The development of EBV and KSHV driven lymphomas in the oral cavity is a serious clinical issue in HIV infected subjects. Despite its relatively frequent occurrence in some geographic areas, including South America, little is known how the herpesvirus specific immunity or lack thereof, is associated with disease control. In particular essentially no data exist regarding the impact of acute HIV infection on the pre-existing EBV and KSHV specific immunity and its consequences for later disease manifestation. This lack of knowledge is largely due to logistical difficulties to examine the herpesvirus-specific cellular immune response in individuals immediately before and after HIV infection. The availability of a closely monitored cohort of individuals at high risk for HIV infection, combined with detailed immune analyses would overcome this important gap in our understanding how immune events during acute HIV infection predispose individuals for long-term control of herpesviral infections. The present study aims to establish such as cohort and to assess EBV and KSHV specific immune responses on a single epitope level before and after HIV infection. Using sensitive and multi-parameter flow-cytometryapproaches the proposed studies will help to assess whether HIV infection leads to a complete loss of some herpesvirus specific T cell responses or whether HIV infection leads to a possibly transient functional silencing of these reactivities. Comparing blood samples to cells obtained form tonsilar biopsies, the studies will address whether the changes in the peripheral blood are a consequence of profound immune aberrations in the tonsil, an important site of viral replication for orally transmitted viruses. The tonsil samples will also allow to perform viral gene expression analyses in projects 2 and 3 of this proposal, helping to link detected immune responses to the presence or absence of viral antigens in this site. Together, the analyses in project 4 will provide unique insight into the early immune events that surround acute HIV infection and that may determine herpesvirus control in these co-infected subjects. Performing these analyses in a untreated HIV cohort in Lima, Peru will also deepen our understanding of cellular immunity against herpesvirus infections common to this geographic area and frequently associated with disease manifestation in the oral cavity Massachusetts General Hospital/PARC - Boston, MA Asociacion Civil IMPACTA Salud y Educacion, Lima, Peru PHS 398 (Rev. 04/06) . Page 2 Form Page 2-continued Number the following pages consecutively throughout the application. Do not use suffixes such as 4a, 4b. Principal Investigator/ProgramDirector (Last, First, Middle): Brandei", Christian KEY PERSONNEL. See instructions. Usecontinuation pagesas neededto provide the required information Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name eRA Commons User Name Organization Brander, Christian CBRANDER MGH Frahm, Nicole NFRAHM MGH Lucchetti, Aldo IMPACTA Zuniga, Rosario IMPACTA in the format shown below. Role on Project PI Co-Investigator Co-Investigator Co-Investigator OTHER SIGNIFICANT CONTRIBUTORS Name Organization Role on Project Human Embryonic Stem Cells ^ No D Yes If the proposed project involves human embryonic stem cells, list below the registration number of the specific cell line(s) from the following list: http://StemcellS.nih.gov/reqistrv/index.asp. Use continuation pages as needed. If a specificline cannot be referenced at this time, include a statement that one from the Registry will be used. Cell Line Disclosure Permission Statement. Applicable toSSIR/STTR Only. See instructions. I I Yes I I No PHS 398 (Rev. 04/06) Page 3 Form Page 2-continued Number the followingpages consecutively throughout the application. Do not use suffixes such as 4a, 4b. Principal Investigator/Program Director (Last, First, Middle): Brander, Christian The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page i_ Description,
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