Immune Correlates of HSV-2 Disease Severity

David Koelle, MD

HSV-2 is an important pathogen in neonates and immunosuppressed persons and contributes to HIV-1 transmission.   The clinical severity and viral shedding rates of HSV-2 differ, for unknown reasons, between persons.   One hypothesis is that acquired CD8 T-cell responses may be associated with the severity of HSV-2 infection.   Little is known about the immunodominant CD8 T-cell antigens and epitopes of HSV-2.   In this five-year, NIH-finded RO1 grant, which beings in Spring of 2003, we will continue our antigen discovery efforts to define new, potentially immunodominant CD8 antigens, and make suitable vaccinia recombinants.   Epitope discovery uses expression cloning to screen libraries of HSV-2 DNA, a method we also use to discover CD4 antigens.   We will then enroll and sample HLA A*0201-expressing persons with virologically defined mild and severe HSV-2 infection, and compare immune responses to defined CD8 antigens between these populations.   The overall goal is determine if CD8 responses correlate with disease severity, and to contribute to the rational design of HSV-2 vaccines.

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Publications:

Macdonald WA, Purcell AW, Mifsud N, Ely LK, Williams DS, Chang L, Gorman JJ, Clements CS, Kjer-Nielsen L, Koelle DM, Burrows SR, Tait BD,
Holdsworth R, Brooks AG, Lovrecz GO, Lu L, Rossjohn , McCluskey J. 2003.  A naturally selected dimorphism within the HLA-B44 supertype
alters class I structure, peptide repertoire and T cell recognition.  Journal of Experimental Medicine 198: 679-691.

Koelle DM. Discovery of viral antigens and epitopes recognized by T-cells using expression cloning. 2003. Methods 29:213-226.

Posavad CM, Wald A, Hosken N, Huang ML, Koelle DM, Ashley RL, Corey L. 2003. T cell immunity to herpes simplex virus in seronegative persons:
silent infection or acquired immunity? Journal of Immunology 170: 4380-4388.

Koelle DM, Liu Z, McClurkan CM, Cevallos R, Vieira J, Hosken NA, Meseda CA, Snow DC, Wald A, Corey L. 2003. Immunodominance amongst
herpes-simplex virus-specific CD8 T-cells expressing a tissue-specific homing receptor. Proceedings of the National Academy of Sciences, In
Press

Koelle DM , Chen HB, McClurkan CM, Petersdorf EW.   2002.   Herpes simplex virus type 2-specific CD8 CTL cross-reactive against prevalent HLA class I alleles.   Blood 99:3844-3847.

Koelle DM, Chen H, Gavin MA, Wald A, Kwok WW, Corey L.   2001.   CD8 CTL from genital herpes simplex lesions: recognition of viral tegument and immediate early proteins and lysis of infected cutaneous cells.   Journal of Immunology 166:4049-4058.

Koelle DM , Posavad CM, Barnum GR, Johnson ML, Frank JM, Corey L.   1998.   Clearance of HSV-2 from recurrent genital lesions correlates with infiltration of HSV-specific cytotoxic T lymphocytes.   Journal of Clinical Investigation 101:1500-1508.

Koelle DM , Schomogyi M, McClurkan C, Reymond SN, Chen HB.   2000.   CD4 T-cell responses to herpes simplex virus type 2 major capsid protein VP5: comparison with responses to tegument and envelope glycoproteins.   Journal of Virology 74:11422-11425.