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Mike McCune, MD, PhD

Mike McCune, MD, PhD
Professor & Chief, Division of Experimental Medicine
Research Summary:
Pathogenic Mechanisms, Treatment, and Prevention of HIV Disease

Research in the McCune Lab has focused on the definition of pathogenic mechanisms of viral diseases, particularly HIV disease. This focus has spanned a range of fields, from understanding critical structural determinants of infectivity, to devising a small animal model (the SCID-hu Thy/Liv mouse) to study HIV pathogenesis and to prioritize antiretroviral compounds against HIV, to studying mechanisms of T cell depletion and repletion in vivo. Throughout this body of work, he has engaged in hypothesis-driven, patient-oriented research that has involved collaborative teams of basic scientists, translational researchers, and clinicians. Most recently, he has devoted all of his attention to understanding the correlates of protective immunity against HIV, with the specific intent to work with others to eradicate HIV. This change of focus has now been materialized at UCSF by the creation of the Division of Experimental Medicine, of which Dr. McCune is the Chief. From 2005-2008, he served as the PI and Director of the Clinical and Translational Science Institute at UCSF, an organization whose mission is to enhance and to facilitate the process by which better therapies can be brought from the lab bench to the community more quickly. In this capacity, he also served as the Senior Associate Dean of Clinical and Translational Research in the Schools of Dentistry, Medicine, Nursing, and Pharmacy at UCSF.

In the Division of Experimental Medicine, he has established a multidisciplinary, collaborative environment for the analysis of the human immunology of chronic infectious diseases of medical importance, including those caused by HIV, TB, malaria, and helminthic worms. The underlying hypothesis of the Division is that each of these agents has established patterns of interaction with the host which, in most cases, do not lead to overt disease; that these patterns are likely to embrace protective immune responses with mechanistic overlaps; and that elucidation of such common patterns of successful host-pathogen interaction may inform the development of interventions (e.g., vaccines and medicines) to successfully fight HIV.

Selected Publications

Hartigan-O’Connor D, Abel K, McCune JM. Suppression of SIV-specific CD4+ T cells by infant but not adult macaque regulatory T cells: implications for SIV disease progression, J. Exp. Med., 204:2679-92, 2007.
 
Napolitano LA, Schdmit D, Gotway MB, Ameli N, Filbert EL, Ng MM, Clor JL, Epling  L, Sinclair E, Baum PD, Li K, Killian ML, Bacchetti P, McCune JM. Growth hormone enhances thymic function in HIV-infected adults. J. Clin. Invest. 118:1085-98, 2008.
 
Schweneker M, Favre D, Martin JN, Deeks SG, McCune JM. HIV-induced changes in T cell signaling pathways. J. Immunol. 180:6490-6502, 2008.
 
Ladell K, Hellerstein M, Cesar D, Busch R, Boban D, McCune JM. Central memory CD8+ T cells have a shorter lifespan and reduced abundance as a function of HIV disease progression. J. Immunol. 180:7907-7918, 2008.
 
Burt TD, Agan BK, Marconi VC, He W, Kulkarni H, Mold JE, Cavrois M, Huang Y, Mahley RW, Dolan M, McCune JM, Ahuja SK. Reply to Pomara et al and Valcour et al: Age and the APOE-e4/e4 genotype in HIV-1-associated dementia. Proc. Natl. Acad. Sci., USA, 105:E65, 2008.
 
Mold JE, Michaelsson J, Burt TD, Muench MO, Beckerman KP, Busch MP, Lee T-H, Nixon DF, and McCune JM. Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. Science, 322:1562-65, 2008. PMCID: PMC2648820
 
Favre D, Lederer S,* Kanwar B,* Min Ma Z,* Proll S, Kasakow Z, Mold J, Swainson L, Barbour JD, Baskin CR, Palermo R, Pandrea I, Miller C, Katze M, McCune JM. Critical loss of the balance between TH17 and T regulatory cell populations in pathogenic SIV infection. PLoS Pathogens, e1000295, Epub Feb 13 2009. (*co-equal authors). PMCID: PMC2635016
 
Stoddart CA, Keir ME, McCune JM.  IFN--mediated induction of CCR5 leads to expanded HIV-1 tropism in vivo. PLoS Pathogens, 6:e1000766, 2010. PMCID: PMC2824759
 
Favre D,* Mold J,* Hunt P, Kanwar B, Loke P, Seu L, Barbour J, Lowe MM, Jayawardene A, Aweeka F, Huang Y, Douek D, Brenchley JM, Martin JN, Hecht FM, Deeks SG, McCune JM. Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of Th17 and regulatory T cells in HIV disease. Science Translational Medicine, 2:32ra36, 2010. (*co-equal authors) PMCID: PMC3034445
 
Loke P,* Favre D,* Hunt PW, Leung JM, Kanwar B, Martin JN, Deeks SG, McCune JM. Correlating cellular and molecular signatures of mucosal immunity that distinguish HIV controllers from non-controllers. Blood 115(15): e20-32, 2010. (*co-equal authors) PMCID: PMC2858476
 
