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HIV-hepatitis C virus co-infection is associated with decreased plasmatic IL-7 levels
[Research Letters]
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AIDS: Volume 21(2) 11 January 2007 p 253-255
Soriano-Sarabia, Nataliaa; Vallejo, Alejandroa; Molina-Pinelo, Soniaa; Genebat, Miguela; del Mar Rodriguez, Mariaa; Sanchez-Quijano, Armandob; Martinez-Moya, Manuelc; Vivancos, Jorgec; Leal, Manueld
aViral Hepatitis and AIDS Unit, Spain
bDepartments of Internal Medicine, Spain
cRadiology, Spain
dInfectious Diseases, Virgen del Rocio University Hospital, Seville, Spain.
Note from Jules Levin: The authors main finding is to suggest that since HCV/HIV coinfected patients have lower plasma IL7 levels compared to HIV monoinfected patients, these lower levels explain at least in part the lower CD4 increases after HAART in coinfected patients, but the study also hypothesized that impaired liver function as a result of HCV infection would decrease IL-7 production by the liver, which in turn would affect the total plasmatic IL-7 levels. Although the results did not show an association (p>0.05) between the rates of liver fibrosis and total plasmatic IL-7 levels, patients with a higher fibrosis score showed a tendency to have lower levels. Increasing the number of patients would give significance to this difference. However, the study found healthy volunteers had lower IL7 plasma levels than HIV monoinfected and HCV coinfected ART-naive patients.
Abstract
We analysed the potential influence of hepatitis C virus (HCV) co-infection over IL-7 levels and thymic function in naive HIV-infected patients and after effective HAART. HIV-HCV-co-infected patients had lower plasmatic IL-7 levels compared with HIV-monoinfected patients. This effect may not be associated either with HCV monoinfection or with the rate of liver injury. These lower levels may explain, at least partly, the lower CD4 cell repopulation of HIV-HCV-co-infected patients after HAART.
HIV-infected patients co-infected by hepatitis C virus (HCV) may have an increased risk of progression to AIDS and lower CD4 cell repopulation after HAART [1]. Although these results have not been confirmed by other authors [2], a recent meta-analysis supported these findings [3]. This lower CD4 cell repopulation may be explained partly by the impairment of at least one of the main mechanisms involved in T-cell homeostasis, thymic function and plasmatic IL-7 levels [4,5]. A recent work has reported lower T-cell rearrangement excision circle (TREC) levels in HCV-monoinfected patients compared with non-infected controls, suggesting an immune impairment [6].
Whether HCV co-infection influences this CD4 cell homeostatic system has not been studied. In this work, we performed a cross-sectional study to analyse the potential influence of HCV co-infection over IL-7 levels and thymic function in both naive HIV-infected patients and after effective HAART.
The CD4 cell count and IL-7 levels (Quantikine HS IL-7 immunoassay kit; R&D Systems, Minneapolis, Minnesota, USA) were measured in 97 naive HIV-infected patients, including 40 HCV-co-infected patients. Among these patients, 25 HIV-monoinfected and 20 HIV-HCV-co-infected patients had previously participated in other studies and had their thymic volume measurements recorded [7]. In addition, 92 HIV-infected patients on HAART, with undetectable HIV plasma viraemia, including 49 HCV-co-infected patients, were also analysed. Among them, 29 HIV-monoinfected and 24 HIV-HCV-co-infected patients had their thymic volume recorded [8]. A comparison of thymic volume between these two study populations was not possible because of technical changes. However, the analysis of the effect of HCV co-infection could be performed within each single group (naive patients and HAART-treated patients). The only limitation for the selection of the patients was the availability of frozen plasma samples. None of the HCV-infected patients had received treatment for HCV infection.
Control populations for IL-7 level quantification included 28 healthy volunteers and 31 HCV-monoinfected patients who had never received treatment. In addition, in order to analyse the potential influence of liver injury on IL-7 levels, an additional group of 34 HIV-HCV-co-infected HAART-treated patients were studied. Subjects' written informed consent had been obtained and the ethical committee approved the study.
Real-time polymerase chain reaction (LightCycler; Roche Diagnostics, Branchburg, New Jersey, USA) was used for the quantification of both the characteristic signal-joint sequences harboured in the generated TREC, and β-globin gene [7]. TREC levels were measured in peripheral blood mononuclear cells, yielding the number of TREC per 106 peripheral blood mononuclear cells in the same patients whose thymic volume had previously been measured.
