Mechanisms of HIV/SIV entry and target cell tropism, and their role in pathogenesis.
Monocyte/macrophage activation in HIV infection: mechanisms, role in pathogenesis, and modulation.
Microbiome and molecular microbiology of the human respiratory tract.
HIV, SIV, virus, tropism, signal transduction, gp120, viral envelope, macrophage, microbiome, lung microbiology.
Description of Research
Project 1. HIV/SIV entry. Our lab studies HIV and SIV infection, focusing on the mechanisms of entry into different target cells and how viral target cell tropism influences disease. HIV and SIV target T lymphocytes and macrophages, and within the T lymphocyte group several subsets of cell populations may be infected. Current work is focuses on how entry pathways including CCR5 and CXCR4, and in particularly non-cannonical entry coreceptors, are used in pathogenic (HIV-1, SIVmac infection of rhesus macaques) and non-pathogenic natural host (SIVsmm infection of sooty mangabeys), and how differential entry corecepto use and cell targeting may underlie outcome from infection.
Project 2. Monocyte/macrophage activation in HIV infection: mechanisms, role in pathogenesis and modulation. Immune activation, combined with viral replication, is an important driver of pathogenesis. In particular, neuropathogenesis (HIV dementia) is linked to monocyte activation in the systemic circulation and macrophage activation within the brain. Even in ART-treated subjects with viral suppression, activation persists and is associated with development of neurocognitive defecits. We are studying the features and mechanisms of persistent monocyte/macrophage immune activation, link to neuropathogenesis, and novel approches to combine with ART viral suppression that may modulate monocyte/macrophage activation.
Project 3. Human respiratory tract microbiome. The human lungs are normally thought to be sterile below the vocal cords. New molecular approaches now enable comprehensive analysis of bacterial, fungal and viral populations within particular niches. We are using high-stringency sampling, high-density sequencing, and novel bioinformatic approaches to determine the microbial inhabitants in the lower resiratory tract and upper respiratory tract in healthy people, and in disease states such as HIV infection, lung transplantation, and other lung diseases, and how microbial communities influence disease. We are also developing novel approaches to broad-range diagnostics for lung colonization and infection.
1. Define the distribution and use of alternative entry coreceptors on human, rhesus and mangabey lymphoid and monocytoid cell subsets.
2. Map viral determinants of SIV alterntative coreceptor utilization.
3. Test immune activation suppression of monocyte activation by HIV Env and LPS.
4. Transcriptional profiling of residual monocyte activation in ART-suppressed subjects.
5. Define the uncultured bacterial 16S sequences in lungs samples from patients with pneumonia
6. Determine fungal ITS sequences in lung samples.
Sarah Elliott (graduate student)
Nick Francella (graduate student)
Emily Charlson (graduate student)
Nadeene Riddick (graduate student)
Steven Bryan (Technician)
Yanjie Yi, PhD (Senior Research Investigator)
Anjana Yadav, PhD (Senior Research Investigator)
Farida Shaheen, PhD (Senior Research Investigator)
Ayannah Fitzgerald, BSN (Study Coordinator)
Zetola, N.M., Modongo, C., Moonan P.K., Ncube R., Matlhagela K., Sepako E., Collman, R.G., Bisson, G.P.: Clinical outcomes among persons with pulmonary tuberculosis disease caused by M. tuberculosis isolates with phenotypic DST heterogeneity. J. Infectious Diseases 209(11): 1754-63, June 2014.
Tebas, P., Stein, D., Tang, W.W., Wang, S.Q., Lee, G., Giedlin, M.A., Gregory, P.D., Ando, D.A., Holmes, M.C., Nichol, G., Kalos, M., Collman, R.G., Binder-Scholl, G., Plesa, G., Hwang, W.T., Levine, B.L., June, C.H.: Genome Editing with Zinc Finger Nuclease Modified Autologous CD4 T-cells. New England Journal of Medicine 370(10): 901-10, March 2014.
Francella, N., Elliott, S.T.C., Yi, Y., Gwyn, S.E., Li, B., Derdeyn, C.A., Collman, R.G.: Decreased plasticity of coreceptor use by CD4-independent SIV Envs that emerge in vivo. Retrovirology 10(1): 133, Nov 2013.
