HIV and GB Virus C — Can Two Viruses Be Better Than One?
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《新英格兰医药杂志》
GB virus C (GBV-C), an RNA virus in the Flaviviridae family, is a close relative of the hepatitis C virus. Although it has been shown that many people worldwide are infected with this virus, no clear association between the virus and a known disease state has been demonstrated. GBV-C has been shown to replicate in human peripheral-blood mononuclear cells in vitro, and it commonly coinfects patients with human immunodeficiency virus (HIV). GBV-C is transmitted through predominantly parenteral routes and has a high seroprevalence among intravenous-drug users. Nonetheless, the sexual transmission of GBV-C has also been demonstrated recently. Infection with or carriage of the virus can be quite prolonged in many people, but most eventually clear the GBV-C RNA that is detectable in peripheral blood.
Over the past several years, there has been substantial controversy regarding the interactions between GBV-C and HIV in vivo. A number of studies have demonstrated a surprising survival benefit among patients who are coinfected, as compared with those who are infected with only HIV. Other studies, however, have not shown such a survival advantage. The article by Williams et al. in this issue of the Journal (pages 981–990) may settle certain aspects of this question. This thorough and well-performed analysis of data from the Multicenter Acquired Immunodeficiency Syndrome (AIDS) Cohort Study clearly demonstrates that five to six years after HIV seroconversion, patients were more likely to die if they were infected only with HIV than if they were coinfected with HIV and GBV-C. This significant survival advantage was not observed during the first 12 to 18 months after HIV seroconversion. This time dependence may account for the contradictory results of some studies regarding the protective effects of GBV-C in patients with HIV infection. As further evidence of the protective effect of dual infections, Williams et al. also demonstrated that the course of HIV disease was adversely affected by the clearance of GBV-C viremia.
The mechanism of this protective effect remains to be determined, and there are a number of possibilities (see Figure). Along with colleagues at the University of Catania (Sicily, Italy), we have shown that there is an alteration of the cytokine profile in patients who are dually infected: the levels of type 1 helper T (Th1) cytokines such as interleukin-2 are normal or elevated in patients who are coinfected, whereas in many patients who are chronically infected with HIV alone, there are increasing levels of type 2 helper T (Th2) cytokines (e.g., interleukin-4 and interleukin-10) and decreasing levels of Th1 cytokines. Changes in the helper T-cell response have been demonstrated to have a key role in the progression to AIDS in HIV-infected patients. Such patients have a normal or elevated Th1 cytokine profile early in the course of disease, and many have a shift in the ratio of the Th1 cytokine level to the Th2 cytokine level (with the Th2 level gradually becoming higher than the Th1 level) in association with progression to full-blown AIDS. Thus, the intact helper T cytokine profile in patients who are infected with both HIV and GBV-C may be at least one of the immune-based mechanisms responsible for the protective effect of dual infection. Further studies are necessary to determine whether the levels of T-cell subtypes themselves are altered by dual infection with GBV-C and HIV.
Figure. Molecular Interactions between HIV and GBV-C.
The possible mechanisms underlying the protective effects of GBV-C infection in patients who are also infected with HIV include the maintenance of a Th1-dominant cytokine profile rather than a Th2-dominant profile, the down-regulation of CCR5 and hence the inhibition of the entry and spread of HIV, the augmentation of innate intracellular immune mechanisms, and a decrease in the efficiency of the transcription of HIV from the integrated provirus.
In addition, some studies have suggested that HIV replication may be directly reduced by GBV-C. The fact that both HIV and GBV-C can infect and replicate within peripheral-blood mononuclear cells suggests that GBV-C and HIV have similar cell tropism, which could potentially allow the two viruses to interact either directly or indirectly, possibly through effects on the cell cycle. Various stages of the HIV life cycle may be affected by GBV-C. These include, in stepwise fashion, retroviral binding to target cells through the high-affinity receptor CD4 and several chemokine coreceptors, internalization and reverse transcription, integration into the host-cell genome to create the HIV provirus, viral transcription and translation, and viral morphogenesis and budding.
