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The risk-factor-based prediction of atherosclerotic coronary artery disease (CAD) remains suboptimal, particularly in the absence of any of the standard modifiable cardiovascular risk factors (SMuRFs), making the discovery of biomarkers that correlate with atherosclerosis burden critically important. We hypothesized that cytokines and receptors associated with inflammation in CAD—tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), interleukin-18 (IL-18), and osteoprotegerin (OPG)—would be independently associated with CAD. To determine this, we measured the serum biomarker levels of 993 participants from the BioHEART study who had CT coronary angiograms that were scored for severity of stenosis and plaque composition. We found that the quartiles of TRAIL, OPG, and IL-18 were significantly associated with disease scores, and that the IL-18/TRAIL and OPG/TRAIL ratios demonstrated significant differences between no CAD vs. STEMI whereas only the OPG/TRAIL ratio showed differences between no CAD and obstructive CAD (stenosis > 50%). However, these associations did not persist after adjustment for age, sex, SMuRFs, and a family history of CAD. In conclusion, TRAIL, IL-18, and OPG and the derived ratios of IL-18/TRAIL and OPG/TRAIL demonstrate significant associations with raw disease scores and risk factors, but these markers are not discriminatory biomarkers for the prediction of CAD when incorporated into multi-variable risk models.

Risk-factor-based scoring systems for atherosclerotic coronary artery disease (CAD) remain concerningly inaccurate at the level of the individual and would benefit from the addition of biomarkers that correlate with atherosclerosis burden directly. We hypothesized that serum soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) would be independently associated with CAD and investigated this in the BioHEART study using 968 participants with CT coronary angiograms, which were scored for disease burden in the form of coronary artery calcium scores (CACS), Gensini scores, and a semi-quantitative soft-plaque score (SPS). Serum sLOX-1 was assessed by ELISA and was incorporated into regression models for disease severity and incidence. We demonstrate that sLOX-1 is associated with an improvement in the prediction of CAD severity when scored by Gensini or SPS, but not CACS. sLOX-1 also significantly improved the prediction of the incidence of obstructive CAD, defined as stenosis in any vessel >75%. The predictive value of sLOX-1 was significantly greater in the subgroup of patients who did not have any of the standard modifiable cardiovascular risk factors (SMuRFs). sLOX-1 is associated with CAD severity and is the first biomarker shown to have utility for risk prediction in the SMuRFless population.

HIV-1 infection rapidly leads to a loss of the proliferative response of memory CD4+ T lymphocytes, when cultured with recall antigens. We report here that CD73 expression defines a subset of resting memory CD4+ T cells in peripheral blood, which highly express the α-chain of the IL-7 receptor (CD127), but not CD38 or Ki-67, yet are highly proliferative in response to mitogen and recall antigens, and to IL-7, in vitro. These cells also preferentially express CCR5 and produce IL-2. We reasoned that CD73+ memory CD4+ T cells decrease very early in HIV-1 infection. Indeed, CD73+ memory CD4+ T cells comprised a median of 7.5% (interquartile range: 4.5–10.4%) of CD4+ T cells in peripheral blood from healthy adults, but were decreased in primary HIV-1 infection to a median of 3.7% (IQR: 2.6–6.4%; p = 0.002); and in chronic HIV-1 infection to 1.9% (IQR: 1.1–3%; p < 0.0001), and were not restored by antiretroviral therapy. Moreover, we found that a significant proportion of CD73+ memory CD4+ T cells were skewed to a gut-homing phenotype, expressing integrins α4 and β7, CXCR3, CCR6, CD161 and CD26. Accordingly, 20% of CD4+ T cells present in gut biopsies were CD73+. In HIV+ subjects, purified CD73+ resting memory CD4+ T cells in PBMC were infected with HIV-1 DNA, determined by real-time PCR, to the same level as for purified CD73-negative CD4+ T cells, both in untreated and treated subjects. Therefore, the proliferative CD73+ subset of memory CD4+ T cells is disproportionately reduced in HIV-1 infection, but, unexpectedly, their IL-7 dependent long-term resting phenotype suggests that residual infected cells in this subset may contribute significantly to the very long-lived HIV proviral DNA reservoir in treated subjects.