Curr Infect Dis Rep DOI 10.1007/s11908-010-0142-z
Current Views on the Pathophysiology of GB Virus C Coinfection with HIV-1 Infection Esaki Muthu Shankar & Pachamuthu Balakrishnan & Ramachandran Vignesh & Vijayakumar Velu & Palanisamy Jayakumar & Suniti Solomon
# Springer Science+Business Media, LLC 2010
Abstract GB virus C (GBV-C), a member of the Flaviviridae family of viruses, recently received considerable attention largely owing to its potential role in decelerating HIV-1 disease progression by interfering with HIV replication. With similar transmission features, GBV-C is parenterally transmitted, similar to the serum hepatitis viruses and HIV-1, and replicates in hemopoietic cells and T lymphocytes in particular, with no observable disease pathology. Progressive T-cell depletion and subsequent immune abrogation being the cardinal features of HIV-1 infection, accumulating evidence indicates that GBV-C effectively overturns HIV’s chances of exploiting the Tcell machinery and leads to enhanced survival rates of HIVinfected subjects. Much effort has been devoted to understanding the beneficial role of GBV-C in HIV disease. This review discusses recently proposed mechanisms underlying the pathophysiology of GBV-C coinfection in HIV disease. Keywords HIV-1 . GBV-C . Coinfection . T cells . Survival rates . Flaviviridae . Hepatitis E. M. Shankar (*) : P. Balakrishnan : R. Vignesh : S. Solomon Department of Infectious Diseases, YRG Centre for AIDS Research and Education, VHS Hospital Campus, IT Corridor, Taramani, Chennai 600 113, India e-mail:
[email protected] V. Velu Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA P. Jayakumar Antiretroviral Therapy Centre, Government Rajaji Hospital and Madurai Medical College, Madurai, India
Introduction Scientific observations pertinent to the existence of a systemic manifestation that prevents or ameliorates the severity of another disease have led to important therapeutic advancements, exemplified historically by Edward Jenner’s use of cowpox pustular lesions to prevent smallpox [1]. Research has shown that certain hemopoietic disorders, namely β-thalassemia and sickle cell anemia, effectively lessen the magnitude of pathology from malaria [2]. The concept is further exemplified by the notion that carriers of cystic fibrosis may confer genetic resistance to tuberculosis [3] and/or secretory diarrhea [4]. Similarly, it is believed that the natural immune mechanisms generated owing to leprosy could prevent psoriasis [5], and individuals with an X-linked agammaglobulinemia trait are resistant to infection with Epstein-Barr virus [6]. One study showed that active tuberculosis does not always increase HIV viral load, which further raises the possibility that more such diseases influencing coexisting conditions otherwise could exist [7]. For example, it has been documented that dengue virus could suppress HIV-1 viral load [8]. Interestingly, it was recently discovered that GB virus C (GBV-C; previously called hepatitis G virus) has been linked to slow progression of HIV disease [9, 10], reduction of HIV replication, and improved survival in HIV-infected individuals [11, 12]. Although it is known that HIV/AIDS is prevented or modified by co-receptor mutations (notably the CCRΔ32 chemokine mutation) [13], recent investigations provide provocative data supporting previous observations that coinfection with GBV is associated with a more favorable prognosis in HIV-positive patients. A Japanese team first published the effect of GBV-C during the course of HIV infection in 41 patients with hemophilia [14]. The study reported the detection of GBV-C viremia in
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11 (26.8%) individuals and, interestingly, the coinfected patients in their investigation had lower mean HIV RNA levels. Statistical analysis demonstrated an improved survival trend when progression to AIDS occurred [14]. The study findings generated immense interest among researchers to uncover the precise role of protection conferred by GBV-C in HIV infection. Subsequent studies also showed improved survival benefit among subjects who were coinfected compared with individuals infected with only HIV-1. One study also showed that GBV-C infection in injecting drug users persisted with no apparent clinical signs of any illness for years [15]. Thereafter, numerous attempts were made to link GBV-C with other disease pathologies, namely hepatocellular carcinoma, lichen planus, cryoglobulinemia, and some hematologic illnesses, which nonetheless failed to correlate with any specific disease manifestation. Despite being a persistent viral infection similar to hepatitis C, GBVC infection does not cause any overt disease pathology in the infected host [16], and a decrease in GBV-C viral loads has been associated with rapid disease progression and increased mortality rates [12]. Recent reports are also suggestive of improved initial response to antiretroviral regimens [17] and sustained suppression of HIV viral loads for prolonged periods [18]. Studies also associate the role of GBV-C in increasing interferon-γ (IFN-γ) and plasmacytoid dendritic cell (pDC) maturation to mediate innate antiviral immune responses in the host [19, 20]. The disease attributes underlying HIV-1/GBV-C coinfection need to be discussed in detail; therefore, we reviewed the published literature for recent research findings on the pathophysiology of GBV-C infection and its impact on HIV disease progression. GBV-C belongs to the family of Flaviviridae, and contains a single-stranded, positive-sense linear RNA genome that encodes a polyprotein that is posttranslationally cleaved into functional structural and nonstructural proteins. It has about 9,400 nucleotides and only one open reading frame. The structural proteins of GBV-C are E1 and E2, and the nonstructural protein-5 has two components, nonstructural phosphoprotein 5A (NS5A) and NS5B, the former required for infectivity and replication and the latter holding the polymerase functions [21]. GBVC, a close relative of the hepatitis C virus with about 30% similarity [22], is transmitted parenterally [23]. Mother-tochild and sexual routes have also been reported to play a prominent role in GBV-C transmission, similar to HIV-1 [23–27]. Interestingly, GBV-C and HIV-1 seem to be rarely co-transmitted [28]. A recent observational study suggested the possible transmission of maternal GBV-C during pregnancy and delivery. The study showed that maternal receipt of antiretroviral treatment increased the maternal transmission of GBV-C. However, the precise mechanisms whereby transmission of GBV-C is mediated remain to be determined [28].
