Infection with the human immunodeficiency virus (HIV) is eventually fatal in the absence of antiretroviral therapy. However, approximately 0.3% of patients have the ability to efficiently control the virus for long periods without treatment (elite controllers). It has been shown that HLA class I restricted CD8+ T cells play a crucial role in this process. There is a strong genetic association between the ability to control the virus and certain alleles of the HLA-B complex (particularly HLA-B*27 and B*57). However, there is also a subset of patients that control HIV in absence of these so-called “protective” alleles, but this mechanism of protection is unclear. Even more strikingly, the recent VISCONTI study showed induction of control in the absence of protective alleles in some patients that received very early therapy (post treatment controllers). Based on these observations, the aim of this study is to determine functional characteristics of CD8+ T cells in elite controllers without protective alleles. T cells and T cell clones of those patients will be functionally phenotyped using in vitro assays and mass cytometry, a very recent technology allowing single cell analysis of up to 37 markers simultaneously. Furthermore, this study will analyze whether elite controllers without protective HLA-B alleles engage additional mechanisms that support functional T cell responses. In particular, the recently described immunoregulatory role of NK cells and the consequences of innate-adaptive crosstalk for immune control of HIV-1 will be assessed.
Results from these studies will provide important new insights into the mechanisms that support protective CD8+ T cell responses against HIV, even in absence of protective HLA alleles. The knowledge of how CD8+ T cells achieve efficient control of the disease will be important for designing T cell based HIV vaccines or immunotherapies that also protect individuals with a susceptible genetic background.
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