Publications

Persistent immune activation and inflammation despite sustained antiretroviral therapy (ART)-mediated viral suppression has emerged as a major challenge of the modern HIV treatment era. While immune activation, inflammatory, and coagulation markers typically decline during suppressive ART, they remain abnormally elevated in many HIV-infected individuals and predict subsequent mortality and non-AIDS morbidities including cardiovascular disease. The goal of this review is to summarize the current state of our knowledge regarding the underlying causes of persistent immune activation during ART-mediated viral suppression as well as the link between persistent immune activation and morbidity and mortality in this setting. Several recent studies have linked surrogate markers of this persistent inflammatory state to clinical outcomes, validating persistent immune activation as a viable therapeutic target. Other recent studies have helped clarify the roles of persistent HIV expression and/or replication, microbial translocation, and co-infections in driving this persistent inflammatory state, identifying targets for novel interventions.

BACKGROUND

Shear stress gradients and inflammation have been causally associated with atherosclerosis development in carotid bifurcation regions. The mechanism underlying higher levels of carotid intima-media thickness observed among HIV-infected individuals remains unknown.

METHODS AND RESULTS

We measured carotid intima-media thickness progression and development of plaque in the common carotid, bifurcation region, and internal carotid artery in 300 HIV-infected persons and 47 controls. The median duration of follow-up was 2.4 years. When all segments were included, the rate of intima-media thickness progression was greater in HIV-infected subjects compared with controls after adjustment for traditional risk factors (0.055 vs. 0.024 mm/year, P=0.016). Rate of progression was also greater in the bifurcation region (0.067 vs. 0.025 mm/year, P=0.042) whereas differences were smaller in the common and internal regions. HIV-infected individuals had a greater incidence of plaque compared with controls in the internal (23% vs. 6.4%, P=0.0037) and bifurcation regions (34% vs. 17%, P=0.014). Among HIV-infected individuals, the rate of progression in the bifurcation region was more rapid compared with the common carotid, internal, or mean intima-media thickness; in contrast, progression rates among controls were similar at all sites. Baseline hsCRP was elevated in HIV-infected persons and was a predictor of progression in the bifurcation region.

CONCLUSIONS

Atherosclerosis progresses preferentially in the carotid bifurcation region in HIV-infected individuals. hsCRP, a marker of inflammation, is elevated in HIV and is associated with progression in the bifurcation region. These data are consistent with a model in which the interplay between hemodynamic shear stresses and HIV-associated inflammation contribute to accelerated atherosclerosis. (J Am Heart Assoc. 2012;1:jah3-e000422 doi: 10.1161/JAHA.111.000422.)

CLINICAL TRIAL REGISTRATION

URL: http://clinicaltrials.gov. Unique identifier: NCT01519141.

OBJECTIVE

HIV-infected individuals are at increased risk for myocardial infarction. Given observations that cytomegalovirus (CMV) infection, CMV-specific T cells, and CX3CR1 have each been associated with atherosclerosis, we hypothesized that CMV-induced T-cell immunopathology could contribute to HIV-associated atherosclerosis.

METHODS

We measured the expression of CX3CR1 on peripheral blood mononuclear cells and its association with carotid artery intima-media thickness (IMT) in 29 HIV-infected individuals and 48 uninfected controls. We analyzed the phenotype and specificity of CX3CR1(+)CD4(+) T cells, the production of CX3CL1 (the ligand of CX3CR1) by CMV-infected endothelial cells in vitro, and the migration of CD4(+) T cells induced by CX3CL1.

RESULTS

The progression of atherosclerosis in HIV-infected individuals, as assessed by longitudinal measurements of carotid IMT, was associated with a high frequency of CD4(+) T cells that express the chemokine receptor CX3CR1. Such CD4(+)CX3CR1(+) T cells were antigen-primed, produced high levels of pro-inflammatory cytokines, and composed the majority of the CMV-specific CD4(+) T cells. CMV-stimulated CD4(+) T cells were also found to induce the production of CX3CL1 (the ligand for CX3CR1) by human arterial endothelial cells, driving the transendothelial migration of pro-inflammatory CD4(+) T cells. Finally, we observed that CD4(+)CX3CR1(+) T cells could be localized to the coronary arterial wall in HIV disease.

CONCLUSION

HIV-associated atherosclerosis may be driven by a positive feedback pathway in which a high frequency of antigen-stimulated, CMV-specific CD4(+)CX3CR1(+) T cells induce endothelial cells to secrete CX3CL1, which itself drives progressive infiltration of the arterial wall by pro-inflammatory cells.