By Dean L. Winslow, MD, FACP, FIDSA

Professor of Medicine, Division of General Medical Disciplines, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine

Dr. Winslow reports no financial relationships relevant to this field of study.

SYNOPSIS: CX3CR1+ CD8+ T-cells home to vascular endothelium and are enriched in ART-treated patients with HIV. These cells may play an important role in CVD risk in HIV-infected patients.

SOURCE: Mudd JC, Panigrahi S, Kyi B, et al. Inflammatory function of CX3CR1+ CD8+ T cells in treated HIV infection is modulated by platelet interactions. J Infect Dis 2016;214:1808-1816.

Researchers studied cells obtained from 35 HIV-infected patients receiving ART and 17 HIV-negative controls. PBMCs were purified by standard Ficoll-Hypaque centrifugation and isolated using a MACS Pro separator. Flow cytometry was used to characterize both lymphocyte and platelet populations and to look at cytokine production and cell surface marker expression. The researchers isolated platelets and specifically examined them for CD62P and TGF-B expression using flow cytometry. Cultures of PBMCs, T-cells, and T-cells with purified platelets were incubated with various concentrations of thrombin. In other experiments, anti-TGF-B was added to the cultures.

The main results included the following: 1) CX3CR1 identified a population of circulating memory T-cells; 2) CX3CR1+ CD8+ T-cells express the thrombin receptor PAR-1; 3) PAR-1 activation influences CD8+ T-cell function; 4) Platelet-derived TGF-B impairs CD8+ T-cell function.

COMMENTARY

This paper nicely shows that CX3CR1+PAR-1+ T-cells are increased in antiretroviral-treated HIV patients. Because this population of cells has a known ability to interact with vascular endothelium, thrombin, and platelets, this subset of T-cells likely contributes to thrombosis, accelerated atherosclerosis, and cardiovascular disease (CVD) that is known to complicate HIV infection.

It has been known for some time that HIV induces a “pro-inflammatory” state that, unfortunately, is not completely reversed even in the presence of fully suppressive ART. Past research has placed much emphasis on the early occurrence of CD4+ T-cell depletion from gut-associated lymphoid tissue in the setting of HIV infection, increased neutrophil infiltration, and apoptosis in the small intestine, and increased microbial translocation — which is thought to drive the observed increase in pro-inflammatory cytokines (IL-6, SCD14), acute phase reactants (hs-CRP), and activation of coagulation (D-dimer). This pro-inflammatory state also is linked to increased LDL/Apo-B and reduced HDL/Apo-A1. All of these factors are thought to contribute to the accelerated atherosclerosis and CVD that is seen in HIV.

This study demonstrates the likely contribution of CD8+ T-cells, platelets, and their interaction with the coagulation system in this complicated process. Perhaps in the future we will have targeted therapies to address these factors.