Although alterations in viral transcription and other mechanisms that inhibit HIV replication after the integration of the HIV provirus may be operative, some recent studies have suggested that GBV-C may actually block the entry of HIV into important cellular targets, such as CD4+ T lymphocytes and macrophages. In cell cultures, the GBV-C envelope protein E2 decreases entry of HIV by down-regulating a major chemokine coreceptor of HIV, CCR5. This down-regulation appears to result from the direct binding of GBV-C E2 to CD81 on CCR5+ cells, which, in turn, alters the quantity of CCR5 on the cell surface. In addition, certain beta-chemokines, especially RANTES (regulated upon activation normal T-cell expressed and secreted), may be up-regulated in patients with dual infection; E2 induces such an up-regulation in vitro. RANTES binds to CCR5 and thus may block viral entry directly or may act through the down-regulation of CCR5.
The two major subtypes of HIV have different patterns of use of coreceptors, with certain strains of virus using CCR5 to gain entry into cells, and others using CXCR4. CXCR4-tropic viruses have greater cytopathogenicity than CCR5-tropic viruses, along with a greater capacity to deplete CD4+ T lymphocytes. If GBV-C does block or down-regulate CCR5 in vivo, it appears not to induce a switch from a CCR5-tropic strain of HIV to a CXCR4-tropic strain. Such a shift might have been expected to occur as the virus mutated in order to use a new pathway for entry into the cell, and it would have led to a more rapid depletion of CD4+ T lymphocytes.
Recent studies have suggested that there are innate immune mechanisms that inhibit HIV, both early and late in the retroviral life cycle, in various types of cells in humans and nonhuman primates. GBV-C may also increase the levels or augment the activity of intracellular inhibitors of HIV internalization. In addition, GBV-C may have cell-specific effects in certain key cellular targets of HIV, including macrophages and dendritic cells. These types of cells have been shown to be critical in the pathogenesis of HIV disease and the dissemination of the virus throughout the infected person. Studies have demonstrated that variants of GBV-C differ with respect to tissue and cell-type tropism. It is important to determine whether only specific GBV-C strains exert a protective effect in HIV-infected persons. Some combination of the immune-based and direct antiviral effects described above may come into play in patients who are dually infected with HIV and GBV-C.
There is a long history of interactions between viruses whereby one virus augments the pathogenicity of another. Studies have suggested that various herpesviruses, including cytomegalovirus and herpes simplex virus types 1 and 2, may augment the transmission of HIV and the progression of the resultant disease. It is highly unusual to find an interaction between viruses that appears to be beneficial to patients who are dually infected. A greater understanding of the interactions between GBV-C and HIV may point to therapeutic approaches to mimicking the clinically protective effects of GBV-C in patients with HIV infection.
Source Information
From the Center for Human Virology and Biodefense, Division of Infectious Diseases and Environmental Medicine, Thomas Jefferson University, Philadelphia.(Roger J. Pomerantz, M.D.,)
Over the past several years, there has been substantial controversy regarding the interactions between GBV-C and HIV in vivo. A number of studies have demonstrated a surprising survival benefit among patients who are coinfected, as compared with those who are infected with only HIV. Other studies, however, have not shown such a survival advantage. The article by Williams et al. in this issue of the Journal (pages 981–990) may settle certain aspects of this question. This thorough and well-performed analysis of data from the Multicenter Acquired Immunodeficiency Syndrome (AIDS) Cohort Study clearly demonstrates that five to six years after HIV seroconversion, patients were more likely to die if they were infected only with HIV than if they were coinfected with HIV and GBV-C. This significant survival advantage was not observed during the first 12 to 18 months after HIV seroconversion. This time dependence may account for the contradictory results of some studies regarding the protective effects of GBV-C in patients with HIV infection. As further evidence of the protective effect of dual infections, Williams et al. also demonstrated that the course of HIV disease was adversely affected by the clearance of GBV-C viremia.
The mechanism of this protective effect remains to be determined, and there are a number of possibilities (see Figure). Along with colleagues at the University of Catania (Sicily, Italy), we have shown that there is an alteration of the cytokine profile in patients who are dually infected: the levels of type 1 helper T (Th1) cytokines such as interleukin-2 are normal or elevated in patients who are coinfected, whereas in many patients who are chronically infected with HIV alone, there are increasing levels of type 2 helper T (Th2) cytokines (e.g., interleukin-4 and interleukin-10) and decreasing levels of Th1 cytokines. Changes in the helper T-cell response have been demonstrated to have a key role in the progression to AIDS in HIV-infected patients. Such patients have a normal or elevated Th1 cytokine profile early in the course of disease, and many have a shift in the ratio of the Th1 cytokine level to the Th2 cytokine level (with the Th2 level gradually becoming higher than the Th1 level) in association with progression to full-blown AIDS. Thus, the intact helper T cytokine profile in patients who are infected with both HIV and GBV-C may be at least one of the immune-based mechanisms responsible for the protective effect of dual infection. Further studies are necessary to determine whether the levels of T-cell subtypes themselves are altered by dual infection with GBV-C and HIV.
