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JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/QAI.0b013e3181add695
Letters to the Editor

CD8+ Hyperactivation and Senescence Correlate With Early Carotid Intima-Media Thickness in HIV+ Patients With No Cardiovascular Disease

Tincati, Camilla MD*; BellistrÌ, Giusi M BS*; Casana, Maddalena MD*; Merlini, Esther BS*; Comi, Laura MD*; Bai, Francesca MD*; Sinigaglia, Elisabetta BS†; Cristina, Maurizio MD‡; Carpani, Giovanni MD†; Bini, Teresa MD*; Monforte, Antonella d'Arminio MD*; Marchetti, Giulia MD, PhD*

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*Department of Medicine, Surgery and Dentistry, Clinic of Infectious and Tropical Diseases, San Paolo Hospital, University of Milan, Milan, Italy, †Blood Transfusion Center, San Paolo Hospital, Milan, Italy, ‡Chair of Internal Medicine, San Paolo Hospital, University of Milan, Milan, Italy

Supported by grant from “Fondo Interno Ricerca Scientifica e Tecnologica” (FIRST), 2007 and 2008-Università degli Studi di Milano, from Istituto Superiore di Sanità, “National research program in AIDS,” Italy, and from Fondazione Romeo and Enrica Invernizzi, Italy.

Presented in part at 9th International Congress on Drug Therapy in HIV Infection, November 9-13, 2008, Glasgow, United Kingdom, Abstract #097.

To the Editor:

HIV-infected patients are at increased risk for atherosclerosis and cardiovascular disease (CVD).1 By assessing atherosclerosis, carotid artery intima-media thickness (IMT) also proved a predictor of future vascular events.2 HIV-positive patients display higher carotid IMT and progression compared with healthy controls.3 Besides conventional risk factors, atherosclerosis and IMT increases in HIV-positive patients may be hastened by immune and inflammatory pathways,4,5 given T-lymphocyte hyperactivation in HIV/AIDS.6

Given these premises, we cross sectionally investigated the possible correlations between CD8+ activation/maturation profiles and early carotid IMT increase in 64 HIV-infected patients: 17 experienced CVD within the past 2 years, whereas 47 patients never experienced CVD. This latter group of patients underwent carotid artery Doppler ultrasonography (ESAOTE power color-Doppler, 7.5 MHz probes) and were divided in the following: increased IMT patients (IIMT, n = 19) if either left and/or right carotid IMT ≥ 1 mm and normal IMT (NIMT, n = 28) if both left and right carotid IMT < 1 mm.

Figure 1A shows the characteristics of patients under study. Aiming to assess patients' inflammatory profile, we quantified plasma proinflammatory cytokines, tumor necrosis factor α (TNF-α), and interleukin-6 (IL-6) in a subgroup of 25 unselected subjects (R&D, Abingdon, UK). As expected, CVD patients (n = 6) presented higher TNF-α levels reaching significance vs NIMT (n = 10), whereas no differences were shown between CVD and IIMT (n = 9) (CVD: 3.39 ± 0.5; IIMT: 2.79 ± 0.6; NIMT: 2.2 ± 0.35, P = 0.04 and 0.56 for CVD vs NIMT and IIMT, respectively). Interestingly, IIMT subjects displayed a tendency to more elevated TNF-α compared with NIMT (P = 0.24). No differences were shown in plasma IL-6 among groups (Fig. 1B). Having shown a similar proinflammatory cytokine pattern in IIMT and CVD patients, we detailed CD8+ phenotype by flow cytometry: CD8/CD38, CD8/CD95, CD8/127, and CD8/CD38/45R0 (Coulter ESP; Beckman Coulter, Milano, Italy). As compared with IIMT and NIMT as a whole, CVD patients displayed significantly higher mean activated CD38+ CD8+ (CVD: 2.8% ± 0.65%; IIMT and NIMT: 1.4% ± 0.2%, P = 0.03) (Fig. 1C). Interestingly, when confronted individually, IIMT displayed significantly higher CD38+ CD8+ than NIMT, whereas no differences were shown between IIMT and CVD patients (IIMT: 2.1% ± 0.4%; NIMT: 1% ± 0.21%, P = 0.005 for IIMT vs NIMT and CVD vs NIMT; P = 0.58 for CVD vs IIMT) (Fig. 1C). Furthermore, when confronted to NIMT, IIMT patients showed a nonsignificant trend to lower CD8+ expression of the death receptor Fas (CD95+) (IIMT: 2.3% ± 0.54%; NIMT: 3% ± 0.65%, P = 0.2), suggesting a possible CD95 internalization on apoptosis-committed cells7 (Fig. 1C) and significantly lower mean central memory CD127+ CD8+ (IIMT: 11.7% ± 0.79%; NIMT: 14.8 ± 0.98%, P = 0.04) (Fig. 1D). No differences were detected between IIMT and CVD in both parameters (CVD: CD95+ CD8+: 2.67% ± 0.73%, P = 0.9; CD127+ CD8+: 14.3% ± 1.46%, P = 0.2) (Figs. 1C, D). Similar proportions of terminally differentiated CD38+ 45R0+ CD8+ were measured among groups (CVD: 10.93% ± 2.9%; IIMT: 9.1% ± 1.1%; NIMT: 9.4 ± 0.99, P > 0.05 for each pairwise comparison) (Fig. 1D). We further investigated the possible association between immune parameters, IMT and clinical-metabolic parameters. Considering all patients as a whole, activated CD38+ CD8+ subset correlated positively with waist circumference (R = 0.35, P = 0.016) and carotid IMT (R = 0.5, P = 0.001) and negatively with CD127+ CD8+ (R = −0.29, P = 0.05). When analyzed separately, a trend to a significant positive association was yielded only in IIMT between IMT and CD38+ CD8+ (R = 0.49, P = 0.067), whereas no correlation was shown in NIMT.

