Interleukin-16 serum levels during the course of HIV-1 infection

Abstract

IL-16, initially termed lymphocyte chemoattractant factor, is a CD8 T cell-derived cytokine that induces the chemotaxis of CD4 T cells, monocytes and eosinophils at nanomolar concentrations [1–3]. The suppression of HIV replication in CD8-depleted peripheral blood mononuclear cells by IL-16 has been reported [4]. This has been confirmed by the finding that IL-16 is a potent inhibitor of HIV replication in monocyte-derived macrophages and in T lymphocytes [5]. In addition, HIV replication is reduced when IL-16 is expressed in human CD4 T cell lines [6]. Although IL-16 has been described as a natural CD4 cell ligand [3], it does not simply block virus entry by competing with the gp120 surface protein of HIV for the CD4 cell binding site. Instead, IL-16 seems to downregulate HIV long-term repeat promoter activity [7]. We investigated the in-vivo relationships between the stage of HIV disease, the amount of HIV replication and the IL-16 serum levels. First, we compared the IL-16 levels of HIV-1-positive and HIV-1-negative serum samples. The mean values of all seronegative samples [IL-16 concentration (pg/ml) mean 63.636; SD 14.988] were significantly lower (P = 0.0204) than the values of seropositive samples [IL-16 concentration (pg/ml) mean 42; SD 47] Mann–Whitney U test. With the total variance (mean 42; SD 47) of significant P = 0.0004 (simple factorial analysis of variance), different Centers for Disease Control and Prevention (CDC) stages of HIV infection showed markedly varying IL-16 serum concentrations, whereas simple variances of every CDC stage did not differ significantly (P = 0.884) (Fig. 1). IL-16 serum concentrations of stages A and B differed with significant P = 0.001 by heterogeneity of variances [mean difference (MD) −66.6588;P = 0.009], and in stages B and C with P = 0.001 by heterogeneity of variances (MD 60.281 and P = 0.021). IL-16 serum concentrations in stages B2 and B3 were significantly different with P = 0.033, by heterogeneity of variances (MD 42.6000 and P = 0.017), although the clinical symptoms of the patients were comparable.Fig. 1.: IL-16 plasma concentrations and CDC stages of HIV-1-positive patients.IL-16 serum levels in non-viraemic patients correlated with the period of time since the date of first diagnosis of HIV infection. IL-16 levels were low in long-term non-progressing non-viraemic patients (year of first HIV diagnosis between 1985 and 1989), and high in non-viraemic patients diagnosed between 1990 and 1993 (r = 0.8666;P = 0.001). HIV-positive symptomatic patients with non-detectable virus load on average had IL-16 serum concentrations twice as high as patients with detectable viral loads (P = 0.030; IL-16 serum concentration in patients with virus load: mean 29 pg/ml; without viral load: mean 68 pg/ml). The data give strong evidence that IL-16 levels increase in response to HIV infection. Our study could only partly confirm the findings of Darcissac and coworkers [8], who reported an increase of IL-16 serum levels in asymptomatic HIV-positive patients and a decrease in IL-16 serum levels in AIDS patients (CDC stage C). In our study we observed the highest IL-16 serum concentrations in CDC stage B2 followed by a decrease in IL-16 serum levels in AIDS patients (CDC stage C). Therefore for reasons not yet known, IL-16 serum concentrations reflected the immunological and clinical state of patients in toto, and corresponded significantly with the CDC stages. IL-16 serum concentrations increased with the onset of clinical symptoms. The relatively high amount of serum IL-16 during CDC stages A2, B1 and B2 probably reflects an adequate immune response to a persisting infection. However, in the final stages of HIV infection, when the immune system is highly compromised (stage B3 and finally in stages C2 and C3), an increase in plasma viral load and a decrease in IL-16 serum levels have been observed. Long-term non-progressors did not show detectable IL-16 serum levels. In the absence of symptoms or the absence of a plasma viraemia, the trigger for an IL-16 increase may be missing. Our study provides a possible explanation for the contradictory results of the published IL-16 studies: IL-16 serum levels have to be analysed separately in patients with and without HIV viraemia. In addition, different statistical procedures may have led to some of the incongruous findings. In conclusion, our data suggest that antiretroviral therapy should be initiated as soon as a patient is staged into CDC A2 or B1, and support the model that IL-16 is involved in the control of viral replication in vivo. In the future, studies should be undertaken to evaluate the possible use of IL-16 as a surrogate marker to define the appropriate therapeutic intervention point. Armin Badera Norbert Brockmeyera Eiko Schnaitmanna Lutz Mertinsa Ahlert Ottekenb Reinhardt Kurthb Albrecht Wernerb