Correspondence
GB Virus C and Mortality from HIV Infection
N Engl J Med 2002; 346:377-379January 31, 2002
- Article
To the Editor:
The reports of Xiang et al.1 and Tillmann et al.2 (Sept. 6 issue) further document that coinfection with the apparently nonpathogenic flavivirus GB virus C (GBV-C, or hepatitis G virus) prolongs survival in patients infected with the human immunodeficiency virus (HIV). As the accompanying editorial3 emphasizes, there are no causal inferences to be drawn from these observations, and the suggestion that therapy with GBV-C might improve survival among HIV-infected patients is correctly labeled as “premature.” Although viral cross-talk of this sort has been described in a number of other experimental systems,4 there are other possible explanations for the “protective” effect. For example, a potent cytotoxic-T-lymphocyte response to one viral infection may reduce the level of cytotoxic-T-lymphocyte activity directed to infection by a second virus.5 Persons who have a strong cytotoxic-T-lymphocyte response to HIV may have more difficulty mounting such a response to GBV-C and may thus be less likely to clear GBV-C infection. Tillmann et al. demonstrate no clear protective effect of exposure to GBV-C (as determined by a test for anti-E2 antibodies) but do demonstrate an obvious “protective” effect in those in whom GBV-C RNA was detected. Failure to clear active GBV-C infection may thus be an indirect marker of a particularly potent cytotoxic-T-lymphocyte response to HIV. This hypothesis, which can be readily tested, predicts that “therapeutic” coinfection with GBV-C would have no benefit for HIV-infected patients.
5 ReferencesDonald E. Mosier, Ph.D., M.D.
Francis V. Chisari, M.D.
Scripps Research Institute, La Jolla, CA 92037
dmosier@scripps.edu 1
Xiang J ,Wunschmann 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
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Tillmann H ,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
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Stosor V ,Wolinsky S . GB virus C and mortality from HIV infection. N Engl J Med 2001;345:761-762
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Cavanaugh VJ ,Guidotti LG ,Chisari FV . Inhibition of hepatitis B virus replication during adenovirus and cytomegalovirus infections in transgenic mice. J Virol 1998;72:2630-2637
Web of Science | Medline5
Selin LK ,Vergilis K ,Welsh RM ,Nahill SR . Reduction of otherwise remarkably stable virus-specific cytotoxic T lymphocyte memory by heterologous viral infections. J Exp Med 1996;183:2489-2499
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To the Editor:
We are concerned that the analysis of Xiang et al. may not have taken into account the changes that occurred in the management of HIV between 1988 and 2000. These changes have dramatically decreased mortality from HIV. On the basis of the data presented in the article by Xiang et al., we calculate that 27 of the 144 patients with GBV-C viremia (19 percent) enrolled in the study before 1990, as compared with 67 of the 218 patients without GBV-C viremia (31 percent, P=0.005). It is unclear how the investigators adjusted for this difference. The conclusion regarding improved survival may be confounded by the era of HIV therapy.
Alexander R. Macalalad, M.D.
David R. Snydman, M.D.
New England Medical Center, Boston, MA 02111
amacalalad@lifespan.org To the Editor:
In cases of coinfection with hepatitis C virus (HCV) and HIV, differences in the progression of HIV infection according to the HCV genotype have been reported.1 Three studies of GBV-C and HIV — those of Yeo et al.,2 Xiang et al., and Tillmann et al. — included patients from the United States and Europe. However, data on GBV-C genotypes were not reported. An analysis of the association between coinfection with various GBV-C genotypes and the progression of HIV disease might help to explain the mechanism underlying the delayed development of AIDS in patients coinfected with HIV and GBV-C.
2 ReferencesJunki Takamatsu, M.D.
Hidenori Toyoda, M.D.
Yoshihide Fukuda, M.D.
