Mucosal CTL Induction After HIV Exposure & Vaccination

Fred Hutchinson Cancer Research Center, Seattle WA

Investigators

Linked publications & trials

Abstract

Transmission of Human immunodeficiency virus (HIV) infection occurs predominantly through mucosal[unreadable] routes, and it is essential that HIV vaccine regiments stimulate[unreadable] protective immunity in the mucosal compartment. In addition to local[unreadable] antibody production, both CD8+ CTL, the major effector cells in viral[unreadable] resistance, and CD4+ T helper cells will likely play a critical role in[unreadable] HIV mucosal immunity. Investigations of mucosal immunity in HIV[unreadable] infection have been directed primarily to the detection of local antibody[unreadable] responses, and little is known about cellular immune response. Analysis[unreadable] of the requirements to achieve mucosal protection in human vaccine trials[unreadable] has been limited by lack of systematic method to collect adequate[unreadable] specimens as well as the availability of vaccine regimens that can[unreadable] stimulate detectable mucosal response. Consequently, the overall goal[unreadable] of the proposed study is to identify the specific cellular components in[unreadable] the genital and rectal mucosa that participate in HIV immune surveillance[unreadable] and thus may be important to elicit by HIV preventive vaccines. Initial[unreadable] efforts will be directed toward the analysis of specimens from the[unreadable] mucosal regions of HIV-infected individuals for analysis of in vitro[unreadable] cellular responses. Mucosal sites to be examined in this project include[unreadable] cervical brushings and biopsies, rectal biopsies, and semen. Subsequent[unreadable] studies will focus on the mucosal HIV-specific responses elicited by AVEG[unreadable] candidate vaccines HIV-uninfected volunteers. Such studies will[unreadable] complement the mucosal antibody studies in Project II of the[unreadable] collaborative proposal.[unreadable] [unreadable] The major aims of this project will be identify and characterize the HIV-[unreadable] specific CTL and helper T cells in the mucosal sites of HIV-infected[unreadable] persons and HIV-uninfected vaccine recipients. Mucosal CTL responses to[unreadable] HIV gene products will be amplified by a variety of stimulation and[unreadable] cloning techniques, and the MHC restriction patterns, cell phenotypes and[unreadable] capacity to recognize and lyse HIV-infected cells will be analyzed. In[unreadable] selected subjects, the precursor CTL frequency in the mucosal compartment[unreadable] will be measured and correlated with local HIV genomic copy number to[unreadable] determine the role of these effector cells in viral clearance. Companion[unreadable] studies will characterize the T helper responses in the mucosal region,[unreadable] with analysis of antigen recognition and cytokine induction profiles.[unreadable] Collaborative studies will compare the T cell effector and helper[unreadable] responses with the local production of mucosal immunoglobulin. These[unreadable] investigations will provide insight into the components of mucosal[unreadable] immunity that may be beneficial to elicit with HIV vaccines and will[unreadable] advance the technology required to detect these responses following[unreadable] immunization.