Francella, N., Gwyn, S.E., Yi, Y., Li, B., Elliott, S.T., Ortiz, A.M., Hoxie, J.A., Paiardini, M., Silvestri, G., Derdeyn, C.A., Collman, R.G. : CD4+ T cells support production of SIV Env antibodies that enforce CD4-dependent entry and shape tropism in vivo. J. Virology 87(17): 9719-9732. Jul 3. [Epub ahead of print] Sept 2013.
Lozupone, C., Cota-Gomez, A., Palmer, B.E., Charlson, E.S., Sodergren, E., Mitreva, M., Abubucker, S., Martin, J., Yao, G., Campbell, T.B., Flores, S.C., Ackerman, G., Stombaugh, J., Urse, L., Beck, J.M., Curtis, J.L., Young, V.B., Lynch, S.V., Huang, L., Weinstock, G.M., Knox, K.S., Twigg, H., Morris, A., Ghedin, E., Bushman, F.D., Collman, R.G., Knight, R., Fontenot, A.P., for the Lung HIV Microbiome Project.: Widespread colonization of the lung by Tropheryma whipplei in HIV infection. Am J Respiratory Critical Care Medicine 187(10): 1110-7, May 2013.
Elliott STC, Riddick ND, Francella N, Paiardini M, Vanderford TH, Li B, Apetrei C, Sodora DL, Derdeyn CA, Silvestri G, Collman RG : Cloning and analysis of sooty mangabey alternative coreceptors that support SIVsmm entry independently of CCR5. J. Virology 86(2): 898-908, Jan 2012.
Charlson, E.S., Diamond, J.M., Bittinger, K., Fitzgerald, A.S., Yadav, A., Haas, A.R., Bushman, F.D., Collman, R.G.: Lung-enriched organisms and aberrant bacterial and fungal respiratory microbiota following lung transplant. Am J Respiratory Critical Care Medicine 186(6): 536-45, Sept 2012.
Charlson ES, Bittinger K, Haas AR, Fitzgerald AS, Frank I, Yadav A, Bushman FD, Collman RG: Topographical continuity of bacterial populations in the healthy human respiratory tract. Am J Respiratory Critical Care Medicine 184(8): 957-63, Oct 2011.
Paiardini M, Cervasi B, Reyes-Aviles E, Micci L, Ortiz AM, Chahroudi A, Vinton C, Gordon S, Bosinger S, Francella N, Hallberg PL, Cramer E, Schlub T, Chan ML, Riddick NE, Collman RG, Apetrei C, Pandrea I, Else J, Munch J, Kirchhoff F, Davenport MP, Brenchley JM, Silvestri G : Reduced susceptibility to SIV infection in central-memory CD4+ T cells of sooty mangabeys is associated with limited CCR5 up-regulation upon activation. Nature Medicine 17(7): 830-6, June 2011.
Loftin LM, Kienzle MF, Yi Y, Lee B, Lee FH, Gray L, Gorry PR, Collman RG: Constrained use of CCR5 on CD4+ lymphocytes by R5X4 HIV-1: efficiency of Env-CCR5 interactions and low CCR5 expression determine a range of restricted CCR5-mediated entry. Virology 402(1): 135-48, Jun 2010.
Riddick NE, Hermann EA, Loftin LM, Elliott ST, Wey WC, Cervasi B, Taaffe J, Engram JC, Li B, Else JG, Li Y, Hahn BH, Derdeyn CA, Sodora DL, Apetrei C, Paiardini M, Silvestri G, Collman RG: A novel CCR5 mutation common in Sooty mangabeys reveals SIVsmm infection of CCR5-null natural hosts and efficient alternative coreceptor use in vivo PLoS Pathogens 6(8): e1001064, Aug 2010.
Monticelli LA, Sonnenberg GF, Abt MC, Alenghat T, Angelosanto JM, Laidlaw BJ, Yang CY, Diamond JM, Goldrath AW, Collman RG, Wherry EJ, Artis D: Innate lymphoid cells promote tissue homeostasis in the lung following acute influenza virus infection. Nature Immunology 12(11): 1045-54, Nov 2011.
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Last updated: 10/07/2016
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