GB Virus C and Survival in Persons with HIV Infection
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《新英格兰医药杂志》
To the Editor: Williams et al. (March 4 issue)1 propose that GB virus C (GBV-C) interferes with the progression of human immunodeficiency virus (HIV) infection. Previous cross-sectional studies have shown that HIV-infected patients with GBV-C viremia have increased rates of survival.2,3,4 Williams et al. found no survival benefit associated with GBV-C viremia 12 to 18 months after HIV seroconversion but did observe that GBV-C viremia 5 to 6 years after HIV seroconversion was associated with a survival benefit.
In a similar, longitudinal study,5 we determined the GBV-C status both in the earliest available serum sample after the diagnosis of HIV infection in 230 patients and in the last available sample before death or highly active antiretroviral therapy (median duration of follow-up, 4.3 years). We found that baseline GBV-C viremia had no effect on survival. However, patients with GBV-C viremia in whom the GBV-C disappeared during follow-up, without the development of E2 antibodies, had a poor prognosis. The association of GBV-C viremia with prognosis appears late during HIV infection. We propose that the accelerated course of HIV infection causes loss of GBV-C viremia, and not the other way around.
Per Bj?rkman, M.D., Ph.D.
Leo Flamholc, M.D.
Anders Widell, M.D., Ph.D.
Malm? University Hospital
SE-20502 Malm?, Sweden
References
Williams CF, Klinzman D, Yamashita TE, et al. Persistent GB virus C infection and survival in HIV-infected men. N Engl J Med 2004;350:981-990.
Xiang J, Wünschmann S, Diekema DJ, et al. Effect of coinfection with GB virus C on survival among patients with HIV infection. N Engl J Med 2001;345:707-714.
Tillmann HL, Heiken H, Knapik-Botor A, et al. Infection with GB virus C and reduced mortality among HIV-infected patients. N Engl J Med 2001;345:715-724.
Yeo AET, Matsumoto A, Hisada M, Shih JW, Alter HJ, Goedert JJ. Effect of hepatitis G virus infection on progression of HIV infection in patients with hemophilia. Ann Intern Med 2000;132:959-963.
Bj?rkman P, Flamholc L, Nauclér A, Molnegren V, Wallmark E, Widell A. GB virus C during the natural course of HIV-1 infection: viremia at diagnosis does not predict mortality. AIDS 2004;18:877-886.
To the Editor: We agree with Williams and colleagues that GBV-C RNA in the plasma of HIV-infected patients could be a favorable marker for nonprogression of HIV disease, as we also recently observed.1 However, the key question concerning whether GBV-C has a direct anti-HIV role or whether its presence at detectable levels is a mere consequence of higher CD4+ T-cell counts still remains to be answered. In fact, since GBV-C replicates preferentially in CD4+ T cells, its clearance may theoretically be due to the HIV-induced reduction in the target cells. In the study by Williams et al., no significant beneficial effect was in fact observed at the early visits, when CD4+ T-cell counts and HIV viremia were not affected by the GBV-C status.
It would be of interest to evaluate the long-term effect of GBV-C coinfection on plasma HIV levels in patients with similar and constantly high levels of CD4+ T cells, in order to underline possible direct viral interference in vivo. We therefore believe that in vitro and in vivo studies should be conducted before GBV-C is considered as a prognostic or therapeutic tool for the care of patients with HIV infection.
Filippo Canducci, M.D.
Andriano Lazzarin, M.D.
Massimo Clementi, M.D.
Vita-Salute San Raffaele University
20131 Milan, Italy
canducci.filippo@hsr.it
References
Canducci F, Uberti Foppa C, Boeri E, et al. Characterization of GBV-C infection in HIV-1 infected patients. J Biol Regul Homeost Agents 2003;17:191-194.
The authors reply: Does GBV-C prolong survival in HIV-positive persons, or is it a marker of high CD4+ cell counts? In our study, men with HIV seroconversion who had persistent GBV-C viremia were 2.4 times as likely to survive as were persons who did not have viremia at either time point (95 percent confidence interval, 1.2 to 5.2; P<0.01), strongly supporting a causal role for GBV-C. The duration of HIV infection in men with and without GBV-C was the same, and the stage of HIV disease was not based on surrogate markers. Nevertheless, we found that the CD4+ cell count and the plasma HIV RNA concentration were related to GBV-C status. We also demonstrated prolonged survival in HIV-positive men with baseline CD4+ cell counts of less than 50 per cubic millimeter.1 The relative protection conferred by persistent GBV-C viremia in men with HIV seroconversion was greater than that observed for men who were heterozygous for the CC chemokine receptor 5 (CCR5) 32 polymorphism in the HIV coreceptor gene.2 As mentioned in the Discussion section of our article, we agree that it is important to determine whether the decline in CD4+ cells occurs before the clearance of GBV-C or whether the loss of GBV-C is associated with more rapid CD4+ cell decline. Ongoing studies in persons with HIV seroconversion should answer this question.
