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T-cell activation and senescence associate with carotid artery disease in HIV-positive women

Richard Jefferys, TAG

In the early 1990s, UCLA researcher Janis Giorgi [1] 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. [3] 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 [4] 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 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 optimise the long-term care of HIV-infected individuals.” [5]

Source: Source: TAG basic science blog. (14 January 2011).

http://www.treatmentactiongroup.org/basicsciblog.aspx

References:

  1. Janis Giorgi, In Memorium.
    http://www.universityofcalifornia.edu/senate/inmemoriam/JanisGiorgi.htm
  2. Statens Serum Institut (SSI)
    http://www.ssi.dk/sitecore/content/home/english.aspx
  3. Kaplan RC et al. T cell activation and senescence predict subclinical carotid artery disease in HIV-infected women. J Infect Dis. (2011) doi: 10.1093/infdis/jiq071. First published online: January 10, 2011.
    http://jid.oxfordjournals.org/content/early/2011/01/10/infdis.jiq071.full
  4. Tincati, C et al. CD8+ hyperactivation and senescence correlate with early carotid intima-media thickness in HIV+ patients with no cardiovascular disease. JAIDS: August 2009 – Volume 51 – Issue 5 – pp 642-644 doi: 10.1097/QAI.0b013e3181add695.
    http://journals.lww.com/jaids/Fulltext/2009/08150/CD8__Hyperactivation_and_Senescence_Correlate_With.20.aspx
  5. Triant VA and Grinspoon SK. Immune Dysregulation and Vascular Risk in HIV-Infected Patients: Implications for Clinical Care. J Infect Dis. (2011) doi: 10.1093/infdis/jiq084. First published online: January 10, 2011.
    http://jid.oxfordjournals.org/content/early/2011/01/10/infdis.jiq084.full

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