Dr. Cox’s laboratory investigates the host immune response to chronic human viral infections, particularly HIV and hepatitis C virus (HCV). HCV infects nearly 200 million people worldwide, resulting in chronic infection in about 75% of cases. They examine the role of the immune response in clearance of HCV upon exposure to this virus by studying responses to HCV from the earliest phases of infection through years following infection in a longitudinal, prospective cohort of people at risk of HCV infection. This allows a comparison of the innate, humoral and cellular immune responses to infection with clearance versus persistence.
They have demonstrated that spontaneous control of HCV does not uniformly generate sterilizing immunity, but reinfection is associated with a reduction in the magnitude and duration of viremia (compared with the initial infection), broadened cellular immune responses and generation of cross-reactive humoral responses. These findings are consistent with development of adaptive immunity that is not sterilizing but protects against chronic disease.
To identify mechanisms of protective immunity against HCV infection and improve prophylactic HCV vaccine design, they are determining the cellular and humoral responses associated with repeated HCV control. A significant barrier to the development of an HCV vaccine is that HCV is a highly diverse virus. The laboratory has also developed and evaluated methods of HCV vaccine design that may overcome this diversity and stimulate an effective immune response.
Cox AL, Siliciano RF. "HIV: Not-so-innocent bystanders." Nature. 2014 Jan 23;505(7484):492-3. doi: 10.1038/505492a. No abstract available.
Serti E, Werner JM, Chattergoon M, Cox AL, Lohmann V, Rehermann B. "Monocytes activate natural killer cells via inflammasome-induced interleukin 18 in response to hepatitis C virus replication." Gastroenterology. 2014 Jul;147(1):209-220.e3. doi: 10.1053/j.gastro.2014.03.046. Epub 2014 Mar 28.
Osburn WO, Snider AE, Wells BL, Latanich R, Bailey JR, Thomas DL, Cox AL, Ray SC. "Clearance of hepatitis C infection is associated with the early appearance of broad neutralizing antibody responses." Hepatology. 2014 Jun;59(6):2140-51. doi: 10.1002/hep.27013. Epub 2014 Apr 29.
Wojcik GL, Thio CL, Kao WH, Latanich R, Goedert JJ, Mehta SH, Kirk GD, Peters MG, Cox AL, Kim AY, Chung RT, Thomas DL, Duggal P. "Admixture analysis of spontaneous hepatitis C virus clearance in individuals of African descent." Genes Immun. 2014 Apr;15(4):241-6. doi: 10.1038/gene.2014.11. Epub 2014 Mar 13.
Chattergoon MA, Latanich R, Quinn J, Winter ME, Buckheit RW 3rd, Blankson JN, Pardoll D, Cox AL. "HIV and HCV activate the inflammasome in monocytes and macrophages via endosomal Toll-like receptors without induction of type 1 interferon." PLoS Pathog. 2014 May 1;10(5):e1004082. doi: 10.1371/journal.ppat.1004082. eCollection 2014 May.
Cox AL, Appella E, Engelhard VH: Characterization of peptides bound to the class I MHC molecule HLA-A2.1 by mass spectrometry. Science 1992 March 6 255(5049):1261-1263.
Cox AL, Sakaguchi K, Appella E, Grey HM, Sette A: Peptides presented to the immune system by the murine class II major histocompatibility complex molecule I-Ad. Science 1992 June 26 256(5065):1817-1820.
Cox AL, Henderson RA, Hunt DF, Engelhard VH: Recognition of human melanoma cells by HLA-A2.1 restricted cytotoxic T-lymphocytes is mediated by at least six shared peptide epitopes. Journal of Immunology 1993 April 150(7):2955-2963.
Cox, AL, Chen Y, Henderson RA, Huczko EL, Michel H, Sakaguchi K: Mass spectrometric analysis of peptides associated with the human class I MHC molecules HLA-A2.1 and HLA-B7 and identification of structural features that determine binding. Chemical Immunology 1993; 57:39-62
Cox AL*, Henderson RA*, Sakaguchi K, Apella E, Hunt DF, Engelhard VH: Direct identification of an endogenous peptide recognized by multiple HLA-A2.1-specific cytotoxic T cells. Proceedings of the National Academy of Sciences of the USA 1993 November 1 90(21):10275-9. * The paper notes that these authors contributed equally to this work.
