Fighting Virus With Virus, a New Trend?-->可可转移

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Editorial

Fighting Virus With Virus? GB Virus C and HIV Coinfections

Jeffrey Laurence, MD

[The AIDS Reader 11(11):539-540, 2001. ?2001 Cliggott Publishing Co., Division of SCP/Cliggott Communications, Inc.]







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In each of the past 2 editions of Wormser's textbook AIDS and Other Manifestations of HIV Infection, I've contributed a chapter entitled, "Viral cofactors in the immune pathogenesis and clinical manifestations of HIV infection."[1] The clinical impact of all of the cofactors I discussed is bad: exogenous factors typically enhanced the virulence of HIV. Facilitation of female-to-male HIV transmission in resource-poor countries may also involve concurrent infections, particularly with members of the herpesvirus family.[2]



The mechanisms for these interactions involve a multitude of cellular and immunologic factors[1,3]:





Activation of cellular targets.



Induction of proliferation in resting, latently HIV-

infected cells.



Induction of cytokines, which can transcriptionally activate HIV.



Induction of chemokines, which facilitate trafficking of cells to infected reservoirs.



Up-regulation of HIV receptors and coreceptors.



Coinfection of single cells, with direct transcriptional activation of HIV.



In the next edition of the textbook, I'll be including some good news about HIV cofactors. Two groups, 1 from Iowa[4] and 1 from Germany,[5] have confirmed an observation that is almost 7 years old. Back then, a new virus, GB virus C (GBV-C), was isolated from the blood of a 34-year-old surgeon, with the initials "GB," who had acute hepatitis. Simultaneously, as part of a search for agents other than the hepatitis C virus (HCV) that might be responsible for what used to be called non-A, non-B hepatitis, viral sequences were uncovered from an archival, early 1960s peripheral blood sample obtained from a surgeon who had acute, undiagnosed hepatitis.[6] That virus did not appear to be hepatotoxic and had no impact on the course of coinfections with known hepatitis viruses. It was of the same family as a "hepatitis G" virus described by others but was soon found to be identical to GBV-C.



GBV-C turned out to be a common, nonhepatotoxic RNA virus related genetically to HCV. But, remarkably, coinfection with HIV-1 and GBV-C appears to decrease HIV mortality.



The rate of progression of HIV infection usually parallels the level of replication of pathogenic forms of HIV. That such a direct correlation may not always be seen clinically -- a disconnection between CD4[+] T-cell counts and viral load can occur in some patients receiving antiretroviral therapy -- typically involves drug-resistant viral forms. Under continued pressure of antiretrovirals, these resistant forms can have a much reduced fitness. Indeed, a recent randomized study of the utility of viral load measurements in the long-term management of HIV disease concluded that more frequent HIV RNA evaluations than US Public Health Service guidelines recommend -- every 3 to 4 months rather than semiannually -- may be appropriate.[7]



In this multicenter trial, 206 HIV-positive patients with CD4 cell counts below 500/礚 were given antiretroviral therapy as dictated by their own physicians, without protocol restrictions. They were evaluated every 2 months. In addition, either frequent (baseline and every 2 months) or typical (baseline and every 6 months) HIV RNA testing was performed. A highly statistically significant maintenance of mean HIV RNA levels below 400 copies/mL, as well as undetectable viral levels, was seen in those tested frequently. There was also a trend toward improved survival in this group.[7]



The question now raised by the new studies with GBV-C is, Can an ostensibly nonpathogenic infectious agent itself decrease HIV viral load and affect survival?



GBV-C is approximately the same genome size as HIV, 9400 nucleotides. It is transmitted parenterally, vertically, and through sexual intercourse, and although it can replicate in myriad cells in vitro, in vivo reservoirs for infection are unknown.[6] Approximately 2% of voluntary blood donors and up to 20% of injection drug users in the United States have detectable levels of plasma GBV-C RNA.[4,6] It is not screened for in blood collections.