As shown in Fig. 1, HIV-HCV-co-infected patients, both naive and HAART-treated patients, showed statistically lower IL-7 levels than HIV-monoinfected patients. In addition, healthy volunteers showed statistically lower levels than naive HIV-infected patients, although no statistical differences with either HAART-treated patients or HCV-monoinfected patients were found.
Fig. 1. Comparison of IL-7 levels among the study populations according to hepatitis C virus infection, and control groups. HIV-hepatitis C virus (HCV)-co-infected patients are shown with shaded boxes. P values between groups are shown below the figure (Mann-Whitney U-test).
![HAART-1.gif](../images/011807/HAART-1.gif)
In order to determine which factors were associated with IL-7 levels, HIV-infected populations under study were analysed together (97 naive plus 92 HAART-treated patients). The CD4 cell count, HCV co-infection, TREC levels and thymic volume had P < 0.1 in the univariate analysis and were introduced in the stepwise multiple linear regression. An analysis of variance test (OR; 95% CI) showed that the CD4 cell count (P < 0.001, -0.02; -0.02 to -0.14) and HCV co-infection (P < 0.001, -6.37; -11.8 to -0.9) were independently associated with IL-7 levels.
On the other hand, naive HIV-HCV-co-infected patients (N = 20) showed similar TREC levels (P = 0.3) and a statistically bigger thymic volume (P = 0.02) than HIV-monoinfected patients (N = 25; Mann-Whitney U-test). However, neither TREC levels (P = 0.6) nor thymic volume (P = 0.8) were statistically different between HIV-HCV-co-infected (N = 24) and HIV-monoinfected (N = 29) HAART-treated patients.
As expected, both naive HIV-monoinfected patients and naive HIV-HCV-co-infected patients showed an inverse correlation between IL-7 levels and the CD4 cell count (N = 57, r = -0.4, P = 0.08 and N = 40, r = -0.4, P = 0.07, respectively). Nevertheless, among HAART-treated patients only HIV-HCV-co-infected patients showed this inverse correlation (N = 49, r = -0.35, P = 0.015).
The 34 HIV-HCV-co-infected patients whose liver biopsies were available were classified according to a HAI-Knodell score from 0 (no fibrosis) to 4 (cirrhosis). Twenty-three patients showed a low level of fibrosis (scores 0, 1 and 2) and had median IL-7 levels of 6.7 (4.5-11) pg/ml. The remaining 11 patients showed high level of fibrosis (scores 3 and 4) and had median IL-7 levels of 4.9 (3.3-9.4) pg/ml. There were no statistical differences between both groups (P > 0.05, Mann-Whitney U-test).
The previously reported lower CD4 cell repopulation in HIV-HCV-co-infected patients [1,3] might be caused by lower plasmatic IL-7 levels, although further longitudinal studies are needed. In our study, we found a correlation between IL-7 levels and the CD4 cell count in HIV-HCV-co-infected patients on HAART, supporting the theory that HCV co-infection may alter IL-7 levels.
A sex bias could limit this study, because higher IL-7 levels have been reported in HIV-infected women [9]. However, in our study we did not find statistical differences according to sex. Moreover, this variable was not required to perform the multivariate analysis.
A recent work [6] reported decreased levels of TREC in HCV-monoinfected patients. However, lower TREC levels or smaller thymic volumes were not found among HIV-HCV-co-infected patients in the present study. This fact suggests that thymic function may not be influenced by HCV infection. The smaller thymic volume in our naive HIV-monoinfected population could be explained because they had higher HIV plasma viral loads, and thymic volume was inversely correlated with the HIV viral load (r = -0.32, P = 0.001).
Finally, we hypothesized that impaired liver function as a result of HCV infection [10] would decrease IL-7 production by the liver [11], which in turn would affect the total plasmatic IL-7 levels. Although our results did not show an association between the rates of liver fibrosis and total plasmatic IL-7 levels, patients with a higher fibrosis score showed a tendency to have lower levels. Increasing the number of patients would give significance to this difference.
In summary, not only the CD4 cell count but also HCV co-infection are involved in the level of plasmatic IL-7. HIV-HCV-co-infected patients have lower plasmatic IL-7 levels compared with HIV-monoinfected patients. This effect does not seem to be associated either with HCV monoinfection or with the rate of liver injury. These lower levels may explain, at least partly, the lower CD4 cell repopulation of HIV-HCV-co-infected patients after HAART.
References
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