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T-Cell Activation and Senescence Linked to Carotid Lesions in HIV+ Women
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from Jules: this appears to me to be THE POSTER of CROI because it's the first connection between a clinical comorbidity outcome & senescence. The findings were in a relatively more advanced patient population so a key question is if you look at patients with high CD4s of say 650 and treat them with HAART will you see similar correlation with senescence; my guess is yes, senescence occurs as a result of activation & inflammation which is ongoing at some level regardless of CD4 count & undetectable viral load due to the presence of virus, HIV, regardless of whether its low or high virus levels. Perhaps the degree of senescence is less if CD4 is high & viral load low but thisT is one of many studies that need to be conducted but I think yes you will still find senescence, maybe not as often or as much but it appears HIV causes senescence.
17th Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010, San Francisco
Mark Mascolini
CD4- and CD8-cell activation and T-cell senescence (proliferative exhaustion) independently correlated with carotid artery signals of early cardiovascular disease in HIV-infected women enrolled in the Women's Interagency HIV Study (WIHS) [1].
Robert Kaplan (Albert Einstein College of Medicine, New York) and coworkers believe their findings "are consistent with a model in which untreated HIV infection results in immune activation, accelerated immunologic aging and the emergence of a population of potentially dysfunctional immunosenescent T cells."
HIV researchers have known for two decades that CD38, a T-cell activation marker, predicts HIV disease progression [2]. T-cell activation may contribute to loss of these immune cells or failure to reconstitute T-cell populations fully during suppressive antiretroviral therapy. More recent evidence suggests that T-cell senescence (defined as loss of CD28 and/or presence of CD57 on T cells) may play a role in HIV disease progression, inflammatory response, and cardiovascular disease [3].
WIHS researchers compared four groups of women, 43 without HIV, 28 with an undetectable viral load during antiretroviral therapy, 41 untreated women with HIV, and 46 treated women with a detectable viral load. The four groups were equivalent in age (mean 45 to 48 years across groups) and rates of diabetes and hepatitis C virus infection. A larger proportion of HIV-negative women smoked (70%) than did treated suppressed women with HIV (34%), untreated women with HIV (49%), or treated unsuppressed women (57%).
Rates of CD4 and CD8 activation (defined as expression of CD38 and HLA-DR) were significantly higher in all three HIV-infected groups than in the women without HIV (P < 0.001 for both CD4s and CD8s). Activation rates were lower in antiretroviral-treated women with an undetectable viral load than in the other HIV groups, but an average 6 years of antiretroviral therapy did not return activation rates in successfully treated women to levels seen in women without HIV.
T-cell activation correlated negatively with current T-cell count (-0.73, P < 0.01 for CD4s; -0.32, P < 0.01 for CD8s) and positively with higher current viral load. There was a trend toward a negative correlation between CD4-cell senescence (defined as expression of CD57 but not CD28) and current CD4 count (-0.14, P = 0.13) (more senescence correlated with lower CD4)
Higher expression of T-cell activation markers was associated with carotid lesions identified by B-mode ultrasonography of the right common carotid artery, the internal carotid artery, and the carotid bifurcation (P = 0.023 for CD8-cell activation, P = 0.061 for CD4-cell activation). Greater T-cell senescence was also associated with reduced carotid artery distensibility (r = -0.276, P = 0.0028 for CD4 cells; r = -0.265, P = 0.0042 for CD8 cells). (from Jules: Carotid distensibility (CD) is a measure of carotid artery elasticity that has been introduced as a risk factor for cardiovascular disease. Morphological studies have indicated that arterial distensibility depends on different factors such as blood pressure and age. Aging is the main variable responsible for functional changes in the arterial wall leading to an increase in arterial stiffness)
A multivariate model adjusted for age and antiretroviral classes determined that CD4 and CD8 activation and CD8-cell senescence independently raised the risk of ultrasound-detected carotid lesions:
· Prevalence ratio 1.6 for CD4 activation, P = 0.02
· Prevalence ratio 2.0 for CD8 activation, P < 0.01
· Prevalence ratio 1.9 for CD8 senescence, P = 0.01
Further adjustment for cardiovascular risk factors, viral load, and socioeconomic factors did not affect these correlations. Activation and senescence of both CD4 and CD8 cells also correlated independently with carotid artery distensibility. The investigators found no correlations between T-cell activation or senescence and carotid artery measures in HIV-negative women.
Kaplan and colleagues propose that "antiretroviral therapy-mediated suppression of HIV replication may only partially reverse or prevent this process" of T-cell activation and senescence. They add that "a large population of activated and/or senescent T cells may be causally associated with the premature onset of cardiovascular disease." The findings also underline the heightened cardiovascular risks associated with HIV and its treatment in women, despite the lower overall heart disease risk in women versus men in the general population.
References
1. Kaplan RC, Sinclair E, Landay AL, et al. T-cell senescence and T-cell activation predict carotid atherosclerosis in HIV-infected women. 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 709.
2. Giorgi JV, Hultin LE, McKeating JA, et al. Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J Infect Dis. 1999;179:859-870.
3. Liuzzo G, Biasucci LM, Trotta G, et al. Unusual CD4+CD28-null T lymphocytes and recurrence of acute coronary events. J Am Coll Cardiol. 2007;50:1450-1458.
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