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CELL-MEDIATED IMMUNE RESPONSE AGAINST HIV/SIV AND ITS SIGNIFICANCE FOR VACCINE DEVELOPMENT

Objective

The general objectives of the Concerted Action have been to obtain information pertinent to HIV vaccine development. To obtain this goal, the occurrence and nature of cell-mediated immune responses have been studied both in HIV-infected human beings, in individuals exposed to HIV but without classical markers of infection, and in immunized experimental animals.
The objective of this work was to study the nature and extent of cell mediated immunity (CMI) in human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) infected or vaccinated human beings and primates. Furthermore, methods to induce strong cell mediated immunity with eventual protective potential in vaccinated experimental animals have been studied. This approach has involved altered immunogens as well as various live vaccines. In evaluation of the specific cell mediated immunity, both the target proteins and specific epitopes have been identified. Also, CD4 mediated helper T cell (TH) responses and CD8 CD4 mediated cytotoxic T lymphocyte responses have been studied.
Cohorts of HIV infected patients have been followed up for several years, and the nature and extent of their CMI has been evaluated. The general observation has been that TH responses in infected individuals towards HIV virions and HIV proteins is weak, but specific responses have been observed to core, Nef and Tat proteins and, to a certain extent, to Env protein too. Furthermore, T cell recognition of gp160 and to Nef were observed in exposed but noninfected individuals. Several groups have used overlapping synthetic peptides to identify TH epitopes.
CTL responses in HIV infected individuals have been observes towards Gag, Env and Nef but the occurrence and strength of the responses seem to fade during the course of the disease. Again the use of synthetic peptides has made it possible to identify specific CTL epitopes and their association to HLA has been identified.
In vaccine experiments, TH and CTL epitopes have been identified in the vaccine preparates. Experiments showing protective vaccine activity have mainly come from studies where the animals have received nonvirulent viruses and have later been challenged with virulent wild type virus.
Attempts to produce live attenuated vaccines have been based on the fact that the Rev protein is necessary for the expression of virion structural proteins and thus, rev deficient viruses either have a low virus production or express only the early auxiliary gene products. Using site directed mutagenesis, several constructs with different levels of rev activity have been obtained, starting from the infectious SIVmac251 clone PBK1.
A working hypothesis for the project has been that cellular immune response, especially when mediated by cytotoxic T lymphocytes capable of destructing infected cells, may have a stronger role than neutralizing humoral antibody response in protective immunity against HIV. Also, the problems raised by HIV envelope protein variability might be overcome by this approach.

The proposal has an organizational structure where the different European facilities have been most effectively joined and where standardized necessary techniques and reagents have been distributed to all groups participating in the project. Special emphasis has been paid to the production of reagents for the study of cytotoxic T lymphocyte responses, where HLA-matched target cell lines expressing HIV proteins or live vectors used for immunization are required. Secondly, in order to identify the antigenic epitopes recognized synthetic peptides have been produced and distributed to the participating groups.

A Methodological Aims

To generate and to distribute suitable target cell lines, such as EBV-transformed B cell lines with known HLA phenotypes.

To construct and distribute Vaccinia recombinants carrying different HIV genes derived either from standard isolates (III B, LAV-1 etc.) or from isolates derived from prospectively followed patient material.

To produce and distribute synthetic peptides especially from the regulatory HIV proteins for the identification of helper and cytotoxic T cell epitopes.

To generate new methods to express HIV antigens in target cell lines for CTL assays, especially systems for noncytopathic protein expression. These may include the use of mammalian cell lines cotransfected with human or primate MHC antigens and HIV/SIV genes, oncogenes to stabilize the growth potential of the cells expressing HIV proteins or EBV/CMV promoter/enhancer sequences.
To produce continuously growing T cell lines, both with helper T cell or cytotoxic T cell character, in order to further identify and characterize the T cell-specific antigenic epitopes.

B Experimental Aims

To study the helper T cell and cytotoxic T cell responses in HIV-infected human beings with different phases of the disease, in non-infected but exposed individuals and in patients undergoing different modes of antiretroviral therapy.

To study the helper T cell response and cytotoxic T cell response in experimentally immunized primates.
To identify epitopes recognized by T cells and to study the role of antigenic variation as well as MHC (HLA) association in T cell responses.
To study eventual protective effect of immunization in animal models using SIV-1 or HIV-2 in macaques or HIV-1 in chimpanzees.

Coordinator

University of Tampere
Address

33101 Tampere
Finland