Figure. Molecular Interactions between HIV and GBV-C.
The possible mechanisms underlying the protective effects of GBV-C infection in patients who are also infected with HIV include the maintenance of a Th1-dominant cytokine profile rather than a Th2-dominant profile, the down-regulation of CCR5 and hence the inhibition of the entry and spread of HIV, the augmentation of innate intracellular immune mechanisms, and a decrease in the efficiency of the transcription of HIV from the integrated provirus.
In addition, some studies have suggested that HIV replication may be directly reduced by GBV-C. The fact that both HIV and GBV-C can infect and replicate within peripheral-blood mononuclear cells suggests that GBV-C and HIV have similar cell tropism, which could potentially allow the two viruses to interact either directly or indirectly, possibly through effects on the cell cycle. Various stages of the HIV life cycle may be affected by GBV-C. These include, in stepwise fashion, retroviral binding to target cells through the high-affinity receptor CD4 and several chemokine coreceptors, internalization and reverse transcription, integration into the host-cell genome to create the HIV provirus, viral transcription and translation, and viral morphogenesis and budding.
Although alterations in viral transcription and other mechanisms that inhibit HIV replication after the integration of the HIV provirus may be operative, some recent studies have suggested that GBV-C may actually block the entry of HIV into important cellular targets, such as CD4+ T lymphocytes and macrophages. In cell cultures, the GBV-C envelope protein E2 decreases entry of HIV by down-regulating a major chemokine coreceptor of HIV, CCR5. This down-regulation appears to result from the direct binding of GBV-C E2 to CD81 on CCR5+ cells, which, in turn, alters the quantity of CCR5 on the cell surface. In addition, certain beta-chemokines, especially RANTES (regulated upon activation normal T-cell expressed and secreted), may be up-regulated in patients with dual infection; E2 induces such an up-regulation in vitro. RANTES binds to CCR5 and thus may block viral entry directly or may act through the down-regulation of CCR5.
The two major subtypes of HIV have different patterns of use of coreceptors, with certain strains of virus using CCR5 to gain entry into cells, and others using CXCR4. CXCR4-tropic viruses have greater cytopathogenicity than CCR5-tropic viruses, along with a greater capacity to deplete CD4+ T lymphocytes. If GBV-C does block or down-regulate CCR5 in vivo, it appears not to induce a switch from a CCR5-tropic strain of HIV to a CXCR4-tropic strain. Such a shift might have been expected to occur as the virus mutated in order to use a new pathway for entry into the cell, and it would have led to a more rapid depletion of CD4+ T lymphocytes.
Recent studies have suggested that there are innate immune mechanisms that inhibit HIV, both early and late in the retroviral life cycle, in various types of cells in humans and nonhuman primates. GBV-C may also increase the levels or augment the activity of intracellular inhibitors of HIV internalization. In addition, GBV-C may have cell-specific effects in certain key cellular targets of HIV, including macrophages and dendritic cells. These types of cells have been shown to be critical in the pathogenesis of HIV disease and the dissemination of the virus throughout the infected person. Studies have demonstrated that variants of GBV-C differ with respect to tissue and cell-type tropism. It is important to determine whether only specific GBV-C strains exert a protective effect in HIV-infected persons. Some combination of the immune-based and direct antiviral effects described above may come into play in patients who are dually infected with HIV and GBV-C.
There is a long history of interactions between viruses whereby one virus augments the pathogenicity of another. Studies have suggested that various herpesviruses, including cytomegalovirus and herpes simplex virus types 1 and 2, may augment the transmission of HIV and the progression of the resultant disease. It is highly unusual to find an interaction between viruses that appears to be beneficial to patients who are dually infected. A greater understanding of the interactions between GBV-C and HIV may point to therapeutic approaches to mimicking the clinically protective effects of GBV-C in patients with HIV infection.
Source Information
From the Center for Human Virology and Biodefense, Division of Infectious Diseases and Environmental Medicine, Thomas Jefferson University, Philadelphia.(Roger J. Pomerantz, M.D.,)