Cox AL, Sakaguchi K, Henderson RA, Appella E, Hunt DF, Sette A, Engelhard VH: Naturally processed peptides longer than nine amino acid residues bind to the class I MHC molecule HLA-A2.1 with high affinity and in different confirmations. Journal of Immunology 1994 March 15 152(6):2874-2881.
Cox AL, Stover JM Jr, Moore MM, Hunt DF, Engelhard VH: Cytotoxic T-lymphocyte response to autologous human squamous cell cancer of the lung: epitope reconstitution with peptides extracted from HLA-Aw68. Cancer Research 1994 May 15 54 (10):2731-2737.
Cox AL, Skipper J, Chen Y, Henderson RA, Darrow TL, Shabanowitz J, Engelhard VH, Hunt DF, Slingluff CL Jr.: Identification of a peptide recognized by five melanoma-specific human cytotoxic T cell lines. Science 1994 April 29 264 (5159): 716-719.
Cox A, Dick R 2nd, Shabanowitz J, Chien YH, Matis L, Hunt DF, Bluestone JA: Functional expression and recognition of nonclassical MHC class I T10b is not peptide-dependent. Journal of Immunology 1995 Sep 1 155(5):2379-2386.
Cox A, Hellmann DB, Fishman E: Acute colonic ischaemia in a patient with systemic lupus erthematosus: diagnosis with spiral and computed tomographic angiography. Journal of Diagnostic Radiology and Imaging 1999 2(1):45-48.
Cox A, Hoover D, Wang X-H, Mao Q, Ray S, Strathdee S, Vlahov, D, Thomas D: Protection Against Hepatitis C Persistence, Lancet 2002 357:1478-1483.
Cox A., Netski D., Mosbruger T., Sherman S, Strathdee S, Ompad D, Vlahov D; Chien D, Shyamala V, Ray S., Thomas D; Prospective Evaluation of Community-Acquired Acute-Phase Hepatitis C Virus Infection, Clinical Infectious Diseases 2005 40: April 1 951-958.
Cox A, Mosbruger T, Mao Q, Liu Z, Wang X-H, Yang H-C, Sidney J, Sette A, Pardoll D, Thomas D, Ray R.;Cellular Immune Selection with Hepatitis C Virus Persistence in Humans, The Journal of Experimental Medicine 2005 201: 1741-1752.
Cox A, Mosbruger T, Lauer G, Pardoll D, Thomas D, Ray S, Comprehensive Analyses of CD8+ T cell Responses During Longitudinal Study of Acute Human Hepatitis C, Hepatology, 2005 42: 104-112.
Cox A; Humoral Immune Response in Acute HCV Infection, Clinical Infectious Diseases, 2005; 41:667–75.
Netski D, Mosbruger T, Astemborski J, Mehta S, Thomas D, Cox A; CD4+ T cell dependent reduction in hepatitis C virus specific humoral immune responses after HIV infection, The Journal of Infectious Diseases, 2007 Mar 15;195(6):857-63.
Barnes E, Salio M, Cerundolo V, Confrancesco L, Pardoll D, Klenerman P, Cox A; Monocyte derived dendritic cells retain their functional capacity in patients following infection with hepatitis C virus. The Journal of Viral Hepatitis, 2008 Mar;15(3):219-28.
Cox A, Thomas D, Ray S. Human Immunodeficiency Virus-related Microbial Translocation and Progression of Hepatitis C, Gastroenterology, 2008, 135:226–233
a A, Mosbruger T, Mao Q, Li H, Netski D, Ray S, Pardoll D, Sidney J, Sette A, Allen T, Kuntzen T, Kavanagh D, Kuball J, Greenberg P, Cox A. Hepatitis C Virus Immune Escape via Exploitation of a Hole in the T cell Repertoire, Journal of Immunology, 2008, 181: 6435-6446.
