Rahm Gummuluru, Ph.D.
Associate Professor of Microbiology
72 East Concord Street
Office: R518; 617-414-8075
Lab: R509; 617-414-8077
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.
- Xu, 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. Commun. 5:4136. PMID: 24947940
- 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. Virology. 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 2009 Feb 4. [Epub ahead of print] 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. [Epub ahead of print] PMID: 18945959
- Editors’ Choice: Highlights of the recent literature. Virology section: HIV Hijacks Exosomes. Science 311(5760):437, 2006.
- Nguyen DH, Gummuluru S, Hu J. 2007. Deamination-independent inhibition of hepatitis B virus reverse transcription by APOBEC3G. J Virol. 81(9):4465-4472
- 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.
- Gummuluru, S., Rogel, M., Stamatatos, L. and Emerman, M. (2003). Binding of human immunodeficiency virus type 1 to immature dendritic cells can occur independently of DC-SIGN and mannose binding C-type lectin receptors in a cholesterol dependent manner. J.Virol. 77:12865-12874.
- Gummuluru, S., and Emerman, M. (2002). AIDS, a year in review: Advances in HIV molecular biology. AIDS. 16:S17-S23.
- Gummuluru, S., KewalRamani, V., and Emerman, M. (2002). Dendritic cell mediated viral transfer to T cells is required for HIV-1 persistence in the face of rapid cell turnover. J.Virol. 76:10692-10701.
- Gummuluru, S., Kinsey, C.M., and Emerman, M. (2000). An in vitro rapid turnover assay for human immunodeficiency virus type 1 replication selects for cell-to-cell spread of virus. J.Virol. 74:10882-10891.
- Gummuluru, S. and Emerman, M. (1999). Cell Cycle and Vpr-Mediated Regulation of HIV-1 Expression in Primary and Transformed T Cell Lines. J.Virol. 73:5422-5430.
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