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Fatigue-related HIV disease gene-networks identified in CD14+ cells isolated from HIV-infected patients

ABSTRACT: HIV-related fatigue is multi-causal in origin and potentially related to mitochondrial dysfunction caused by toxicity from nucleoside reverse transcriptase inhibitor (NRTI) antiretroviral therapy. CD14+ cells are undifferentiated macrophages, vulnerable to HIV infection, and easily accessible for gene expression experiments in a purified cell population. We utilized a novel mitochondrially-specific gene expression microarray to assess mitochondrial and nuclear genes in CD14+ cells of low- and high-fatigued, NRTI-treated HIV/AIDS patients (n=5 each). Novel Bayesian and liquid association network methods identified 33 genes predictive of low versus high fatigue and 32 genes predictive of healthy versus HIV infection. Sulfotransferase 2B1 (SULT2B1) is relevant to both the cholesterol and testosterone pathway, and like several inner mitochondrial membrane genes also identified, predictive of fatigue status, while outer mitochondrial membrane genes were predictive of HIV status. A surprising finding was that adenylate cyclase 2 (ADCY2) was a predictor of both HIV and fatigue; it had the highest Kendall’s Tau association value in the HIV group, but in reverse, the lowest Tau value in the fatigue group. Assaying CD14+ cells may provide an alternative to muscle biopsy and a minimally invasive procedure to evaluate patient mitochondrial function, and Bayesian and network tools are useful to identify the link between subjective symptom perceptions and underlying biologically pathways. Fatigue status in HIV patients treated with NRTIs was found to be linked to RNA expression differences related to mitochondrial function. Additional studies are needed to confirm the relevance of our findings in CD14+ cells in other tissues (e. g. skeletal muscle) and to understand the significance of key genes such as SULT2B and ADCY2 in fatigue and HIV disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE18468 | GEO | 2009/10/08

SECONDARY ACCESSION(S): PRJNA118195

REPOSITORIES: GEO

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Project description:HIV-related fatigue is multi-causal in origin and potentially related to mitochondrial dysfunction caused by toxicity from nucleoside reverse transcriptase inhibitor (NRTI) antiretroviral therapy. CD14+ cells are undifferentiated macrophages, vulnerable to HIV infection, and easily accessible for gene expression experiments in a purified cell population. We utilized a novel mitochondrially-specific gene expression microarray to assess mitochondrial and nuclear genes in CD14+ cells of low- and high-fatigued, NRTI-treated HIV/AIDS patients (n=5 each). Novel Bayesian and liquid association network methods identified 33 genes predictive of low versus high fatigue and 32 genes predictive of healthy versus HIV infection. Sulfotransferase 2B1 (SULT2B1) is relevant to both the cholesterol and testosterone pathway, and like several inner mitochondrial membrane genes also identified, predictive of fatigue status, while outer mitochondrial membrane genes were predictive of HIV status. A surprising finding was that adenylate cyclase 2 (ADCY2) was a predictor of both HIV and fatigue; it had the highest Kendallâs Tau association value in the HIV group, but in reverse, the lowest Tau value in the fatigue group. Assaying CD14+ cells may provide an alternative to muscle biopsy and a minimally invasive procedure to evaluate patient mitochondrial function, and Bayesian and network tools are useful to identify the link between subjective symptom perceptions and underlying biologically pathways. Fatigue status in HIV patients treated with NRTIs was found to be linked to RNA expression differences related to mitochondrial function. Additional studies are needed to confirm the relevance of our findings in CD14+ cells in other tissues (e. g. skeletal muscle) and to understand the significance of key genes such as SULT2B and ADCY2 in fatigue and HIV disease. The design was a comparison of HIV high fatigue to HIV low fatigue. Low fatigue was determined as 3-7 on the Revised Piper Fatigue Score and High fatigue was a score of 7 or greater. Five HIV negative control samples were used to compare normal fatigue and non-disease status.