Nagoya University School of Medicine, Nagoya 466-8550, Japan
jtkmtsu@med.nagoya-u. ac. jp 1
Sabin CA ,Telfer P ,Phillips AN ,Bhagani S ,Lee CA . The association between hepatitis C virus genotype and human immunodeficiency virus disease progression in a cohort of hemophilic men. J Infect Dis 1997;175:164-168
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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
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Macalalad and Snydman question whether changes in the management of HIV confounded our analysis, especially since there were fewer patients with GBV-C viremia than patients without GBV-C viremia enrolled before 1990. We do not believe that such confounding occurred, since we found no significant difference between the patients with and those without GBV-C viremia in terms of the proportion who began receiving care in the era before highly active antiretroviral therapy became available (84 percent vs. 89 percent, P=0.20). However, to address this issue, we stratified the patients according to the time of entry into the clinic and repeated the Cox proportional-hazards analysis with adjustment for the same prognostic variables. The association between GBV-C viremia and improved survival was significant for patients who began receiving care both before 1990 and after 1990. This relation held regardless of which year between 1990 and 1994 was chosen as the cutoff for stratification. We also conducted an analysis excluding the patients who began receiving care before 1990 and including only those whose care began between 1990 and 1996 to exclude any effect of highly active antiretroviral therapy. This analysis confirmed the association between GBV-C viremia and improved survival (adjusted relative risk of death for patients who were GBV-C–negative, 3.5 [95 percent confidence interval, 2.2 to 5.7]).
Takamatsu and colleagues question whether differences in GBV-C genotype might explain the underlying mechanism of delayed progression of HIV disease in persons coinfected with GBV-C. All of our GBV-C isolates tested to date with use of the method of Naito and Abe1 were of genotype 2, reflecting the geographic origin of our patients. Given the low level of variation in amino acid sequences observed in different geographically and phylogenetically defined groups of viruses,2 it seems unlikely that there are substantial biologic differences between genotypes that would explain the underlying mechanism of the association we observed.
Mosier and Chisari question whether GBV-C viremia is a marker of reduced GBV-C–specific cytotoxic-T-lymphocyte responses that occur as a result of a potent HIV-specific cytotoxic-T-lymphocyte response, which is ultimately the reason for the delayed progression of HIV disease. Our studies do not rule out the possibility of altered immunologic responses to HIV or GBV-C in coinfected persons, and differences in host cytokines and chemokines are probably involved in the varying rate of progression of HIV disease among infected persons. However, our in vitro model of coinfection demonstrated diminished HIV replication in the presence of GBV-C infection, strongly suggesting that GBV-C replication has an effect on HIV replication that is independent of cytotoxic-T-lymphocyte responses.
2 ReferencesJack T. Stapleton, M.D.
Daniel J. Diekema, M.D.
Jinhua Xiang, M.D.
University of Iowa College of Medicine, Iowa City, IA 52242
jack-stapleton@uiowa.edu 1
Naito H ,Abe K . Genotyping system of GBV-C/HGV type 1 to type 4 by the polymerase chain reaction using type-specific primers and geographical distribution of viral genotypes. J Virol Methods 2001;91:3-9
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Smith DB ,Cuceanu N ,Davidson F , et al. Discrimination of hepatitis G virus/GBV-C geographical variants by analysis of the 5' non-coding region. J Gen Virol 1997;78:1533-1542
Web of Science | Medline
Author/Editor Response
We agree with Mosier and Chisari that the reason for slower progression of disease in HIV-infected patients who also harbor GBV-C still needs to be identified. Although we favor the theory that GBV-C has a direct role in ameliorating HIV infection, we cannot rule out the possibility that GBV-C is only a marker of a factor that has yet to be identified. One such factor could be a potent cytotoxic-T-lymphocyte response against HIV associated with a weak cytotoxic-T-lymphocyte response against GBV-C, as suggested by Mosier and Chisari. In that case, however, one would expect to find more rapid progression among anti-E2–positive patients than among patients who had not been exposed to GBV-C. Furthermore, on the basis of the data indicating that HIV replication is reduced by coinfection with GBV-C in vitro, a direct interaction of the two viruses seems likely. Still, the cytotoxic-T-lymphocyte responses to HIV and GBV-C antigens must be investigated. Our ongoing work includes the analysis of immune responses.
