Several studies have shown GBV-C viremia to be associated with slower HIV-1 disease progression [5,7,20
]. This includes an inverse relationship between GBV-C and HIV-1 RNA levels as well as an increase in GBV-C RNA levels in those starting potent antiretroviral therapy [20
]. These observations argue for a causal virus-virus interaction which is supported by in vitro evidence for an attenuating effect of GBV-C on HIV replication [21–24
]. Despite that, some authors still argue that the observation only indicates an epiphenomenon [25
]. In evaluating the role of GBV-C viremia in this well characterized cohort of HIV-1-infected and -uninfected hemophiliac children and adolescents we identified three findings : 1) low prevalence of GBV-C in both groups during the early phase of the study, increasing to levels more consistent with what has been described in other cohorts at later points of time; 2) milder clinical course of HIV-1 disease in subjects being GBV-C positive at later point of time, which, however, was lost when controlled for baseline factors; and 3) a higher rate of HCV clearance in patients never found to be GBV-C viremic.
The low prevalence of GBV-C viremia at baseline in both groups was surprising. However, after a median of 4.6 years of follow-up for HIV-1-infected and 6.1 years for HIV-1-uninfected patients, prevalence of GBV-C infection was 24.6% and 26.3%, respectively. These later rates are similar to what has been seen in other cohorts of HIV-1- and HCV-infected individuals (15–45% GBV-C-infected) [9–17
]. Degradation of GBV-C RNA is an unlikely explanation for the low prevalence at baseline as we were able to detect HCV RNA in GBV-C negative samples and repeated thaw-and-freeze cycles of GBV-C positive plasma did not show loss of GBV-C RNA (unpublished data). Furthermore, we reliably detected HCV RNA in samples from the early cycles (data not shown). HIV-1 and HCV infection in the HGDS cohort is associated with receipt of virus contaminated clotting factors [1,2,26,27
]. Low prevalence of GBV-C infection directly after exposure to such clotting factors but increasing during follow-up could suggest that GBV-C is less efficiently transmitted by pooled blood products than HCV or HIV, but is transmitted by other normal contacts or during routine health care. Several studies have shown that HCV transmission can occur in association with increasing numbers of hospital visits [28–31
]. If also true for GBV-C it could explain the higher GBV-C prevalence at the end of the study e.g. caused by increased frequency of exposure to clotting factors. The identification of a highly significant correlation between time period of follow-up and increased risk of GBV-C infection would be consistent with this hypothesis and what has been observed in other studies [32–35
]. Another possible explanation for our findings is that target cells might become more susceptible to GBV-C as patients age. Some studies evaluated the GBV-C prevalence in children and also found evidence for increase of GBV-C prevalence in older compared to younger children [32,36
]. The fact that children do not have fully developed their immune systems may promote HIV-1 replication and depletion of CD4+
cells, whereas a lack of totally differentiated immune cells may impair GBV-C replication and its potential effect on HIV-1 infection. In fact, having higher CD4+
cell counts and lower HIV-1 RNA levels at baseline was predictive of becoming GBV-C RNA positive. Finally, it is possible that hemophiliacs are at somewhat lower risk since pooled sera/plasma can contain anti-E2 antibodies which could neutralize co-existing GBV-C viremia. This would be consistent with other observations that the rate of GBV-C viremia is relatively low in hemophiliacs exposed to GBV-C containing blood products [37
We demonstrated that among HIV-1-infected children and adolescents, those that became GBV-C infected at follow-up had higher CD4+
cell counts and lower plasma HIV-1 RNA levels at the time of the follow-up visit than those without detectable GBV-C. However, these associations were no longer significant when controlling for baseline CD4+
cell count or plasma HIV-1 RNA. The lack of improved prognosis after controlling for baseline factors is in line with another study in perinatally HIV-1-infected children [34
]. However, it cannot be ruled out that subdetectable GBV-C infection might have already been present and responsible for the better baseline values. Furthermore, it can be discussed if adjusting for CD4+
cell count or plasma HIV-1 RNA CD4 is appropriate as both variables might well be influenced by an underlying GBV-C infection.
HCV infection is very common in HIV-1-infected patients (33–47%) and the clinical course of HCV infection is influenced by HIV-1 [38,39
]. In this study we found a difference in the likelihood of clearing HCV depending on HIV-1-infection status (at baseline and follow-up): 31.9% (38/119) of HIV-1-uninfected patients versus 6.4% (13/202) of HIV-1-infected patients. Furthermore, as previously reported from this cohort [26
], HCV RNA levels were lower in those HIV-1-uninfected than -infected patients. These findings can be explained by impairment of cellular immune response due to HIV-1 infection [40,41
]. In contrast, there was no relationship between GBV-C infection and HCV RNA level in either the HIV-1-infected or -uninfected patients. However, HCV RNA clearance was significantly (p=0.023) more common amongst those HIV-1-uninfected who were never found to be GBV-C-infected than those that were GBV-C viremic at follow-up. In fact, among the HIV-1-infected patients, HCV clearance was only seen amongst those that were never found to be GBV-C-infected. However, only so few patients clear HCV in the HIV population that this difference was not significant. However, similar trends have been seen in other studies: a French cohort of hemophiliac patients [42
], and in a study in a peritoneal dialysis population [43
]. This also fits with some reports of higher sustained viral response for HCV in patients clearing GBV-C viremia during interferon based therapies [9,44
]. The relation between HCV persistence and GBV-C viremia may suggest similar effectors of immune response leading to simultaneous control of both viruses. Single HCV proteins have to be shown to block the activation of the immune system and thereby inhibit the efficient elimination of the virus [45–47
], and based upon the close phylogenetic relationship between GBV-C and HCV, it is conceivable that such a characteristic could be shared with GBV-C proteins. Recently, IL28B
, emerged as predictor of spontaneous and treatment-induced HCV clearance [48
]. In one cohort where we could confirm the role of IL28B
for HCV clearance, we did not find a role for IL28B
in relation to GBV-C clearance [49
There are several limitations of this study, including the retrospective nature of the study and the relatively small number of patients. In addition, the small number of patients with AIDS related death precluded statistical tests. The study is further limited by the variability in the sample availability at different points of time. Nevertheless, our study provides new insights into GBV-C, HIV-1 and/or HCV co-infection in hemophiliac children and adolescents.
In summary, our data suggest a better prognosis of HIV-1 disease in patients who are eventually GBV-C infected. It cannot be excluded that GBV-C is a mere marker for a more benign course of disease. Interestingly, absence of GBV-C viremia was associated with a higher rate of HCV clearance.