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CFAR Network of Integrated Clinical Systems (CNICS)

ABSTRACT:

Advances in antiretroviral therapies (ART) and patient management have improved survival of people living with HIV (PLWH). However, with exposure to ART and associated side effects and toxicities as well as to the virus itself, PLWH are at an increased risk of several chronic diseases. The Centers for AIDS Research (CFAR) Network of Integrated Clinical Systems (CNICS) research network integrates longitudinal clinical data and treatment management of PLWH and provides research infrastructure to support HIV-associated clinical, social, and behavioral outcomes and comparative effectiveness research using data collected from 8 Centers for AIDS Research clinical sites across United States. For detailed study description, see Kitahata et al. (2008, PMID:18263650).

PROVIDER: phs001788 | dbGaP |

REPOSITORIES: dbGaP

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			Action	DRS
	GapExchange_phs001788.v1.p1.xml	Xml
	dbGaPEx2.1.5.xsd	Other
	Study_Report.phs001788.SMOKARRAY_CNICS.v1.p1.MULTI.pdf	Pdf
	manifest_phs001788.SMOKARRAY_CNICS.v1.p1.c1.GRU-IRB.pdf	Pdf
	datadict_v2.xsl	Other

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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:We assessed correlates of protection from disease progression in a rare subset of HIV-infected individuals, viremic non-progressors (VNPs). These individuals have high viral load for several years, but in contrast to the majority of infected individuals, they do not progress to AIDS. Here we found this lack of progression was associated with selective preservation of two essential subsets of memory CD4+ T cells, central memory (TCM) and stem-cell memory (TSCM) cells. Compared to HIV-infected putative progressors, VNPs had higher proliferation of these indispensable subsets of memory cells, which was associated with the number of TCM. In addition, the long-lived CD4+ TCM and TSCM cells in VNPs had decreased HIV infection compared to the less critical effector memory CD4+ T cells, which indicates a possible mechanism by which VNPs maintain their CD4+ T cell pool after several years of infection, and remain free from AIDS progression. 6 HIV-infected patients fitting the clinical criteria of Viremic Non-Progressors were identified. VNPs were defined as having confirmed HIV-1 infection for at least 9 years with sustained plasma HIV RNA levels >10,000 copies/ml and maintenance of peripheral blood CD4+ T cell counts >500 cells/mm3 and a CD4% (of all lymphocytes) >15%. As controls, 7 HIV-infected Putative Progressors were identified. PPs were defined as having plasma HIV RNA levels >10,000 copies/mL, CD4+ T cell counts >400 cells/mm3 and having been initially infected with HIV 2-24 months prior to the index visit. The estimated date of initial HIV infection was calculated according to published algorithms that incorporate âde-tunedâ anti-HIV-1 antibody ELISA results or by a documented sero-conversion window of <6 months. All participants were required to be antiretroviral therapy (ART)-naÃ¯ve. RNA from 6 VNP and 7 PPs was purified from PAXgene whole blood tubes and hybridized to Affymetrix U133 Plus 2.0 arrays. During data analysis, one VNP patient (PID 4015) was determined to be an outlier and removed from further analysis. Thus, 5 VNPs and 7 PPs are represented in this Series.

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CFAR Network of Integrated Clinical Systems (CNICS)

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