Impact of HLA class I restricted T cells on HIV-1 disease progression

Abstract

This thesis focuses on the impact of HLA class I restricted T cells on HIV-1 disease progression. It is generally accepted that cytotoxic T lymphocytes (CTL) play an important role in controlling HIV replication. In line with this, it has been well established that HLA class I alleles influence the rate of progression to AIDS. Both HLA heterozygosity as well as the presence of particular HLA alleles (e.g. HLA-B27 and B57) appear to be associated with relatively slow disease progression. The mechanism however via which these HLA alleles are associated with relatively slow disease progression remains largely unclear. In this thesis, several of the hypotheses were tested. We could show that CTL responses restricted via the protective HLA alleles HLA-B27 or B57 were lost at least as fast as CTL responses restricted via the non-protective HLA allele HLA-A2, indicating that maintenance of CTL responses per se is not the main determinant of protection against progression to AIDS. Furthermore, we showed that the low frequency of HLA-B27 and B57 in the human population is not the reason why these HLA alleles are associated with relatively slow HIV-1 disease progression. When comparing the number of CTL escape mutations that have been accumulating since the start of the epidemic for different HLA molecules, we did not find any evidence that adaptation of HIV to the human immune system has mainly occurred for CTL restricted by common HLA alleles. In contrast, we found that most CTL escape mutations have been accumulating for CTL restricted by the relatively rare HLA molecules HLA-B27 and B57. Our data suggest that instead of the frequency of HLA molecules in the human population it is the selection pressure exerted by the HLA-restricted CTL that determines the number of escape mutations that have accumulated throughout the epidemic. Moreover, we found that HLA-B27 and B57 have a strikingly different effect on the total HIV-specific T cell response in individuals expressing these HLA alleles. HLA-B57 clearly dominates the total CTL response, which might be mediated by the strong interaction between HLA-B57-peptide complexes and the T cell receptor. In sharp contrast, expression of HLA-B27 seems to preserve the total CTL response, leading to increased responses towards peptides restricted through not only HLA-B27 but also other HLA alleles expressed by the individual. These data suggest a different mechanism of protection for HLA-B27 and B57. Additionally, we investigated whether the presence of cytokine-producing HIV-specific CD8+ T cells early in infection was associated with AIDS-free survival time. We showed that regardless of subsequent clinical outcome, high frequencies of cytokine-producing CD4+ and CD8+ T cells can be found shortly after seroconversion. The fact that both progressors and long-term non-progressors have abundant T cell immunity of the specificity associated with low viral load shortly after seroconversion suggests that the more rapid loss of T cell immunity observed in progressors may be a consequence rather than a cause of disease progression.