Subclinical atherosclerosis in HIV patients on antiretroviral therapy tied to immune signature characterized by lower levels of Th17 cells
Presenter: Tomas Raul Wiche Salinas, MD, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montréal, Canada, and Emory University, Atlanta, Georgia
Despite suppressed HIV-1 replication under antiretroviral therapy (ART), people living with HIV (PLWH) have a higher incidence of coronary artery disease, myocardial infarction, sudden cardiac death, and peripheral artery disease compared with the general population.
According to Tomas Raul Wiche Salinas, MD, postdoctoral fellow, Emory University, Atlanta, Georgia, decreased frequencies of Th17 cells and a lower ratio of Th17/regulating T (Treg) cells are characteristic of subclinical atherosclerosis in PLWH treated with ART as well as associated with higher fibrinogen levels, augmented frequency of nonclassical and Slan monocytes, and diminished frequency of CCR9+ nonclassical monocytes.
These findings were derived from an analysis of the prospective Canadian HIV and Aging Cohort Study, supported by Canadian Institutes of Health Research. People living with HIV and HIV-negative matched controls, 40 years or older, without history or symptoms of coronary artery disease had coronary plaque measured by coronary computed tomography angiography.
The authors hypothesized “…a link between the ‘leaky gut’ caused by Th17 depletion and the development of HIV-associated subclinical atherosclerosis….[and] revealed immunological alterations linked to subclinical atherosclerosis in PLWH that may be monitored in therapeutic interventions aimed to prevent cardiovascular disease occurrence.”
Total plaque volume (TPV) was measured at baseline in all participants and categorized as the absence (TPV- 0 mm3) or presence (TPV+ > 0 mm3) of coronary plaque. Ex vivo phenotyping was performed on peripheral blood monocyte cells by polychromatic flow cytometry for memory CD4+ T cells, effector memory (EM) T cells, central memory (CM) T cells, Th17 cells, and Tregs; classical (CD14++ CD16-), intermediate (CD14++ CD16+), nonclassical (CD14- CD16++), and Slan (M-DC8+) monocytes; human leukocyte antigen-DR isotype (HLA-DR); and chemokine receptor expressions (CCR2, CCR6, CCR9, CX3CR1).
Among PLWH, duration of HIV was a mean of 19.2 years in the 39 participants who were TPV+ versus 14.7 years in those who were TPV- (P = .06). Mean duration of antiretroviral therapy was 16.1 versus 10.7 years in the two groups (P = .003), respectively. Levels of CCL20, a marker of gut damage and systemic inflammation, were increased in the TPV+ compared with TPV- PLWH (P < .0514).
Tregs frequencies did not differ between those with and without coronary plaque among PLWH, despite expansion of Tregs observed in this population. Among PLWH, memory (P = .0166), EM Th17 (P = .0083), and CM Th17 cell (P = .0149) frequencies were decreased in those with coronary plaque compared with those without coronary plaque. Driven by depletion of Th17 cells, the ratios of memory Th17/Tregs (P = .0373) and EM Th17/Tregs (P = .0259) were lower among the TPV+ subset.
An expansion of classical monocytes was observed in PLWH compared with HIV-negative controls (P = .036) to the detriment of intermediate monocytes (P = .039), whereas no differences in the frequencies of nonclassical and Slan M-DC8+ monocytes was observed. There were no changes in monocyte subset frequencies based on coronary plaque status.
Frequency of intermediate (P = .0087) and nonclassical monocytes (P = .0066) expressing CCR9 was diminished in PLWH compared with HIV-negative controls.
In crude analysis, fibrinogen; CCR9-, HLA-DRhigh nonclassical monocytes; and memory, EM, and CM Th17/Treg ratios were associated with the presence of coronary plaque, while frequencies of CCR9+, HLA-DRlow, nonclassical monocytes were associated with absence of coronary plaque.
In a model adjusted for level of low-density lipoprotein cholesterol, smoking, and age, fibrinogen level (P = .05), CCR9-, HLA-DRlow nonclassical monocytes (P = .01), CCR9-, HLA-DRhigh nonclassical monocytes (P = .03), and EM (P =.05) and CM (P = .05) Th17/Treg ratios remained significantly associated with coronary plaque volume.
In a model adjusted for statin use, smoking, and triglyceride levels, a significant association remained between fibrinogen level (P =.01), CCR9-, HLA-negative DRlow nonclassical monocytes (P = .02), and CCR9-negative HLA-negative DRhigh nonclassical monocytes (P = .02).
In conclusion, subclinical atherosclerosis in ART-treated PLWH was associated with higher fibrinogen levels, decreases frequencies of Th17 cells, lower Th17/Treg ratios, augmented frequency of nonclassical Slan monocytes, and diminished frequency of CCR9+ nonclassical monocytes.
Disclosure
Dr. Salinas has no relevant financial relationships to disclose.