Date of Award
Doctor of Philosophy (PhD)
The acquired immune deficiency syndrome (AIDS) is an incurable disease caused by infection with the human immunodeficiency virus (HIV). In the eight years following identification of HIV as the cause of AIDS, little progress has been made in understanding the complex pathogenesis of AIDS or in developing effective therapies to forestall disease progression. All current strategies to treat HIV infection assume that disease progression is directly related to infection of and replication in CD4⁺ lymphocytes by HIV. Recent theoretical and experimental studies have raised the possibility that the pathogenesis of AIDS depends upon indirect effects of HIV infection; namely the induction of deleterious immune responses. In this study, we examined the effects of HIV infection on cytotoxic T lymphocyte (CTL) activity. Three aspects of CTL activity in HIV infection were examined: the role of anti-HIV CTL in suppressing viral replication and disease progression; the role of autoimmune CTL in CD4⁺ lymphocyte depletion in HIV infection; and changes in the CTL repertoire in HIV infection and the relationship of these changes to progressive CD4⁺ lymphocyte depletion. Although a possible role for circulating anti-HIV CTL in suppressing HIV replication in vivo was seen, there was no evidence that these CTL protect against CD4⁺ lymphocyte depletion. This suggests a dissociation between viral replication and CD4⁺ lymphocyte depletion. Autoimmune CTL that lysed uninfected activated CD4⁺ lymphocytes were found in HIV-infected individuals. The natural history of CD4⁺ lymphocyte depletion suggested a relationship between this CTL activity and in vivo depletion of CD4⁺ lymphocytes. Autoimmune CTL had a conventional phenotype, but were not HLA-restricted. The characteristics of these CTL suggested a mechanism of CD4⁺ lymphocyte depletion involving recognition of CD4⁺ T cell receptor (TCR) idiotypes by the autoimmune CTL. Skewing of the CTL repertoire was also demonstrated in HIV infection. The increased incidence of skewing of TCR variable domain (V) gene usage observed in parallel to CD4⁺ lymphocyte depletion is consistent with an interdependence of the selective expansion of CTL and depletion of CD4⁺ lymphocytes. Results of this thesis suggest that autoimmune CTL play a role in the pathogenesis of AIDS and are rational targets for novel therapeutic approaches to the treatment of HIV infection.
Grant, Michael David, "The role of cytotoxic T lymphocytes in HIV infection" (1993). Open Access Dissertations and Theses. Paper 3824.