Figure 1
Figure 1
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Our data suggest that early IMT in HIV-infected patients is associated to a hyperactivated CD8+ phenotype analogous to CVD subjects, allowing to hypothesize an association between pathologic IMT and generalized CD8+ activation. By showing a contraction of CD95-expressing and central memory CD127+ CD8+ T cells despite comparable primed/activated CD38+ 45R0+ CD8+,8,9 our data suggest a likewise senescent CD8+ pool with greater apoptotic history and disrupted maturation as consequences of immune hyperactivation on CD8+ pool in patients with early atherosclerosis and subjects with overt CVD. By delineating a specific CD8+ phenotype in patients with heightened IMT, our data advocate the thorough investigation of immunological parameters as adjuvant markers of cardiovascular risk in HIV/AIDS.

Camilla Tincati, MD*

Giusi M. Bellistrì, BS*

Maddalena Casana, MD*

Esther Merlini, BS*

Laura Comi, MD*

Francesca Bai, MD*

Elisabetta Sinigaglia, BS†

Maurizio Cristina, MD‡

Giovanni Carpani, MD†

Teresa Bini, MD*

Antonella d'Arminio Monforte, MD*

Giulia Marchetti, MD, PhD*

*Department of Medicine, Surgery and Dentistry,

Clinic of Infectious and Tropical Diseases,

San Paolo Hospital,

University of Milan,

Milan, Italy

†Blood Transfusion Center,

San Paolo Hospital,

Milan, Italy

‡Chair of Internal Medicine,

San Paolo Hospital,

University of Milan,

Milan, Italy

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REFERENCES

1. Friis-Moller N, Reiss P, Sabin CA, et al. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med. 2007;356:1723-1735.

2. Lorenz MW, Markus HS, Bots ML, et al. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation. 2007;115:459-467.

3. Hsue PY, Lo JC, Franklin A, et al. Progression of atherosclerosis as assessed by carotid intima-media thickness in patients with HIV infection. Circulation. 2004;109:1603-1608.

4. Willerson JT, Ridker PM. Inflammation as a cardiovascular risk factor. Circulation. 2004;109(21 Suppl 1):II2-II10.

5. Coll B, Parra S, Alonso-Villaverde C, et al. The role of immunity and inflammation in the progression of atherosclerosis in patients with HIV infection. Stroke. 2007;38:2477-2484.

6. Douek DC. Disrupting T-cell homeostasis: how HIV-1 infection causes disease. AIDS Rev. 2003;5:172-177.

7. Lee KH, Feig C, Tchikov V, et al. The role of receptor internalization in CD95 signaling. EMBO J. 2006;25:1009-1023.

8. Paiardini M, Cervasi B, Albrecht H, et al. Loss of CD127 expression defines an expansion of effector CD8+ T cells in HIV-infected individuals. J Immunol. 2005;174:2900-2909.

9. Bofill M, Mocroft A, Lipman M, et al. Increased numbers of primed activated CD8+CD38+CD45RO+ T cells predict the decline of CD4+ T cells in HIV-1-infected patients. AIDS. 1996;10:827-834.

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