Project description:Persistent and elevated systemic inflammation contributes to the increased risk of cardiovascular and metabolic diseases in persons with HIV (PWH). , but aspects of the innate and adaptive immune response to HIV and other chronic co-infections that promote the development of these comorbid conditions remain unclear. We used mass cytometry and the tracking responders expanding (T-REX) workflow to define differences in circulating cells of the innate and adaptive immune arms, which differentiate non-diabetic and prediabetic/diabetic persons with HIV (PWH) on long-term antiretroviral therapy (ART). We found a significantly higher proportion of circulating CD14+ monocytes complexed with T cells, B cells, and NK cells among PWH with diabetes. The CD3+ T cells in these complexes were predominantly CD8+ memory T cells. The CD3+ CD14+ T cell-monocyte complexes are pro-inflammatory and negatively associated with plasma interleukin-10 levels and circulating CD4+ T regulatory cells. Using transmission electron microscopy, we observed heterogeneous interactions between CD3+ T cells and monocytes within the complexes, including formation of immune synapses and phagocytosis. 10x Chromium single-cell sequencing RNA transcriptomic analysis of CD3+ CD14+ doublets showed differential expression of genes involved in T cell activation and the adaptive immune response compared to monocytes that were not complexed with other immune cells. Notably, there were significantly more copies of HIV RNA per cell in the CD3+ CD14+ T cell-monocyte complexes compared to CD14+ monocytes or CD3+ CD4+ T cells alone, and HIV virions were observed in both T cells and monocytes within the doublets?. Metabolically, CD3+ CD14+ T cell-monocyte complexes had high glucose-dependence with minimal mitochondrial dependence. Taken together, CD3+ CD14+ T cell-monocyte pairs are functional and physically interacting immune cell complexes which might be enriched with HIV. These complexesare increased among individuals with diabetes and may be a target for future HIV cure studies and diseases of aging.

Project description:We used Affymetrix U133A 2.0 chips to better understand transcriptional changes associated with HIV-1 infection and perinatal transmission in human PBMCS obtained from young adult mothers with infants in Botswana in vivo. HIV seropositive and drug naÃ¯ve samples:; GSM94333, GSM94334, GSM94335, GSM94336, GSM94337, GSM94338, GSM94340, GSM94342, GSM94343, GSM94345, GSM94351, GSM94353, GSM94354, GSM94355, GSM94357, GSM94358, GSM94360, GSM94361, GSM94362, GSM94364, GSM94365, GSM94367, GSM94369, GSM94370, GSM94378; HIV seronegative samples:; GSM92590, GSM92788, GSM92789, GSM92790, GSM92791, GSM92792, GSM92793, GSM92794, GSM92795, GSM92796, GSM92797, GSM92798, GSM92799, GSM92800, GSM92801, GSM92802, GSM92803, GSM92804, GSM92805, GSM92806; HIV seropositive transmitter mothers:; GSM94333, GSM94334, GSM94335, GSM94336, GSM94337, GSM94338, GSM94340, GSM94342, GSM94343, GSM94345, GSM94378; HIV seropositive nontransmitter mothers:; GSM94351, GSM94353, GSM94354, GSM94355, GSM94357, GSM94358, GSM94360, GSM94361, GSM94362, GSM94364, GSM94365, GSM94367, GSM94369, GSM94370 Experiment Overall Design: Total RNA was extracted from peripheral blood and processed for microarray hybridizations that were conducted using U133A 2.0 chips (Affymetrix, Santa Clara, CA). The 22,777 gene-probes were filtered based on presence/absence, resulting in data for 11,705 gene-probes. The array data sets were then analyzed for differential expression based on HIV status (seronegative, seropositive) and transmitter status (transmitter: TR, nontransmitter: NTR) using BADGE version 1.0, a computer program implementing a Bayesian approach to identify differentially expressed genes (Sebastiani et al, Nat.Gen, 2005). Once differentially expressed genes were identified by BADGE, the biologically enriched categories were identified, as recently described (Montano et al, Int Immunol, 2006), by implementing a stand-alone version of the EASE statistical software (Hosack et al, Genome Biol., 2003). Selected genes were validated using realtime reverse transcription PCR.

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Fatigue-related HIV disease gene-networks identified in CD14+ cells isolated from HIV-infected patients

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