Highly Active Antiretroviral Therapy Alters

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were stimulated with thrombin receptor– activating peptide (TRAP)–SFLLRN peptide (50 μg/mL for 30 minutes; Sigma-. Aldrich, Saint-Quentin Fallavier, France).
Highly Active Antiretroviral Therapy Alters Inflammation Linked to Platelet Cytokines in HIV-1–Infected Patients

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JID 2013:208 (1 September)



CORRESPONDENCE

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TO THE EDITOR—Chronic immune activation and persistent inflammation are critical features of human immunodeficiency virus type 1 (HIV-1) infection [1, 2]. For example, CD40 and its soluble ligand (sCD40L) are upregulated upon human immunodeficiency virus (HIV) infection, and their enhanced interaction inhibits production of interferon α by plasmacytoid dendritic cells [3]. Recently, Naranbhai et al reported that innate immune activation drives HIV acquisition, despite the use of a tenofovir microbicide gel [4]. They suggested that dampening inflammation may reduce primary infection. Among the numerous actors involved in immune activation and inflammation during HIV infection, activated platelets are usually underconsidered. However, platelets are the major source of circulating sCD40L, a master immune activator [5]. Platelets are activated by infectious pathogens, including HIV, because they sense infectious danger and secrete adapted panels of cytokines [6]. Levels of inflammatory platelet-derived products are elevated in the plasma of HIV-1 infected patients [7]. We assessed, in an in vitro model, platelet participation in inflammation in HIV-1–infected patients who were or were not receiving highly active antiretroviral therapy (HAART). A total of 41 HIV-positive patients without coinfection who had been receiving stable HAART for at least 1 year and 30 HIV-positive patients who, in accordance with World Health Organization recommendations (ie, their CD4+ T-cell count was >350 cells/μL), were not receiving HAART were recruited at our hospital. Written informed consent was obtained for inclusion into the study, which was approved by the French

National Agency for the Safety of Medicines and Health Products (study B111011-40). Forty healthy blood donors were recruited as negative controls after signing the donation form, which states that donation of blood does not preclude use of the donation for nontherapeutic purposes (in accordance with the French Public Health Code). Clinical data on patients of different groups are presented in Table 1. Platelet-free and platelet-rich plasma (PRP) samples were prepared as described previously [6, 8]. Freshly isolated platelets were stimulated with thrombin receptor– activating peptide (TRAP)–SFLLRN peptide (50 μg/mL for 30 minutes; SigmaAldrich, Saint-Quentin Fallavier, France). Supernatants were cryopreserved at −80°C until later assay. Levels of soluble CD40L (sCD40L), growth-regulated oncogene (GRO)–α, regulated and normal T-cell expressed and secreted (RANTES), and soluble CD62P (sCD62P) were quantitated in plasma samples and PRP supernatants by Luminex technology (Merck-Millipore, Molsheim, France). Concentrations are expressed as mean values ± SD, and each sample was assayed in triplicate. The values were compared by the t test or χ² test for proportions. P < .05 was considered statistically significant. HAART recipients and untreated HIV-1–infected patients had comparable platelet counts, which were significantly lower than those in healthy controls (Table 1). Therefore, concentrations of factors released by platelets were normalized for 3 × 108 platelets. Consistent with other studies [7, 9], we observed that plasma levels of several platelet-associated inflammatory molecules were significantly increased in HIV-positive patients, which supports the participation of platelets in systemic immune activation during HIV infection. Moreover, we found that platelets displayed different responses to TRAP according to the HIV status of patients and whether HAART was implemented. Platelets from HAART-treated patients, and even more platelets from untreated patients, released significantly more sCD40L

Table 1. Baseline Demographic Characteristics, Human Immunodeficiency Virus (HIV) Data, and Levels of Inflammatory Factors in Plasma and Released by Platelets HIV-Positive Patients

Variable

HIV-Negative Healthy Blood Donors (n = 40)

Receiving HAART (n = 41)

Not Receiving HAART (n = 30)

43 (36–51)

50 (43–57)a

41 (35–50)

21 (53) 245 (201–276)

34 (82)a 208 (166–245)a

25 (83)a 214 (180–253)a

6.02 (5.12–6.52)

5.82 (4.64–6.85)

5.61 (4.92–6.81)

678 (575–749)

587 (412–722)

523 (410–630)a

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