Swainson LA, Mold JE, Bajpai UD, McCune JM. Expression of the autoimmune susceptibility gene, FcRL3, on human regulatory T cells is associated with dysfunction and high levels of programmed cell death-1. J. Immunol. 184:3639-47, 2010. PMCID: PMC2894810
 
Burt T, Seu L, Mold JE, Kappas A, McCune JM. Naïve human T cells are activated and proliferate in response to the heme oxygenase-1 inhibitor tin mesoporphyrin. J. Immunol. 185:5279-88, 2010. PMID: 290921523. PMC3314532
 
Mold JE, Venkatasubrahmanyam S, Burt TD, Michaelsson J, Rivera J, Galkina SA, Weinberg K, Stoddart CA, McCune JM. Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans. Science, 330:1695, 2010. PMC3276679
 
Favre D, Stoddart CA, Emu B, Hoh R, Martin JN, Deeks, SG, McCune JM. HIV infection generates dysfunctional CD8low naive T cells. Blood, 117:2189-99, 2011. PMCID: PMC3062328
 
Babik JM, Cohan D, Monto A, Hartigan-O’Connor DJ, McCune JM. The human fetal immune response to hepatitis C virus exposure in utero. J. Infect. Dis. 203:196-206, 2011. PMCID: PMC3071071
 
Kanwar B, Estes J, Jeet S, Pastuskovas C, Ogasawara A, Flores J, Diehl L, Refino C, Williams S, McCune JM. Epithelial cell dysfunction mediates inflammation and microbial translocation in the IL-10R model of colitis. under review, 2011.
 
Baum PD, Young JJ, McCune JM. Measurement of absolute T cell receptor rearrangement diversity, J. Immunol. Methods, 368:45-53, 2011. PMID: 21385585 (PMCID in progress)
 
Bacchetti P, Deeks SG, McCune JM. Breaking through sample size dogma to perform innovative research, Science Translational Med. 15:87ps24, 2011. PMC3134305
 
Sacre K, Hunt PW, Hsue PY, Maidji E, Martin JN, Deeks SG, Autran B, McCune JM. A role for CD4+CX3CR1+ T cells and CMV-induced T cell immunopathology in HIV-associated atherosclerosis, AIDS, 26:805-14, 2012.
 
Baum P, Sullam P, Stoddart C, McCune J. Abacavir increases platelet reactivity via competitive inhibition of soluble guanylyl cyclase, AIDS, Sept 21 (Epub ahead of press), 2011. (PMID: 21941165)
 
Seu L, Burt TD, Witte JS, Martin JN, Deeks SG, McCune JM. Variations in the heme oxygenase-1 microsatellite polymorphism are associated with plasma CD14 and viral load in HIV-infected African Americans. Genes and Immunity, AOP November 3, 2011 (dol: 10.1038/gene.2011.76). NIHMS ID 352871
 
Brown JN,* Ortiz GM,* Angel TE, Jacobs JM, Gritsenko M, Chan EY, Purdy DE, Murnane RD, Larsen K, Palermo RE, Shukla AK, Clauss TR, Katze MG, McCune JM,* Smith RD.* Morphine produces immunosuppressive effects in non-human primates at the proteomic and cellular levels, Molec Cell Proteomics, 11:605-18, 2012. *(co-equal first and senior authors). PMID: 22580588.
 
Sacre K, Criswell L, McCune JM. Hydroxychloroquine impairs interferon- and tumor necrosis factor-a production by plasmacytoid dendritic cells in systemic lupus erythematosus, Arthritis Res Ther, 14: R155, 2012.
 
Baum PD, Young JJ, Schmidt D, Zhang , Hoh R, Busch M, Martin J, Deeks S, McCune JM. Blood T cell receptor diversity decreases during the course of HIV infection but the potential for a diverse repertoire persists. Blood, 119: 3469-77, 2012. PMC3325037
 
Hartigan-O’Connor DJ, Abel K, Von Rompay KA, Kanwar B, McCune JM. SIV replication is restricted in macaques with large pre-existing Th17 cell compartments, Science Translational Medicine, 4:136ra69, 2012. PMID: 420502
 
Broadhurst MJ, Leung JM, Lim KC, Girgis NM, Mahesh Gundra U, Fallon PG, Premenko-Lanier M, McKerrow JH, McCune JM, Loke P. Upregulation of retinal dehydrogenase 2 in alternatively activated macrophages during retinoid-dependent type-2 immunity to helminth infection, PLoS Pathogens, 8:e1002883, 2012. PMCID3426520
 
Bajpai UD, Swainson LA, Mold JE, Graf JD, Imboden JB, McCune JM. A functional variant in FCRL3 is associated with higher FcRL3 expression on T cell subsets and rheumatoid arthritis disease activity. Arthritis and Rheumatism 64:2451-59, 2012.
 