Takamatsu et al. raise the issue of GBV-C genotypes, which we are also studying. The effect of coinfection with various HCV genotypes in HIV-positive patients is controversial.1 Furthermore, none of the studies analyzing the relevance of the HCV genotype to the effect of coinfection on HIV have taken into account coinfection with GBV-C. Thus, these issues must be clarified in the light of new information on coinfection with GBV-C and HIV.
1 ReferencesHans L. Tillmann, M.D.
Reinhold E. Schmidt, M.D.
Michael P. Manns, M.D.
Medizinische Hochschule Hannover, D-30623 Hannover, Germany
tillmann@tx-amb.mh-hannover. de 1
Piroth L ,Bourgeois C ,Dantin S , et al. Hepatitis C virus (HCV) genotype does not appear to be a significant prognostic factor in HIV-HCV-coinfected patients. AIDS 1999;13:523-524
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- Citing Articles (10)
Citing Articles
1
Silvia Pérez-López, Marina Nieto-Suárez, Concepció Mestres, M. Asunción Alsina, Isabel Haro, Nuria Vila-Romeu. (2009) Behaviour of a peptide sequence from the GB virus C/hepatitis G virus E2 protein in Langmuir monolayers: Its interaction with phospholipid membrane models. Biophysical Chemistry 141:2-3, 153-161
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W Zhang, K Chaloner, HL Tillmann, CF Williams, JT Stapleton. (2006) Effect of early and late GB virus C viraemia on survival of HIV-infected individuals: a meta-analysis. HIV Medicine 7:3, 173-180
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A. Scott Muerhoff, George J. Dawson, Suresh M. Desai. (2006) A previously unrecognized sixth genotype of GB virus C revealed by analysis of 5′-untranslated region sequences. Journal of Medical Virology 78:1, 105-111
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M. A. Sathar, H. M. Coovadia. (2005) Reply to Martini et al. Clinical Infectious Diseases 40:2, 328-329
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Williams, Carolyn F., Klinzman, Donna, Yamashita, Traci E., Xiang, Jinhua, Polgreen, Philip M., Rinaldo, Charles, Liu, Chenglong, Phair, John, Margolick, Joseph B., Zdunek, Dietmar, Hess, Georg, Stapleton, Jack T., . (2004) Persistent GB Virus C Infection and Survival in HIV-Infected Men. New England Journal of Medicine 350:10, 981-990
Full Text6
Mahomed A. Sathar, Denis F. York, Eleanor Gouws, Anna Coutsoudis, Hoosen M. Coovadia. (2004) GB Virus Type C Coinfection in HIV‐Infected African Mothers and Their Infants, KwaZulu Natal, South Africa. Clinical Infectious Diseases 38:3, 405-409
CrossRef7
A. Scott Muerhoff, Hans L. Tillmann, Michael P. Manns, George J. Dawson, Suresh M. Desai. (2003) GB Virus C genotype determination in GB Virus-C/HIV co-infected individuals. Journal of Medical Virology 70:1, 141-149
CrossRef8
Sarah L. George, Sabina Wünschmann, James McCoy, Jinhua Xiang, Jack T. Stapleton. (2002) Interactions between GB virus type C and HIV. Current Infectious Disease Reports 4:6, 550-558
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Markus Birk, Stefan Lindbäck, Christer Lidman. (2002) No influence of GB virus C replication on the prognosis in a cohort of HIV-1-infected patients. AIDS 16:18, 2482-2485
CrossRef10
Zabrina L Brumme, Keith J Chan, Winnie WY Dong, Theresa Mo, Brian Wynhoven, Robert S Hogg, Julio SG Montaner, Michael V O'Shaughnessy, P Richard Harrigan. (2002) No association between GB virus-C viremia and virological or immunological failure after starting initial antiretroviral therapy. AIDS 16:14, 1929-1933
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