Cox A. High Programmed Death-1 levels on HCV specific T cells during acute infection are associated with viral persistence and require preservation of cognate antigen during chronic infection, Journal of Immunology, 2008, 181: 8215– 8225.
Cox A, Page K, Bruneau J, Shoukry N, Lauer, G, Kim A, Rosen H, Radziewicz H, Grakoui A, Fierer D, Branch A, Kaplan D, and Chang K-M. Rare Birds in North America: Acute Hepatitis C Cohorts, Gastroenterology, 2009;136:26–31.
Dowd K, Netski D, Wang-X-H, Cox A, Ray S. Selection Pressure from Neutralizing Antibodies Drives Sequence Evolution during Acute Infection with Hepatitis C Virus. Gastroenterology 2009;136(7):2377-86.
Cox A. Spontaneous control of primary hepatitis C virus infection and immunity against persistent reinfection. Gastroenterology 2010 Jan; 138(1):315-24.
Burke KP, Cox AL. Hepatitis C virus evasion of adaptive immune responses: a model for viral persistence. 2010, Immunologic Research. Jul;47(1-3):216-27.
Cox AL, Ray SC. Acceleration of HCV envelope evolution in humans is consistent with progressive humoral immune selection during the transition from acute to chronic infection. Journal of Virology 2010 May; 84(10):5067-77.
Cox A, Randall J, Cheng L, and Rosen H. Increased NK cytotoxicity and NKp30 expression protects against HCV infection in high-risk individuals and inhibits replication in vitro. Hepatology 2010 Nov;52(5):1581-9.
Salgado M, Kirk GD, Cox A, Rutebemberwa A, Higgins Y, Astemborski J, Thomas DL, Thio CL, Sulkowski MS, Blankson JN. Protective interleukin-28B genotype affects hepatitis C virus clearance, but does not contribute to HIV-1 control in a cohort of African-American elite controllers/suppressors. 2011 AIDS Jan 28; 25(3):385-7.
Cox A. High plasma interleukin-18 levels mark the acute phase of hepatitis C virus infection. The Journal of Infectious Diseases, 2011 Dec; 204(11):1730-40.
Cox A, Stanislau E, Higgs M, Loo M, Golden- Mason L, Lindenbach B, Baumert T, Randall G, Gale M. A Summary of the 18th International Symposium on Hepatitis C Virus and Related Viruses. Gastroenterology, 2012 Jan; 142(1):e1-5.
Le DT, Brockstedt DG, Nir-Paz R, Hampl J, Mathur S, Nemunaitis J, Sterman DH, Hassan R, Lutz E, Moyer B, Giedlin M, Louis JL, Sugar EA, Pons A, Cox AL, Levine J, Murphy AL, Illei P, Dubensky TW Jr, Eiden JE, Jaffee EM, Laheru DA. A Live-Attenuated Listeria Vaccine (ANZ-100) and a Live-Attenuated Listeria Vaccine Expressing Mesothelin (CRS-207) for Advanced Cancers: Phase I Studies of Safety and Immune Induction. Clin Cancer Res Feb1, 2012 18:858-868
Cox A, Aitken C, Hickman M and Hellard M. The more you look the more you find - Effects of hepatitis C virus testing interval on re-infection incidence and clearance: Implications for future vaccine study design. The Journal of Infectious Diseases, 2012 May;205(9):1342-1350.
Grebely J. Prins M, Hellard M, Cox A, Osburn W, Lauer G, Page K, Lloyd A, Dore, G. Towards a hepatitis C virus vaccine: insights from studies of hepatitis C virus reinfection in injection drug users. The Lancet Infectious Diseases, 2012 May;12(5):408-414.
Munshaw S, Bailey JR, Liu L, Osburn W, Burke K, Cox AL, and Ray SC Computational Reconstruction of Bole1a, a Representative Synthetic Hepatitis C Subtype 1a Viral Genome. Journal of Virology, 2012 May;86 (10):5915-21.
Burke K, Munshaw S, Osburn W, Levine J, Liu L, Sidney J, Sette A, Ray S, and Cox A. Immunogenicity and cross-reactivity of a representative ancestral sequence in HCV infection. Journal of Immunology, 2012 May 15;188(10):5177-88.
