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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

1. Baum PD and McCune JM. Direct measurement of T cell receptor repertoire diversity with AmpliCot: a novel automated assay that measures the sequence diversity of PCR products. Nature Methods, 3:895-901, 2006.

2. 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.

3. 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.

4. Schweneker M, Favre D, Martin JN, Deeks SG, McCune JM. HIV-induced changes in T cell signaling pathways. J. Immunol. 180:6490-6502, 2008.

5. 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.

6. Burt TD, Agan BK, Marconi VC, He W, Kulkarni H, Mold JE, Cavrois M, Huang Y, Mahley RW, Dolan M, McCune JM, Ahuja SK. Apolipoprotein E influences HIV-1 cell entry and disease progression, Proc. Natl. Acad. Sci., USA, 105:8718-8723, 2008. PMCID: PMC2438419

7. 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

8. 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

9. Lederer S,* Favre D,* Walters K-A, Proll S, Kanwar B, Kasakow Z, Baskin CR, Palermo R, McCune JM, Katze MG. Transcriptional profiling reveals significant distinctions in kinetics and tissue compartmentalization between pathogenic and non-pathogenic SIV infection, PLoS Pathogens, e1000296, Epub Feb 13 2009. (*co-equal authors). PMCID: PMC2633618

10. 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

11. 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

12. 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

13. 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

14. 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. NIHMSID 353236

15. Broadhurst MJ, Leung JM, Kashyap V, McCune JM, Mahadevan U, McKerrow JH, Loke P. IL-22 producing gut mucosal CD4+ T cells are associated with therapeutic Trichuris trichiura infection in a patient with ulcerative colitis. Science Translational Medicine, 2:60, 2010. PMID: 21123809

16. 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. NIHMS ID 353100

17. 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

18. 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

19. 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)

20. Bacchetti P, Deeks SG, McCune JM. Breaking through sample size dogma to perform innovative research, Science Translational Med. 15:87ps24, 2011. PMID: 21677197. PMCID: PMC3134305

21. 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

22. 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, in press, 2012.

23. 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, in press, 2012.

24. 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, EPOP, March 5, 2012.

30. McCune JM. The dynamics of CD4+ T-cell depletion in HIV disease. Nature 410:974-979, 2001.

31. Kanwar B, Favre D, McCune JM. Th17 and regulatory T cells: implications for AIDS pathogenesis. Current Opinion in HIV and AIDS, 5:151-157, 2010.

36. Deeks SG, McCune JM. Can HIV be cured with stem cell therapy? Nature Biotech 28:807-810,2 2010. PMID: 20697404

40. Hartigan-O’Connor DJ, Hirao L, McCune JM, Dandekar S. Th17 cells and T-reg in elite control over HIV and SIV, Curr Opin HIV AIDS, Mar 10 2011. PMID: 21399494

43. Mold JE, McCune JM. At the crossroads between tolerance and aggression: revisiting the “layered immune system” hypothesis. Chimerism, 2:35-41, 2011. (PMID: 21912717)

46. Kiem H-P, Jerome K, Deeks SG, McCune JM. Hematopoietic stem cell-based gene therapy for HIV disease. Cell Stem Cell, 10:137-47, 2012.

47. Mold JE and McCune JM. Immunological tolerance during fetal development: From mouse to man. Advances in Immunology, in press, 2012.

49. Deeks SG, Verdin E, McCune JM. Immunosenescence and HIV. Current Opinion Immunology, in press, 2012.