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Glycolytic modulation through HIF signaling determines HIV-1 elite control status

ABSTRACT: Natural control of HIV infection in Elite Controllers (EC) is a characteristic of <1% of HIV infected individuals. Extensive research has tried to elucidate the mechanism of control without any concrete results due to a large heterogeneity in the EC group, both between the sexes and how they obtain control. Therefore, we sought to identify signaling pathways associated with the EC phenotype by proteomics (all male) and transcriptomic (male and female) analysis. Further, we integrated the proteomics and transcriptomic analysis in the male cohort. We found that HIF signaling and downstream glycolysis are specific traits of the EC phenotype. Within this pathway ENO1 was upregulated in EC on a protein level irrespective of sex. We also performed targeted transcriptomic analysis where we identified HIF target genes as specifically de-regulation of in EC group. Namely, we observed an increase in the antiviral transcript GPS2, while CXCR4 and EIF5A were down regulated. Although we could not detect any difference in protein levels of HIF-1α in total PBMCs, we observed a higher portion of HIF-1α and HIF-1β in the nuclei of CD4+ and CD8+ T cells indicating an increased activation of HIF signaling in the male EC. Furthermore, the intracellular glucose levels were elevated in EC even as metabolite transporter expression of Glut1 and MCT-1 was decreased in lymphocytes showing that the EC have a unique metabolic uptake and secretion profile. Combined our data indicate the role HIF-1 signaling and glycolysis has in natural control of HIV infection.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma, T Cell

DISEASE(S): Human Immunodeficiency Virus Infectious Disease

SUBMITTER: Akos Vegvari

LAB HEAD: Akos Vegvari

PROVIDER: PXD023990 | Pride | 2021-04-01

REPOSITORIES: Pride

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			Action	DRS
	20180625_08_Qp1_nTrap_TMT_Ujjwal.xlsx	Xlsx
	20180625_08_Qp1_nTrap_TMT_Ujjwal_EC.raw	Raw
	20180625_09_Qp1_nTrap_TMT_Ujjwal_HC.raw	Raw
	20180625_09_Qp1_nTrap_TMT_Ujjwal_VP.raw	Raw
	checksum.txt	Txt

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Project description:Antiretroviral therapy (ART) has the potency of suppressing systemic viral replication and spread. Still, persistent human immunodeficiency virus type-1 (HIV) survive for decades during treatment in latently infected cells, making up the latent viral reservoir. This reservoir is believed to reside in subtypes of memory T cells and cell from monocytic lineages, but some functional and naïve T cells have also shown to carry latent HIV. Eradication of latently infected cells, in terms of a sterilizing cure, have proven to be a hurdle since there is a heterogeneity in mechanisms governing latency and integration site into the genome. Over the course of suppressive therapy, persisting HIV, sustained by low levels of viral replication, homeostatic proliferation, and cell to cell transmission, is a driver of chronic immune activation in the body. For the immune system to elicit an appropriate inflammatory response it is dependent on secretion of inflammatory molecules, such as chemokines and cytokines. Most chemokines are pro-inflammatory factors that facilitate leukocyte recruitment to site of inflammation where they can exert their regulatory role in response to pathological and physiological stressors e.g., infection, inflammation, and tissue damage. Alterations in chemokine receptor expression and chemokine levels modulates the activity of the immune response and in HIV infection contribute to chronic inflammation and mortality. Therefore, people living with HIV on suppressive therapy (PLWH) are at higher risk of age associated co-morbidities due to elevated immune activation and chronic inflammation induced by ART toxicities, microbiome dysbiosis leading to microbial translocation and dysregulated immune cell activation and function. As a result, the causative HIV pathogenesis and immune dysfunction further chronic immune activation. This result in a vicious cycle as immune activation is driver of HIV disease progression and inflammaeging leading to earlier onset of age-related diseases. An alternative approach in cure strategies is a functional cure for HIV aiming at suppressing viral replication without ART. A model for functional cure studies are elite controllers (EC). EC constitute a small fraction of HIV+ individuals (<0.5%) exhibiting the unique characteristic of natural control of viral replication in absence of ART. However, there is a population-based heterogeneity of how these individuals naturally supress viral replication. This heterogeneity is caused by viral genetic factors, variability of integration site in the human genome, together with host response against the pathogen and immunological factors. In terms of immune cell activation, studies have shown how EC maintain lower levels of inflammatory markers compared to PLWH. Contradictory, some studies have shown elevated inflammatory markers in EC which could be attributed to the heterogeneity of the EC group or as others have shown it is a consequence of loss of spontaneous control of HIV. Therefore, as no consensus exist further studies comparing variability of immune function between EC and ART can aid in understanding the mechanisms of natural control of HIV. In our recent study (Sperk et al 2021, iScience) we hypothesised that modulated CCR6/CCL20 chemokine axis and CCR2-CCL7-CCL2 signalling can play a protective role in the EC phenotype. Downregulation of CCR2 and CCR6 receptors in lymphocytes and higher plasma abundance of CCL4, CCL7 and CCL20 in EC compared to the HIV-negative controls can provide natural resistance to HIV-infection. In the present study, we further extended our analysis to evaluate the expression profile dynamics of key chemokine receptors, CCR2, CCR3, CCR5 and CCR6, in successfully treated PLWH. We compared well treated PLWH with HIV-1 elite controllers and its association with HIV-1 persistence. Furthermore, cell populations of interest were isolated for liquid chromatography mass spectrometry (LC-MS/MS) based untargeted proteomics analysis to evaluate specific characteristics regulating these cell populations and their role in HIV persistence. Our study provides important understanding of the chemokine receptor dynamics and its role in HIV persistence that differentiate elite controllers from long term treated PLWH.

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Glycolytic modulation through HIF signaling determines HIV-1 elite control status

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