Broadhurst MJ, Ardeshir A, Kanwar B, Mirpuri J, Gundra U, Vujkovic-Cvijin I, Yarovinski F, Lerche N, McCune JM, Loke P. Therapeutic helminth infection in monkeys suffering from chronic idiopathic colitis, PLoS Pathogens, 8:e10030000, 2012. PMID: 23166490.
 
Seu L,* Ortiz GM,* Burt TD, Huang Y, Deeks SG, Martin JN, McCune JM. High levels of heme oxygenase-1 expression in classical monocytes is associated with favorable outcomes in HIV disease, submitted, 2012. *(co-equal first authors)
 
Dunham RM, Gordon SN, Vaccari M, Piatak M, Huang Y, Deeks SG, Lifson J, Franchini G, McCune JM. Preclinical evaluation of HIV eradication strategies in the SIV-infected rhesus macaque: a pilot study testing inhibition of indoleamine 2,3-dioxygenease. AIDS Res Hum Retroviruses, AIDS Res Hum Retroviruses, 29:207-14, 2013. PMID: 22924680.
 
Miller CN,* Hartigan-O’Connor DJ,* Lee MS,* Laidlaw G, Cornelissen IP, Matloubian M, Coughlin SR, McDonald DM, McCune JM. Interleukin 7 production in murine lymphatic endothelial cells and induction in the setting of peripheral lymphopenia, International Immunol., doi: 10.1093/intimm/dxt012, 2013. *(co-equal first authors). PMID: 23657000
 
Vujkovic-Cvijin I, Dunham RM, Iwai S, Maher CM, Albright R, Broadhurst MJ, Hernandez RD, Lederman MM, Huang Y, Somsouk M, Deeks SG, Hunt PW, Lynch SV, McCune JM. Dysbiosis of the colonic mucosal-adherent microbiota is associated with HIV disease progression and chronic inflammation, Science Translational Medicine, 5:193ra91, 2013. PMID: 23843452
 
Seu L, Ortiz GM, Epling E, Sinclair E, Swainson LA, Bajpai UD, Huang Y, Deeks SG, Hunt PW, Martin JM, McCune JM. Higher CD27+CD8+ T cells during suppressive antiretroviral therapy predict greater subsequent CD4+ T cell recovery in treated HIV infection. PLoS One 8:e84091, 2013.
 
Lowe MM,* Mold JE,* Kanwar B, Huang Y, Louie A, Pollastri MP, Wang C, Patel G, Franks DG, Schlezinger J, Sherr D, Silverstone AE, Hahn ME,^ McCune JM.^ Identification of cinnabarinic acid as a novel endogenous aryl hydrocarbon receptor ligand that drives IL-22 production, PLOS One, 9:e87877, 2014. *(co-equal first authors) ^(co-equal senior authors)
 
Dunham RM, Vujkovic-Cvijin I, Yukl S, Broadhurst MR, Loke P, Albright R, Wong JK, Lederman MM, Somsouk M, Hunt PW, Martin JN, Deeks SG, McCune JM. Discordance between peripheral and colonic markers of inflammation during suppressive ART. JAIDS, 65:133-41, 2014. PMID: 24121758.
 
Emu B, Moretto WJ, Hoh R, Krone M, Martin DN, Nixon DF, Deeks SG, McCune JM. Composition and function of T cell subpopulations are slow to change despite effective antiretroviral treatment of HIV disease, PLoS One, 9:e85613, 2014.
 
Bakkour S, Baker CAR, Tarantal AF, Wen L, Busch MP, Lee T-H, McCune JM. Analysis of maternal microchimerism in rhesus monkeys (Macaca mulatta) using real-time quantitative PCR amplification of MHC polymorphisms, Chimerism, Jan 17, 2014.
 
Franchini G, Moniuszko M, Liyanage NPM, Doster MN, Parks RW, Grubczak K, Lipinska D, McKinnon K, Brown C, Hirsch V, Vaccari M, Gordon SN, Pegu P, Fenizia C, Flisiak R, Greszczuk A, Dabrowska M, Robert-Guroff M, Silvestri G, Stevenson M, McCune JM. Glucocorticoid treatment at moderate doses of SIVmac251-infected Rhesus macaques decreases the frequency of circulating CD14+CD16++ monocytes but does not alter the tissue virus reservoir, AIDS Res Hum Retroviruses, Jan 16, 2014.
 
Hartigan-O’Connor D, Lin D, Ryan JC, Shvachko VA, Cozen ML, Segal MR, Terrault, NA, Lanier LL, Manos M, McCune JM. Monocyte activation by interferon-alpha is associated with failure to achieve a sustained virologic response after treatment for hepatitis C virus infection. J Infect Dis, Mar 6, 2014.
 
Krow-Lucal ER, Kim CC, Burt TD, McCune JM. Distinct functional programming of human fetal and adult monocytes, Blood, 123:1897-904, 2014.