| 1. |
- Buggert, Marcus, et al.
(författare)
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Limited immune surveillance in lymphoid tissue by cytolytic CD4+ T cells during health and HIV disease
- 2018
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7374. ; 14:4
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Tidskriftsartikel (refereegranskat)abstract
- CD4+ T cells subsets have a wide range of important helper and regulatory functions in the immune system. Several studies have specifically suggested that circulating effector CD4+ T cells may play a direct role in control of HIV replication through cytolytic activity or autocrine β-chemokine production. However, it remains unclear whether effector CD4+ T cells expressing cytolytic molecules and β-chemokines are present within lymph nodes (LNs), a major site of HIV replication. Here, we report that expression of β-chemokines and cytolytic molecules are enriched within a CD4+ T cell population with high levels of the T-box transcription factors T-bet and eomesodermin (Eomes). This effector population is predominately found in peripheral blood and is limited in LNs regardless of HIV infection or treatment status. As a result, CD4+ T cells generally lack effector functions in LNs, including cytolytic capacity and IFNγ and β-chemokine expression, even in HIV elite controllers and during acute/early HIV infection. While we do find the presence of degranulating CD4+ T cells in LNs, these cells do not bear functional or transcriptional effector T cell properties and are inherently poor to form stable immunological synapses compared to their peripheral blood counterparts. We demonstrate that CD4+ T cell cytolytic function, phenotype, and programming in the peripheral blood is dissociated from those characteristics found in lymphoid tissues. Together, these data challenge our current models based on blood and suggest spatially and temporally dissociated mechanisms of viral control in lymphoid tissues.
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| 2. |
- Gertler, Kajsa Noyan
(författare)
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Multidisciplinary analysis of HIV-1 elite controllers
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 3. |
- Zhang, Wang, et al.
(författare)
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Quantitative humoral profiling of the HIV-1 proteome in elite controllers and patients with very long-term efficient antiretroviral therapy
- 2017
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge in evaluating the success of HIV eradication approaches is the need for accurate measurement of persistent HIV during effective antiretroviral therapy (ART). Previous studies have reported that the anti-HIV antibody assay "luciferase immuno-precipitation systems (LIPS)"can distinguish HIV-infected individuals harboring different sizes of the viral reservoirs. We performed antibody profiling of HIV-1 proteomes using LIPS in viremic progressors (n = 38), elite controllers (ECs; n = 19) and patients with fully suppressive long-term antiretroviral therapy (ART) (n = 19) (mean 17 years). IgG was quantified against six HIV-1 fusion proteins: p24, gp41, RT, Tat, integrase and protease. Lower antibody levels to all six-fusion proteins were observed in long-term ART patients compared to viremics (p < 0.05). In contrast ECs had lower antibody levels only against Tat and Integrase (p < 0.05). Principal component analysis and cluster-network analysis identified that 68% (13/19) of the long-term ART patients clustered together with 26% (5/19) ECs. The remaining ECs clustered together with the viremics indicating non-homogeneity among the ECs. The low anti-HIV levels in the long-term treated patients may indicate a restricted remaining viral replication. In contrast, the higher levels in ECs suggest a continuous viral expression with a limited concomitant release of extracellular virus.
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| 4. |
- Zhang, Wang, et al.
(författare)
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Transcriptomics and Targeted Proteomics Analysis to Gain Insights Into the Immune-control Mechanisms of HIV-1 Infected Elite Controllers
- 2018
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Ingår i: EBioMedicine. - : ELSEVIER SCIENCE BV. - 2352-3964. ; 27, s. 40-50
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Tidskriftsartikel (refereegranskat)abstract
- A small subset of HIV-1 infected individuals, the "Elite Controllers" (EC), can control viral replication and restrain progression to immunodeficiency without antiretroviral therapy (ART). In this study, a cross-sectional transcriptomics and targeted proteomics analysis were performed in a well-defined Swedish cohort of untreated EC (n = 19), treatment naive patients with viremia (VP, n = 32) and HIV-1-negative healthy controls (HC, n = 23). The blood transcriptome identified 151 protein-coding genes that were differentially expressed (DE) in VP compared to EC. Genes like CXCR6 and SIGLEC1were downregulated in EC compared to VP. A definite distinction in gene expression between males and females among all patient-groups were observed. The gene expression profile between female EC and the healthy females was similar but did differ between male EC and healthy males. At targeted proteomics analysis, 90% (29/32) of VPs clustered together while EC and HC clustered separately from VP. Among the soluble factors, 33 were distinctive to be statistically significant (False discovery rate = 0.02). Cell surface receptor signaling pathway, programmed cell death, response to cytokine and cytokine-mediated signaling seem to synergistically play an essential role in HIV-1 control in EC.
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