GBV-C Replication GBV-C was widely believed to be a nonpathogenic, nonhepatotropic virus, and thus does not generally appear to multiply in hepatocytes or cause viral hepatitis [29]. Although researchers initially focused on revealing the hepatotropic association of GBV-C, it was subsequently found that the virus replicated in the peripheral blood mononuclear cells (PBMCs) [30]. Studies also showed in vitro replication of GBV-C in PH5GH, HuH-7, and HepG2 hepatic cell lines, albeit inefficiently [31]. Poor replication was also shown in T (MT-2 cells) and B (Daudi cells) cell lineages, and in primary phytohemagglutinin (PHA) and interleukin (IL)-2–activated PBMC cultures [31–34]. A full-length clone of GBV-C produced infectious virus that replicated in CD4+ T cells [32]. Subsequent studies documented that GBV-C also replicated in the bone marrow [34]. Recent lines of evidence also showed that GBV-C replicates in CD8+ and in CD19+ B lymphocytes in a more productive fashion [35]. Notably, GBV-C and HIV coinfection of lymphocytes also appears to inhibit the replication of R5- and X4-tropic HIV [11, 36, 37]. However, the exogenous addition of IL-2 and PHA to GBVC–infected lymphocyte cultures resulted in decreased GBV-C replication [38]. Although at present it is understood that spleen and bone marrow are the primary sites of replication [39], investigations are underway to completely exclude the role of other sites and cells, especially liver cells, as possible sites of replication. The mechanism of protective effects of GBV-C against HIV-1 has been explained in detail, although numerous other possibilities seem to exist [40]. A few of the potential pathophysiologic mechanisms whereby GBV-C confers protection in HIV-1 infection have been outlined here.
How GBV-C Cracks the Whip at HIV-1: Possible Mechanisms GBV-C Down-Regulates Chemokine Receptors to Interfere with HIV-1 Binding to T-Cell Surface It is known that HIV-1 primarily infects cells expressing CD4 molecule, and upon binding to CD4 receptors, makes use of the chemokine receptors CCR5 (on monocytes in the case of R5-tropic HIV-1) or CXCR4 (on CD4+ T cells in the case of X4-tropic viruses) to necessitate membrane fusion and viral entry. The natural ligands of CCR5 are the β-chemokines, namely macrophage inflammatory protein-1α (MIP-1α), and RANTES (regulated on activation, normal T-cell expressed and secreted), whereas stroma-derived factor-1 (SDF-1) and SDF-2 are the natural ligands for CXCR4. In cell cultures, GBV-C reportedly interferes with HIV-1 entry by downregulating CCR5, which appears to result from the direct binding of GBV-C E2 to CD81 on CCR5+ cells, which in
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turn alters the magnitude of CCR5 expression on the cell surface [41]. Recent studies conducted in 38 patients who had advanced HIV-1 disease with GBV-C coinfection showed reduced expression of CCR5 and CXCR4 coreceptors on CD4+ T cells, providing a possible molecular explanation for the clinical benefit of GBV-C coinfection in terminal HIV infection [42]. In addition, RANTES appears to be up-regulated in patients with dual infection [11]. GBV-C E2 reportedly induces the up-regulation of RANTES in vitro, and subsequently, RANTES binds to CCR5 to block viral entry directly or through CCR5 down-regulation. This mechanism is currently believed to contribute to the delayed progression of HIV infection among patients coinfected with HIV-1 and GBV-C. More recently, a study showed precisely how the GBV-C E2 domain disrupts HIV-1 membrane fusion and interferes with the HIV-1 infectivity in a dose-dependent manner, which might open up newer therapeutic options against HIV-1 [43]. Recent studies also showed that GBV-C may increase the levels or augment the activity of intracellular inhibitors of HIV internalization. SDF-1 was suggested to play a role in conferring entry inhibition by X4-tropic HIV-1 [11], although one study did not find any role of SDF-1 in regard to X4 virus internalization [36]. However, this study suggested that GBV-C stimulates CD4+ and CD8+ T cells to secrete and release antiretroviral factors that effectively could inhibit R5- and X4-tropic HIV-1 strains. Further, because no induction of SDF-1 and no down-regulation of CXCR4 were observed, the role of additional unidentified factors was suggested [36]. Xiang et al. [44] recently showed that that an 85-aa sequence of GBV-C NS5A induced RANTES production and inhibited HIV-1 viral replication, in vitro. Hence, it is clear to a certain degree that GBV-C could down-regulate chemokine receptors to interfere with HIV-1’s ability to bind to the T-cell surface, and the beneficial effect of GBV-C E2-specific monoclonal antibodies inhibiting HIV-1 replication in vitro is another encouraging finding [45, 46].
