Details

Rappocciolo presents research on cell cholesterol dysregulation in HIV non-progressors at 2018 Conference on Retroviruses and Opportunistic Infections

image

GIOVANNA RAPPOCCIOLO, assistant professor in the Department of Infectious Diseasese and Microbiology, presented her research at the Conference on Retroviruses and Opportunistic Infections (CROI).

"Biomarkers and Genetics of Cell Cholesterol Dysregulation in HIV Non-progressors"
G. Rappocciolo, D.C. DeLucia, J.J. Martinson, S. Wendell and C.R. Rinaldo
Multicenter AIDS Cohort Study (MACS), Department of Infectious Diseases and Microbiology and Biomedical Mass Spectrometry Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. 
 

Abstract 

Objectives: Professional antigen-presenting cells (APC) from HIV nonprogressors (NP) are inefficient mediators of HIV-1 trans infection of CD4+ T cells due to altered cell cholesterol metabolism (Rappocciolo, et al., mBio 2014), potentially reducing spread of virus and controlling disease progression. Here, we show the impact of host genetic variation and the role of signaling metabolites in control of cell cholesterol homeostasis in NP. 

Methods: We tested 29 NP, 13 HIV progressors (PR) and 10 seronegatives (SN) in the MACS. Plasma-mediated cholesterol efflux (CE) was measured using a Cholesterol Efflux Fluorimetric Assay (Biovision) and the macrophage cell line THP-1. To measure CE from participants APC, B cells and DC were loaded with BODIPY-labelled cholesterol and incubated in the presence of apolipoprotein A-1 (APOA1) as a cholesterol acceptor. Levels of apolipoprotein A-II (APOAII) in participants’ sera were measured by ELISA. Targeted lipidomics analysis was done by LC-MS on lipid fractions obtained from participants’ sera. SNP analysis was performed using TaqMan assays. 

Results: Plasma from NP and SN showed higher induction of CE than PR (p< 0.008). Similarly, B cells and DC from NP had higher CE to APOA1 than APC from PR (p<0.05). CE from CD4+ T cells was similar among PR, NP and SN. Targeted lipidomic analysis revealed significantly higher levels of 5-oxo-eicosatetraenoic acid (5-oxo-ETE) and PGE2, metabolites of arachidonic acid, in sera from NP compared to PR (p<0.05). Finally, the SNP rs5082 (APOAII c.-265 T>C, located in the APOAII gene) was associated with the NP phenotype (p=0.0003 for a dominant role for the minor allele). 

Conclusions: NP have a unique combination of metabolic and genetic factors that impact altered cholesterol homeostasis, conferring on their APC the inability to transfer HIV to CD4+ T cells, thus controlling HIV dissemination. In NP we detected higher levels of 5-oxo-ETE, a metabolite produced by B cells and DC. This is a signaling agent that acts in both an autocrine and paracrine fashion and binds PPARγ nuclear receptor, increasing transcription of ABCA1 thus elevating cell CE. We hypothesize that such autocrine signaling could be a mechanism by which APC from NP escape downregulation of CE induced by HIV. The presence of a SNP in the APOAII gene could contribute to higher cholesterol efflux by modifying HDL composition. These data suggest that HIV eradication interventions need to incorporate strategies to shape cell cholesterol content. 



3/19/2018

Search for an Article