Project description:A paired analysis of peripheral blood mononuclear cells (PBMCs) isolated before and after antiretroviral therapy (ART) from a robust number of HIV-infected patients (N=36). Results identify a total of 4,157 DEGs following ART in HIV-infected participants and the transition from a period of active virus replication before ART to one of viral suppression This study evaluated PBMC gene expression in cells from 36 (4 dropped from analysis) recently HIV-infected individuals to identify differentially expressed genes following 48 weeks of ART
Project description:A paired analysis of peripheral blood mononuclear cells (PBMCs) isolated before and after antiretroviral therapy (ART) from a robust number of HIV-infected patients (N=36). Results identify a total of 4,157 DEGs following ART in HIV-infected participants and the transition from a period of active virus replication before ART to one of viral suppression
Project description:Background. HIV-infected individuals on antiretroviral therapy (HIV/ART) experience higher levels of non-AIDS morbidity than uninfected people, which is believed to be driven by inflammation that persists despite viral suppression. Elevations in plasma cytokines, coagulation markers and both innate and adaptive immune cell activation during untreated infection are often incompletely reversed by ART and associated with these morbidities. Monocytes/macrophages play a central role in many of these complications including neurocognitive and cardiovascular disease. Results. We investigated monocyte surface markers, gene expression and plasma cytokines in 11 HIV-infected older individuals (median age 53 years) who started therapy with low CD4 counts (median 129 cells/ul), with elevated hsCRP (≥2mg/L) despite long-term ART (median 7.4 years), along with age, gender, race and smoking status-matched controls. Major monocyte subsets (based on CD14/CD16/CD163) were not different from controls, but surface levels differed for CD163 (p=0.022), PD1 (p=0.015) and a trend for tissue factor (p=0.098). As a group, HIV/ART subjects had elevated levels of plasma CCL2 (MCP-1; p=0.0001), CXCL9 (MIG; p=0.04) and sIL2R (p=0.015), which were highly correlated, whereas sCD14 and several other markers were not significantly elevated. However, principal component analysis of soluble markers revealed that about half of HIV/ART subjects clustered with controls, whereas the remainder were distinct, driven by IL-10, CCL11, CXCL10, CXCL11 as well as CCL2, CXCL9 and sIL2R. Outlier subjects were significantly older than those who clustered with controls. Gene expression analysis unexpectedly revealed downregulation in HIV/ART monocytes of multiple genes linked to immune functions including inflammation, immune cell development and cell-cell signaling. Conclusions. These results reveal a novel pattern of immune dysregulation involving both aberrant inflammation and monocyte dysfunction, which suggests complex mechanisms linking monocytes and HIV/ART comorbidities.
Project description:Comparison of total RNA-seq data from ex vivo unstimulated and stimulated (with anti-CD3/CD28) cells from two primary cell models of HIV latency (resting-cell and wild-type virus models) and peripheral CD4+ T cells from HIV-infected ART-suppressed individuals (ex vivo cells). Two donors were analyzed per model.
Project description:A small group of HIV-1-infected individuals, termed elite controllers (ECs), display control of HIV replication in the absence of antiretroviral therapy (ART). However, the mechanisms of resistance to HIV in ECs remains largely unknown. To identify host factors specific to the ECs that might be involved in controlling HIV infection, we performed RNA-seq transcriptome analysis, and a total of 44 samples were included. The monocytes from each sample were enriched, sequenced, and subjected to comparative transcriptome analysis to screen candidate genes that might affect resistance to HIV infection. we found several candidate genes with highly divergent expression that might contribute to the different outcomes of HIV infection in ECs and non-ECs. This finding will help elucidate the mechanisms by which ECs restrict HIV replication and represents a new approach for treatment of HIV.
Project description:We investigated if differences in host gene expression modulate the size of the total HIV-1 PBMC reservoir during suppressive ART. Individuals treated with ART during acute infection who demonstrated effective viral suppression but varying frequencies of HIV-1 DNA+ cells were characterized by single-cell RNA sequencing (scRNA-seq). Differentially expressed genes and enriched pathways demonstrated increased monocyte activity in participants with undetectable HIV-1 reservoirs. This was validated in an independent study cohort comprised of 38 participants with different genetic backgrounds and HIV-1 subtype infections.
Project description:Genome wide DNA methylation profiling of CD4 T cells from uninfected and HIV-infected individuals (viremic, ART-suppressed and elite controllers [EC]) The Illumina Infinium 450k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 485,577 CpGs in DNA from peripheral CD4 T cells samples. Samples included: 22 from HIV-uninfected individuals (uninfected group), 42 from HIV-infected individuals (21 from HIV-infected viremic (viremic group) and 21 from the same participants after viral suppression (viral load< 50 copies HIV-1 RNA/plasma) by antiretroviral therapy administrarion (ART group), and 21 from elite controllers (EC group)
Project description:The virus-specific CD4+ T cell dysfunction associated with failure to control chronic infections is poorly understood in humans. An issue of critical clinical relevance is the lack of restoration of effective anti-HIV immunity after suppressive ART: viral rebound is the rule after cessation of therapy. Whether persistent HIV-specific CD4+ T cell dysfunction on ART contribute to this failed response is an important, yet unresolved, question. To decipher the consequences of ongoing viral antigen exposure, versus the results of durable cell-fate decision programs that would persist in former CP individuals after successful viral suppression on ART, we compared trancriptional profiles of chronic progressor before and after the initiation of ART, with the transcriptional profiles of elite controllers, HIV-infected individuals that spontaneously control viral load. Suppression of viremia by ART resulted in a distinct transcriptional landscape, with reduction in TFH gene expression but no correction of the TH1, TH17 and TH22 gene levels compared to the elite controller profile.