mediated by IL-13, IL-25, and IL-33 cytokines) and decreased levels of Th1 cytokines; suggestive of immune activation. Therefore, it appears that GBV-C effectively prevents the onset of immune activation by preserving the Th1 cytokine responses to effectively control viral levels [47]. Also, the ability of HIV and GBV-C to effectively infect PBMCs raises the possibility that the two viruses could interact either directly or indirectly to affect the cell cycle, and that at some point, GBV-C interferes with the life cycle of the retrovirus intracellularly, possibly by inhibiting HIV-1 transcription.
Does GBV-C Preserve Th1 Cytokine Profile to Prevent Immune Activation?
Magnitude of cellular activation is one potential mechanism recently proposed to be associated with protection in GBVC–HIV-1 coinfected individuals. One study investigated the imprints of T-cell activation and found a positive correlation between HIV-1 viral load and the percentage of T cells positive for CD38 and CD8 [51]. The study also showed that GBV-C viremic patients had a lower percentage of T cells positive for CD38-CD4, CD38-CD8, CCR5-CD4, and CCR5-CD8 compared to HIV-1–infected patients who were nonviremic for GBV-C. The study hypothesized the possible association between GBV-C replication and lower T-cell activation as a potential mechanism involved in conferring protection against HIV disease progression. Hence, the role of GBV-C in modulating T-cell activation
GBV-C interference with HIV-1 is also believed to be linked to alterations in the levels of cytokines, as observed in dually infected patients. It is known that changes in Thelper (Th) responses play a cardinal role in progression to terminal HIV disease. AIDS is characterized by a Th2 polarized state rather than Th1, and excessive immune activation. Interestingly, findings suggest that the levels of Th1 cytokines, notably IL-2, are reportedly elevated in GBV-C–HIV coinfected subjects [47], whereas those who are chronically infected with HIV alone generate increased levels of Th2 cytokines (possibly owing to Th2 polarization
Does GBV-C Control HIV-1 Dominance by Increasing Interferon Levels? Two distinct subpopulations of circulating dendritic cells (DCs) have been identified based on their cellular phenotype: myeloid-derived DCs (mDC) and lymphoid-derived pDC. The latter, termed natural IFN-α–producing cells, are the major producers of type 1 IFNs in response to different microbial products. pDC are highly susceptible to HIV infection in vitro [48]. Reduced pDC and impaired function have been reported in HIV infection, and pDC could also be killed by the virus [49]. Recent studies showed that HIV-1 patients coinfected with GBV-C have a higher percentage of CD80+ mature pDCs, which might contribute to effective control of HIV-1 [50]. Evidence also exists that GBV-C infection in HIV-infected patients could lead to the activation of IFN genes [19]. Investigations of GBV-C–positive and GBV-C–negative HIV-infected patients showed that the expression of IFN genes 2-5-OAS, MxA, IFN AR-1, and PKR were relatively increased in HIV–GBV-C coinfected cases. Although studies have associated the role of increased IFN-γ in GBV-C infection [19], it remains to be thoroughly seen if GBV-C enhanced type-1 interferons by pDCs, which possibly could confer HIV-1 protection correlates. Possible Role of GBV-C in Modulating T-Cell Activation
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to downplay HIV-1’s ability to infect activated T cells can be another area of investigation. Role of GBV-C in Preventing Fas-Mediated T-Cell Apoptosis Fas-mediated apoptosis results when Fas ligand (FasL or CD95L) on activated T cells binds to Fas (CD95) receptor. T cells are resistant to Fas-mediated apoptosis during clonal expansion, but become progressively more sensitive after activation, ultimately resulting in activation-induced cell death. This event prevents an exaggerated immune response and eliminates autoreactive T cells. Cross-linking of FasL to Fas triggers apoptosis on the target cell. Recent studies showed that GBV-C–infected cells expressed relatively lesser Fas mRNA [52]. These findings raise the possibility that GBV-C could interfere with apoptosis in the T cells of HIV-coinfected patients. This possibility could be the
explanation behind the increased levels of CD4+ T cells in coinfected individuals, as suggested by the researchers [52].
