Herpes simplex virus (HSV) is ubiquitous among HIV+ persons and is an important opportunistic infection (OI), influencing both the clinical progression of HIV as well as enhancing its transmission and acquisition. Our initial studies defining T cell responses to HSV among HIV+ persons have indicated that HSV-specific CD8+ T cells play a prominent role in the control of HSV reactivation rates of HSV. To our surprise, HAART therapy, while increasing HSV-specific CD4+ T cell responses, had little effect upon HSV reactivation rates, indicating that HSV differs from other herpesvirus infections in this regard. Our proposed studies are directed at defining the relationship between systemic and local HSV-specific CD8+ T cell responses and mucosal reactivation rates of HSV.
Specific Aim #1 will utilize recently developed technologies including ELISpot, intracellular cytokine staining and HLA/peptide tetramers, to quantitate the HSV-specific CD8+ T cell response in HSV-infected persons with acute HIV infection treated early with highly active antiretroviral therapy. These persons should have relatively intact CD4+ T cell responses to HSV and we will test the hypothesis that the rate of HSV reactivation is influenced by the frequency of HSV-specific CD8+ T cells prior to HIV acquisition. We will also measure CD8+ T cell responses in HIV- negative persons with primary HSV infection to test the hypothesis that the memory CD8+ set point established during primary infection is inversely correlated with subsequent reactivation rates of HSV even in the immunocompetent person.
Specific Aim #2 will quantitate the local HSV-specific CD8+ T cell response by T cell clonotype specific assays to determine if the quantitative circulating CD8+ T cell response to HSV is directly correlated with the quantitative mucosal CD8+ T cell response. Local CD8+ T cell responses will be compared among HIV+ persons with low versus high frequencies of pCTL and in persons with low versus high rates of HSV reactivation.
Specific Aim #3 will determine if the effector mechanisms (killing and cytokine/chemokine release) utilized by lesion-derived HSV-specific CD8+ T cells between HIV+ and HIV-negative persons. These proposed studies will provide novel information about the role HSV-specific CD8+ T cell responses play on mucosal reactivation of an OI and offer the potential for providing novel therapeutic approaches for disease management.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37AI042528-05
Application #
6409043
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Savarese, Barbara M
Project Start
1997-12-01
Project End
2007-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
5
Fiscal Year
2002
Total Cost
$346,000
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
075524595
City
Seattle
State
WA
Country
United States
Zip Code
98109
Bender Ignacio, Rachel A; Goldman, Jason D; Magaret, Amalia S et al. (2016) Patterns of human herpesvirus-8 oral shedding among diverse cohorts of human herpesvirus-8 seropositive persons. Infect Agent Cancer 11:7
Milman, Neta; Zhu, Jia; Johnston, Christine et al. (2016) In Situ Detection of Regulatory T Cells in Human Genital Herpes Simplex Virus Type 2 (HSV-2) Reactivation and Their Influence on Spontaneous HSV-2 Reactivation. J Infect Dis 214:23-31
Schiffer, Joshua T; Mayer, Bryan T; Fong, Youyi et al. (2014) Herpes simplex virus-2 transmission probability estimates based on quantity of viral shedding. J R Soc Interface 11:20140160
Zhu, Jia; Peng, Tao; Johnston, Christine et al. (2013) Immune surveillance by CD8ýýýý+ skin-resident T cells in human herpes virus infection. Nature 497:494-7
Schiffer, Joshua T; Corey, Lawrence (2013) Rapid host immune response and viral dynamics in herpes simplex virus-2 infection. Nat Med 19:280-90
Schiffer, Joshua T; Swan, David; Al Sallaq, Ramzi et al. (2013) Rapid localized spread and immunologic containment define Herpes simplex virus-2 reactivation in the human genital tract. Elife 2:e00288
Schiffer, Joshua T; Swan, David A; Corey, Lawrence et al. (2013) Rapid viral expansion and short drug half-life explain the incomplete effectiveness of current herpes simplex virus 2-directed antiviral agents. Antimicrob Agents Chemother 57:5820-9
Jing, Lichen; Haas, Jürgen; Chong, Tiana M et al. (2012) Cross-presentation and genome-wide screening reveal candidate T cells antigens for a herpes simplex virus type 1 vaccine. J Clin Invest 122:654-73
Peng, Tao; Zhu, Jia; Phasouk, Khamsone et al. (2012) An effector phenotype of CD8+ T cells at the junction epithelium during clinical quiescence of herpes simplex virus 2 infection. J Virol 86:10587-96
Cattamanchi, Ashok; Saracino, Misty; Selke, Stacy et al. (2011) Treatment with valacyclovir, famciclovir, or antiretrovirals reduces human herpesvirus-8 replication in HIV-1 seropositive men. J Med Virol 83:1696-703

Showing the most recent 10 out of 40 publications