows for Capture by Mature Dendritic Cells. Proc. Natl. Acad. Sci. USA 109:7475-7480. PMID: 22529395
- Hanley, T.M., Puryear, W., Gummuluru, S., and Viglianti, G. 2010. PPARgamma and LXR signaling inhibit dendritic cell-mediated HIV-1 capture and trans-infection. PLoS Pathog. 6(7):e1000981.
- Hatch, S.C., Archer, J. and Gummuluru, S. 2009. Glycosphingolipid composition of HIV-1 particles is a crucial determinant for Dendritic Cell-Mediated HIV-1 Trans Infection. J. Virol 83:3496-3506. PMID 19193785
- Izquierdo-Useros N, Naranjo-Gomez M, Archer J, Hatch SC, Erkizia I, Blanco J, Borras FE, Puertas MC, Connor JH, Fernandez-Figueras MT, Moore L, Clotet B, Gummuluru S*, Martinez-Picado J. 2008. Capture and transfer of HIV-1 particles by mature dendritic cells converges with the exosome-dissemination pathway. Blood 113:2732-2741. PMID: 18945959 (*co-corresponding authors)
- Editors’ Choice: Highlights of the recent literature. Virology section: HIV Hijacks Exosomes. Science 311(5760):437, 2006.
- Wiley R.D., and S. Gummuluru. 2006. Immature dendritic cell-derived exosomes can mediate HIV-1 trans infection. Proc. Natl. Acad. Sci. USA. 3(103):738-743.
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