Cox AL, Ray SC. Spontaneous clearance of primary acute hepatitis C virus infection correlated with high initial viral RNA level and rapid HVR1 evolution. Hepatology 2012 Jun;55(6):1684-91.
Page K, Osburn W, Evans J, Hahn J, Lum P, Asher A, Delwart E, Tobler L, Cox AL, Busch M. Frequent longitudinal sampling of HCV infection in IDU reveals intermittently detectable viremia and reinfection. Clinical Infectious Diseases, 2013 Feb; 56(3):405-13.
Terilli RR, Cox AL. Immunity and Hepatitis C: A Review. Current HIV/AIDS Reports. 2012 Nov 22.
Cox AL, Klenerman P. Evolution of CD8+ T cell responses after acute PARV4 infection. Journal of Virology. 2013 Jan 2.
Duggal P, Thio C, Wojcik G, Goedert J, Mangia A, Latanich R, Kim A, Lauer G, Chung R, Peters M, Kirk G, Mehta S, Cox AL, Khakoo S, Alric L, Cramp M, Donfield S, Edlin B, Tobler L, Busch M, Alexander G, Rosen H, Gao X, Abdel-Hamid M, Apps R, Carrington M, and Thomas D, Genome-wide Association Study of Spontaneous Resolution of Hepatitis C Virus Infection. Annals of Internal Medicine, 2013, Feb 19;158(4):235-45.
Cox AL. Anti-inflammatory cytokines, pro-fibrogenic chemokines, and persistence of acute HCV infection. J Vir Hep 2013, Jun;20(6):404-13.
Cox AL, Thomas DL. Hepatitis C Virus Vaccines Among People Who Inject Drugs. Clinical Infectious Diseases, 2013, Aug;57 Suppl 2:S46-50.
Grebely J, Morris M, Rice T, Bruneau J, Cox AL, Kim A, McGovern B, Shoukry N, Lauer G, Maher L, Lloyd A, Hellard M, Prins M, Dore G, Page K, on behalf of the InC3 Study Group, Cohort Profile: The International Collaboration of Incident HIV and Hepatitis C in Injecting Cohorts (InC3) Study. International Journal of Epidemiology 2013; 42:1649–1659.
Grebely J, Page K, Sacks-Davis R, Schim van der Loeff M, Rice TM, Bruneau J, Morris MD, Hajarizadeh B, Amin J, Cox AL, Kim AY, McGovern BH, Schinkel J, George J, Shoukry NH, Lauer GM, Maher L, Lloyd AR, Hellard M, Dore GJ, and Prins M on behalf of the InC3 Study Group. The effects of female sex, viral genotype and IL28B genotype on spontaneous clearance of acute hepatitis C virus infection. Hepatology, 2014 Jan;59(1):109-20.
Cox AL., HIV and HCV activate the inflammasome in monocytes and macrophages via endosomal Toll-like receptors without induction of Type 1 interferon. Plos Pathogens 2014 May 01;10(5): e1004082
Wojcik GL, Thio CL, Kao L, Latanich R, Goedert JJ, Mehta SH, Kirk GD, Peters MG, Cox AL, Kim AY, Chung RT, Thomas DL, Duggal D. Admixture Analysis of Spontaneous Hepatitis C Virus Clearance in Individuals of African-Descent. Genes Immun. 2014 Apr;15(4):241-6.
Osburn WO, Snider AE, Wells BL, Latanich R, Fisher BE, Bailey JR, Thomas DL, Cox AL, Ray SC. 2013. Clearance of Hepatitis C Infection is associated with early appearance of deep neutralizing antibody responses. Hepatology. 2014 Jun;59(6):2140-51.
Cox AL, Lohmann V, Rehermann B. Monocytes Activate Natural Killer Cells via Inflammasome-induced Interleukin-18 in Response to Hepatitis C Virus Replication. Gastroenterology. 2014 Mar 28. [Epub ahead of print]
Cox AL, Siliciano RF. Making Sense of HIV Innate Sensing. Immunity. 2013 Dec 12;39(6):998-1000.
Cox AL, Siliciano RF. Not so innocent bystanders. Nature, in press.