In the early 1990s, UCLA researcher Janis Giorgi published evidence that the activation of the immune system by HIV (as measured by expression of a marker called CD38 on CD8 T cells) was a strong predictor of the pace of progression to AIDS. At the time the idea was controversial, but a voluminous amount of evidence has since accumulated confirming Giorgi’s finding and demonstrating that immune activation is central to the pathogenesis of HIV infection. Furthermore, it is now clear that while antiretroviral therapy (ART) greatly reduces immune activation, it can often persist at levels significantly higher than those seen in comparable HIV-negative individuals. The magnitude of this residual immune activation is linked to the CD4 count at the time of ART initiation: the lower the CD4 count, the higher the degree of residual activation.
Because the nadir (lowest ever) CD4 count is also the strongest predictor of the risk of illness in people on ART, there has been reason to suspect that residual immune activation contributes to ill health. Studies documenting associations between elevated levels of inflammatory biomarkers and mortality have bolstered this suspicion. However, data linking immune activation to specific clinical conditions is sparse. Similarly, one of the consequences of persistent immune activation is a type of T cell dysfunction called senescence. Senescent T cells are essentially old and worn out, and they have a bad habit of producing large amounts of inflammatory cytokines and appear to get in the way of T cells that do work properly. While the proportion of senescent T cells has been associated with the pace of disease progression in HIV, their role in specific diseases is unclear.
A new open access paper in the Journal of Infectious Diseases goes some way to addressing these information gaps. Led by Robert Kaplan of the Women’s Interagency HIV Study (WIHS), the research reveals that both CD8 T cell activation and CD8 T cell senescence predict carotid artery disease in HIV-positive women. Disease was assessed based on the extent of carotid lesions, which were defined as focal thickening (>1.5 mm) of the intima-media layer. The authors note that while these measures of subclinical vascular disease predict incident cardiovascular disease events in the general population, this has yet to be formally confirmed in the HIV-positive population. They conclude by stating: “our data provide further evidence that persistent activation of the immune system is associated with vascular abnormalities among HIV-infected individuals. This relationship was suggested by a small prior study that, unlike the present investigation, did not feature multivariate analyses, did not control for potential confounding effects of HIV-related and CVD-related variables, and lacked an HIV-uninfected control group. These results have important implications for assessment of vascular risk among adults with HIV infection.”
An accompanying commentary by Virginia Triant and Steven Grinspoon (link below) further discusses the implications of the findings, and posits that “studies investigating the mechanisms of these immunologic alterations in relation to cardiovascular events and exploring therapies to modify T cell activation and senescence will advance our understanding of this complex field and help to optimize the long-term care of HIV-infected individuals.”
J Infect Dis. (2011)doi: 10.1093/infdis/jiq071
First published online: January 10, 2011
T Cell Activation and Senescence Predict Subclinical Carotid Artery Disease in HIV-Infected Women
Robert C. Kaplan1, Elizabeth Sinclair2, Alan L. Landay4, Nell Lurain4, A. Richey Sharrett5, Stephen J. Gange5, Xiaonan Xue1, Peter Hunt2, Roksana Karim3, David M. Kern1, Howard N. Hodis3 and Steven G. Deeks2
Author Affiliations
1 Department of Epidemiology and Population Health, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York
2 Division of Experimental Medicine, University of California, San Francisco
3 Atherosclerosis Research Unit, Departments of Medicine and Preventive Medicine, University of Southern California, Los Angeles, California
4 Rush University Medical Center, Chicago, Illinois
5 Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
Abstract
Background. Individuals infected with human immunodeficiency virus (HIV) have increased risk of cardiovascular events. It is unknown whether T cell activation and senescence, 2 immunologic sequelae of HIV infection, are associated with vascular disease among HIV-infected adults.
Methods. T cell phenotyping and carotid ultrasound were assessed among 115 HIV-infected women and 43 age- and race/ethnicity-matched HIV-uninfected controls participating in the Women's Interagency HIV Study. Multivariate analyses were used to assess the association of T cell activation (CD38+HLA-DR+) and senescence (CD28−CD57+) with subclinical carotid artery disease.
Results. Compared with HIV-uninfected women, frequencies of CD4+CD38+HLA-DR+, CD8+CD38+HLA-DR+, and CD8+CD28−CD57+ T cells were higher among HIV-infected women, including those who achieved viral suppression while receiving antiretroviral treatment. Among HIV-infected women, adjusted for age, antiretroviral medications, and viral load, higher frequencies of activated CD4+ and CD8+ T cells and immunosenescent CD8+ T cells were associated with increased prevalence of carotid artery lesions (prevalence ratiolesions associated with activated CD4+ T cells, 1.6 per SD [95% confidence interval {CI}, 1.1–2.2]; P = .02; prevalence ratiolesions associated with activated CD8+ T cells, 2.0 per SD [95% CI, 1.2–3.3]; P < .01; prevalence ratiolesions associated with senescent CD8+ T cells, 1.9 per SD [95% CI, 1.1–3.1]; P = .01).
Conclusions. HIV-associated T cell changes are associated with subclinical carotid artery abnormalities, which may be observed even among those patients achieving viral suppression with effective antiretroviral therapy.
J Infect Dis. (2011) doi: 10.1093/infdis/jiq084
First published online: January 10, 2011
Immune Dysregulation and Vascular Risk in HIV-Infected Patients: Implications for Clinical Care
Virginia A. Triant1 and Steven K. Grinspoon2
Author Affiliations
1 Division of Infectious Diseases
2 Program in Nutritional Metabolism, Massachusetts General Hospital, Boston, Massachusetts
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