We also agree that demonstration of viral interference or other mechanisms to explain this epidemiologic association is important. We have previously shown that in vitro coinfection of lymphocytes with GBV-C and HIV results in decreased HIV replication.1 The HIV-inhibitory effect is mediated by the induction of beta-chemokines and the down-regulation of the HIV coreceptor CCR5,3 possibly as a result of interactions between GBV-C E2 protein and CD81.4 Furthermore, clinical studies have demonstrated decreased CCR5 expression on CD4+ lymphocytes4 and favorable type 1 and 2 helper-T-cell cytokine profiles among GBV-C–HIV coinfected people, as compared with those without GBV-C viremia.5 The combination of eight epidemiologic studies demonstrating a survival benefit in GBV-C–infected HIV-positive people, combined with growing evidence of interference between these two viruses, strongly suggests that in HIV-infected people there is a causal relationship between GBV-C and prolonged survival.
Jack T. Stapleton, M.D.
University of Iowa
Iowa City, IA 52242
jack-stapleton@uiowa.edu
Carolyn F. Williams, Ph.D.
National Institutes of Health
Bethesda, MD 20892
Jinhua Xiang, M.D.
Iowa City Veterans Affairs Medical Center
Iowa City, IA 52242
References
Xiang J, Wünschmann S, Diekema DJ, et al. Effect of coinfection with GB virus C on survival among patients with HIV infection. N Engl J Med 2001;345:707-714.
Stapleton JT, Williams CF, Xiang J. GB virus C: a beneficial infection? J Clin Microbiol (in press).
Xiang J, George SL, Wünschmann S, Chang Q, Klinzman D, Stapleton JT. GB virus C infection inhibits HIV-1 replication by increasing RANTES, MIP-1, MIP-1, and SDF-1. Lancet (in press).
Nattermann J, Nischalke HD, Kupker B, et al. Regulation of CC chemokine receptor 5 in hepatitis G virus infection. AIDS 2003;17:1457-1462.
Nunnari G, Nigro L, Palermo F, et al. Slower progression of HIV-1 infection in persons with GB virus C co-infection correlates with an intact T-helper 1 cytokine profile. Ann Intern Med 2003;139:26-30.
In a similar, longitudinal study,5 we determined the GBV-C status both in the earliest available serum sample after the diagnosis of HIV infection in 230 patients and in the last available sample before death or highly active antiretroviral therapy (median duration of follow-up, 4.3 years). We found that baseline GBV-C viremia had no effect on survival. However, patients with GBV-C viremia in whom the GBV-C disappeared during follow-up, without the development of E2 antibodies, had a poor prognosis. The association of GBV-C viremia with prognosis appears late during HIV infection. We propose that the accelerated course of HIV infection causes loss of GBV-C viremia, and not the other way around.
Per Bj?rkman, M.D., Ph.D.
Leo Flamholc, M.D.
Anders Widell, M.D., Ph.D.
Malm? University Hospital
SE-20502 Malm?, Sweden
References
Williams CF, Klinzman D, Yamashita TE, et al. Persistent GB virus C infection and survival in HIV-infected men. N Engl J Med 2004;350:981-990.
Xiang J, Wünschmann S, Diekema DJ, et al. Effect of coinfection with GB virus C on survival among patients with HIV infection. N Engl J Med 2001;345:707-714.
Tillmann HL, Heiken H, Knapik-Botor A, et al. Infection with GB virus C and reduced mortality among HIV-infected patients. N Engl J Med 2001;345:715-724.
Yeo AET, Matsumoto A, Hisada M, Shih JW, Alter HJ, Goedert JJ. Effect of hepatitis G virus infection on progression of HIV infection in patients with hemophilia. Ann Intern Med 2000;132:959-963.
Bj?rkman P, Flamholc L, Nauclér A, Molnegren V, Wallmark E, Widell A. GB virus C during the natural course of HIV-1 infection: viremia at diagnosis does not predict mortality. AIDS 2004;18:877-886.