The 2 new studies of HIV show that mortality was reduced in those persons with detectable GBV-C. One study involved 197 HIV-positive patients, 33 with detectable GBV-C RNA, 112 anti-GBV-C antibody-positive, and 52 GBV-C negative, followed since 1993.[4] Survival and progression to AIDS were significantly longer in those with GBV-C markers. GBV-C positivity also correlated with a lower HIV viral load but not with higher CD4 cell counts. The second study involved 362 HIV-positive patients, 144 with GBV-C viremia, followed for a mean of 4.1 years.[5] Again, the mortality rate for those coinfected was significantly decreased. In the GBV-C group, 28.5% had died, compared with 56.4% of the controls (P < .001).



As with other infectious cofactors for HIV, it is unclear whether GBV-C is directly involved or simply a marker for something else. Nor is it clear, should this virus prove the sole active agent, whether it needs to coinfect the same cell to reduce HIV replication. Given the paucity of cells typically infected with HIV, this would be unlikely. It was also not addressed in in vitro experiments by Xiang and associates.[5] They showed that peripheral blood cells infected with HIV in vitro produced lower levels of HIV core antigen (p24) when GBV-C was added to the cultures, despite the fact that levels of HIV receptor, CD4, and coreceptors CXCR4 and CCR5 were not changed.



Potential mechanisms for in vitro and in vivo interactions between the 2 types of virus could involve all of the processes I described above for HIV stimulatory cofactors, from cytokines and chemokines to immune modulation and dampening of cell activation. Induction of interferon-a is a strong possibility, which was not explored in the GBV-C studies.



The irony of the GBV-C-HIV-1 coinfection phenomenon is that the 2 other prevalent hepatitis viruses, hepatitis B virus[8] and HCV,[9] are linked to increased morbidity and mortality in the setting of HIV. Clarification of the mechanism(s) for this interaction could be key to identifying new modes of HIV treatment. However, I was more than a bit disturbed to read commentaries about these findings in the lay press. Many implied an immediate application for GBV-C coinfection. An editorial accompanying publication of this work was much wiser: "Any suggestion that the intentional infection of persons with GBV-C be explored as a therapeutic approach for HIV infection is premature. Moreover, given that GBV-C frequently coexists with other pathogens, intentional infection by inoculation with peripheral blood from GBV-C-infected persons is inadvisable and inherently dangerous."[6] I'll keep you posted.





References

Laurence J. Viral cofactors in the immune pathogenesis and clinical manifestations of HIV infection. In: Wormser GP, ed. AIDS and Other Manifestations of HIV Infection. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 1998:151-160.

Bentwich Z, Maartens G, Torten D, et al. Concurrent infections and HIV pathogenesis. AIDS. 2000;14:2071-2081.

Clerici M, Butto S, Lukwiya M, et al. Immune activation in Africa is environmentally-driven and is associated with upregulation of CCR5. AIDS. 2000;14:2083-2092.

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.

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.

Stosor V, Wolinsky S. GB virus C and mortality from HIV infection. N Engl J Med. 2001;345:761-762.

Haubrich RH, Currier JS, Forthal DN, et al. A randomized study of the utility of human immunodeficiency virus RNA measurement for the management of antiretroviral therapy. Clin Infect Dis. 2001;33:1060-1068.

Scharschmidt BF, Held MJ, Hollander HH, et al. Hepatitis B in patients with HIV infection: relationship to AIDS and patient survival. Ann Intern Med. 1992;117:837-838.

Wright TL, Hollander H, Pu X, et al. Hepatitis C in HIV-infected patients with and without AIDS: prevalence and relationship to patient survival. Hepatology. 1994;20:1152-1155.









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Dr Laurence is professor of medicine and director of the Laboratory for AIDS Virus Research, New York Presbyterian Hospital-Weill Medical College of Cornell University, New York; senior scientific consultant for programs, American Foundation for AIDS Research (amfAR); and editor in chief of The AIDS Reader.