Rahm Gummuluru, Ph.D.
Professor and Vice Chair of Microbiology
72 East Concord Street
Office: R512; 617-358-1774
Lab: R509; 617-358-1773
Cell Biology of HIV: We study interactions of HIV with myeloid cells, such as conventional dendritic cells or macrophages. Whilst HIV-1 capture by dendritic cells and macrophages can result in phagocytosis and lysosomal degradation of endocytosed virus particles, studies from our laboratory have defined a novel mechanism of viral preservation and dissemination. Selective incorporation of the ganglioside, GM3, in the virus particle membrane results in binding and capture of the virus particle by the myeloid cell-specific sialic acid binding lectin, CD169 (SIGLEC1), and sequestration of virus particles in non-endolysosomal compartments. We are interested in understanding mechanisms by which these CD169+ virus-containing compartments preserve virus infectivity and facilitate cell-associated HIV transmission to CD4+ T cells.
Innate Immune Sensing – HIV: Macrophages and dendritic cells are equipped with multiple innate immune sensors to detect foreign pathogens and induce type I IFN responses. We are specifically interested in identifying nucleic acid sensing mechanisms that detect HIV infection. These research interests stem from our recent findings that have identified a novel innate immune sensing mechanism in myeloid cells which detects de novo expressed intron-containing HIV-1 RNA (HIV icRNA) and induces MAVS-dependent type I IFN responses. While host recognition of non-self, single- and double-stranded RNA with an uncapped triphosphate group by RIG-I-like receptors (RLRs) is well established, host sensing machinery that distinguishes RNA pol II transcribed viral RNAs such as HIV-1 icRNA from host mRNAs have not been identified. We are actively pursuing studies to identify the cytoplasmic viral icRNA sensing mechanism and the ensuing signal transduction pathway.
HIV Immunopathogenic Mechanisms: Chronic inflammation is the chief driver of morbidity and mortality in HIV-infected individuals. Persistent infection of tissue-resident macrophages contributes to chronic immune activation and HIV-associated non-AIDS complications, and remains a major obstacle to HIV cure strategies. While anti-retroviral therapy (ART) suppresses viral loads to undetectable levels, transcriptionally competent viral reservoirs are maintained in secondary lymphoid tissues. We utilize unique cell models, such as induced-pluripotent stem cell (iPSC)-derived microglia (brain-resident macrophages), and leverage access to clinical cohorts of age-matched uninfected and HIV+ individuals to determine the immunopathological consequences of persistent HIV icRNA expression in tissue-resident macrophages, and its contribution to an accelerated aging phenotype in cART-suppressed HIV+ individuals.
Development of Nanoparticle-based Therapeutics: We are leveraging our discovery of the GM3 – CD169 mechanism of virus particle recognition to develop nanoparticle based targeted drug delivery approaches. In collaboration with Dr. Bjoern Reinhard in the Photonics Center we have developed GM3 ganglioside-incorporating membrane encapsulated, biodegradable nanoparticles (GM3-NPs) for specific targeting of CD169+ tissue-resident myeloid cells. The lipidome and size of GM3-NPs is a mimic of HIV-1 particles and are an innovative, immunologically silent, nano-platform for targeted cell and tissue-specific delivery. These GM3-NPs are being exploited to enhance bioavailability of antiretrovirals and host-directed therapeutics in secondary lymphoid tissues to suppress persistent inflammation that exacerbates HIV-driven immunopathology.
- 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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