To the Editor: We agree with Williams and colleagues that GBV-C RNA in the plasma of HIV-infected patients could be a favorable marker for nonprogression of HIV disease, as we also recently observed.1 However, the key question concerning whether GBV-C has a direct anti-HIV role or whether its presence at detectable levels is a mere consequence of higher CD4+ T-cell counts still remains to be answered. In fact, since GBV-C replicates preferentially in CD4+ T cells, its clearance may theoretically be due to the HIV-induced reduction in the target cells. In the study by Williams et al., no significant beneficial effect was in fact observed at the early visits, when CD4+ T-cell counts and HIV viremia were not affected by the GBV-C status.
It would be of interest to evaluate the long-term effect of GBV-C coinfection on plasma HIV levels in patients with similar and constantly high levels of CD4+ T cells, in order to underline possible direct viral interference in vivo. We therefore believe that in vitro and in vivo studies should be conducted before GBV-C is considered as a prognostic or therapeutic tool for the care of patients with HIV infection.
Filippo Canducci, M.D.
Andriano Lazzarin, M.D.
Massimo Clementi, M.D.
Vita-Salute San Raffaele University
20131 Milan, Italy
canducci.filippo@hsr.it
References
Canducci F, Uberti Foppa C, Boeri E, et al. Characterization of GBV-C infection in HIV-1 infected patients. J Biol Regul Homeost Agents 2003;17:191-194.
The authors reply: Does GBV-C prolong survival in HIV-positive persons, or is it a marker of high CD4+ cell counts? In our study, men with HIV seroconversion who had persistent GBV-C viremia were 2.4 times as likely to survive as were persons who did not have viremia at either time point (95 percent confidence interval, 1.2 to 5.2; P<0.01), strongly supporting a causal role for GBV-C. The duration of HIV infection in men with and without GBV-C was the same, and the stage of HIV disease was not based on surrogate markers. Nevertheless, we found that the CD4+ cell count and the plasma HIV RNA concentration were related to GBV-C status. We also demonstrated prolonged survival in HIV-positive men with baseline CD4+ cell counts of less than 50 per cubic millimeter.1 The relative protection conferred by persistent GBV-C viremia in men with HIV seroconversion was greater than that observed for men who were heterozygous for the CC chemokine receptor 5 (CCR5) 32 polymorphism in the HIV coreceptor gene.2 As mentioned in the Discussion section of our article, we agree that it is important to determine whether the decline in CD4+ cells occurs before the clearance of GBV-C or whether the loss of GBV-C is associated with more rapid CD4+ cell decline. Ongoing studies in persons with HIV seroconversion should answer this question.
We also agree that demonstration of viral interference or other mechanisms to explain this epidemiologic association is important. We have previously shown that in vitro coinfection of lymphocytes with GBV-C and HIV results in decreased HIV replication.1 The HIV-inhibitory effect is mediated by the induction of beta-chemokines and the down-regulation of the HIV coreceptor CCR5,3 possibly as a result of interactions between GBV-C E2 protein and CD81.4 Furthermore, clinical studies have demonstrated decreased CCR5 expression on CD4+ lymphocytes4 and favorable type 1 and 2 helper-T-cell cytokine profiles among GBV-C–HIV coinfected people, as compared with those without GBV-C viremia.5 The combination of eight epidemiologic studies demonstrating a survival benefit in GBV-C–infected HIV-positive people, combined with growing evidence of interference between these two viruses, strongly suggests that in HIV-infected people there is a causal relationship between GBV-C and prolonged survival.
Jack T. Stapleton, M.D.
University of Iowa
Iowa City, IA 52242
jack-stapleton@uiowa.edu
Carolyn F. Williams, Ph.D.
National Institutes of Health
Bethesda, MD 20892
Jinhua Xiang, M.D.
Iowa City Veterans Affairs Medical Center
Iowa City, IA 52242
References
Xiang J, Wünschmann S, Diekema DJ, et al. Effect of coinfection with GB virus C on survival among patients with HIV infection. N Engl J Med 2001;345:707-714.
Stapleton JT, Williams CF, Xiang J. GB virus C: a beneficial infection? J Clin Microbiol (in press).
Xiang J, George SL, Wünschmann S, Chang Q, Klinzman D, Stapleton JT. GB virus C infection inhibits HIV-1 replication by increasing RANTES, MIP-1, MIP-1, and SDF-1. Lancet (in press).
Nattermann J, Nischalke HD, Kupker B, et al. Regulation of CC chemokine receptor 5 in hepatitis G virus infection. AIDS 2003;17:1457-1462.
Nunnari G, Nigro L, Palermo F, et al. Slower progression of HIV-1 infection in persons with GB virus C co-infection correlates with an intact T-helper 1 cytokine profile. Ann Intern Med 2003;139:26-30.