Multidisciplinary analysis of HIV-1 elite controllers

Sammanfattning: Chronic HIV-1 infection is characterized by progressive depletion of CD4+ T lymphocytes, persistent immune activation and ongoing viral replication, leading to a profound immunodeficiency state if left untreated with antiretroviral therapy. However, a small percentage of infected individuals are able to maintain durable control of HIV replication and stable CD4 counts, in the absence of antiretroviral treatment (ART). This rare group of individuals are known as Elite Controllers (ECs) and represent evidence that control of infection without ART for years is possible, thereby providing an extraordinary insight into new vaccine and functional cure strategies. Despite extensive studies, the specific mechanisms by which ECs maintain control remain undefined. A better understanding of host factors that contribute to how ECs spontaneously control the infection is crucial for future therapeutic strategies. In Paper I, we showed that ECs possessed a richer gut microbiota compared to untreated HIV-infected individuals, and that several metabolic pathways were significantly different to untreated individuals. Specifically, the tryptophan catabolism pathway in ECs was very similar to healthy subjects, indicating a contributing factor for lower persistent immune activation usually observed in HIV-infected individuals. Our data suggest that the unique bacterial composition and metabolic profile of ECs may be involved in control of infection. Further, in Paper II, we used a modified antibody assay, LIPS, to perform antibody profiling against HIV-1 proteome in ECs. We found that LIPS detected a strong response against several HIV-1 fusion proteins in ECs compared to long-term treated individuals. Interestingly, the observed heterogeneity in antibody levels among ECs were not very different from untreated, viremic patients, indicating a non-homogenous patient group among ECs and a continuous viral expression with limited release of virus. By adapting a comprehensive analysis strategy of transcriptomics and targeted proteomics (Paper III), we demonstrated that more than 150 protein-coding genes and 33 soluble factors were differentially expressed in ECs compared to untreated patients. In particular, CXCR6 and SIGLEC1 (associated with viral entry and formation) were downregulated in ECs. Also, PD-1, an inhibitory receptor associated with T cell exhaustion, was significantly elevated in untreated vs both ECs and healthy subjects. The observed difference between ECs and untreated patients in molecular pathways regulating apoptosis, inflammation and cellular differentiation, suggests they play a synergistic role in HIV control. To further understand the differences in inhibitory receptor expression related to spontaneous HIV control, we assessed the expression of inhibitory molecules associated with T cell exhaustion on CD4+ T cells (Paper IV). We observed that ECs maintain a co-expression pattern of inhibitory receptors similar to healthy subjects and significantly different to both treated and untreated patients. We found that ECs harbor a “healthy” state of inhibitory receptor expression on CD4+ T cells that might play part in maintenance of their control status. In summary, this thesis describes a comprehensive analysis of important immune factors that is associated with natural control of HIV infection in ECs. The multidisciplinary approach has provided a better understanding for the complexity of spontaneous HIV control and possible future therapeutic interventions.