GBV-C and HIV-1 Elite Controllers: Any Possible Association? Elite suppressors are a subgroup of HIV-1–infected individuals who, in spite of antiretroviral treatment, maintain undetectable viral loads while at the same time maintaining normal CD4+ T-cell counts for prolonged periods. The association of potential mechanisms of viral control and CD4+ T-cell maintenance is still elusive. A recent case– control study investigated if GBV-C coinfection was associated with HIV control in 14 progressively infected patients and 14 elite controllers [53•]. Unfortunately, the findings failed to associate the role of GBV-C and elite suppression mechanism (Table 1).
Table 1 Summary of potential pathophysiologic mechanisms whereby GB virus C confers protection in HIV-1 infectiona Molecule/ factor
Functions in HIV-1 infection
GBV-C coinfection
Negative effect on HIV-1
CCR5
Coreceptor for binding by R5-tropic strains of HIV-1 (can also be cellular activation marker) Coreceptor for binding by X4-tropic strains of HIV-1 (can also be cellular activation marker) Chemokines that act as natural ligands of CCR5
Down-regulation
Because of down-regulation of CCR5, HIV-1 cannot effectively bind to target cells and resists viral entry
Down-regulation
Because of down-regulation of CXCR4, HIV-1 cannot effectively bind to target cells and resists viral entry
Up-regulation
MIP-1a
Chemokines that act as natural ligands of CCR5
Up-regulation?
SDF-1
Chemokines that act as natural ligands of CXCR4
Up-regulation?
pDC
Principal producers of type-1 IFN (IFN-α and IFN-β)
Increased cell levels
IFN genes
Viral restriction
IFN-γ
Enhances macrophage functions, NK cell functions, and IL-4 suppression Cross-linking of FasL to Fas triggers apoptosis on the target cell
Increased expression of interferon genes 2-5-OAS, MxA, IFN AR-1, and PKR Increased expression and production?
Because of prior binding of RANTES to CCR5 coreceptors, HIV-1 may not gain access to CCR5 binding sites, which resists viral entry Because of prior binding of RANTES to CCR5 coreceptors, HIV-1 may not gain access to CCR5 binding sites, which resists viral entry Because of prior binding of RANTES to CXCR4 coreceptors, HIV-1 may not gain access to CXCR4 binding sites, which resists viral entry Produces enormous levels of type 1 IFN (and proinflammatory cytokines), which mount an efficient innate response against HIV-1 infection Viral control?
CXCR4
RANTES
Fas receptor
Th1 polarization a
Enhances antiviral immunity (and impedes disease progression?)
Decreased Fas gene expression?
Sustained Th1 status
Intracellular viral control
GBV-C could interfere with T-cell apoptosis in HIV coinfection, which possibly could explain the increased CD4+ T-cell levels in coinfected individuals Effective viral control and host responses
As evident from published findings and hypothesized mechanisms.
CCR CC chemokine receptor; CXCR CXC chemokine receptor; GBV-C virus C; IFN interferon; IL interleukin; MIP macrophage inflammatory protein; NK natural killer; pDC plasmacytoid dendritic cell; RANTES regulated on activation, normal T-cell expressed and secreted; SDF-1 stroma-derived factor-1; Th T helper.
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Conclusions In many interactions between viruses, one virus augments the pathogenicity of another. For example, herpes viruses, including cytomegalovirus and herpes simplex virus types 1 and 2, may augment the transmission of HIV and the progression of the resultant disease. Although numerous infectious agents (eg, Mycobacterium tuberculosis, Mycobacterium avium-intercellularae-scrofulaceum, Mycoplasma penetrans, Mycoplasma fermentans, Mycoplasma pirum, Mycoplasma genitalium, Mycoplasma hominis, Cryptococcus neoformans, and others) have been associated with rapid disease progression, it is highly unusual for a virus to be beneficial for humans, and it is generally rare to find an interaction between viruses that appears to be beneficial to patients who are dually infected [54]. The recent findings by Xiang et al. [55] that the inhibitory effect on HIV was conserved among other flaviviruses (by expressing the NS5 proteins of GBV-C, DV, hepatitis C virus, West Nile virus, and yellow fever virus) in CD4+ T cells is particularly encouraging. Hence, we have valid mechanisms currently available to clearly justify the beneficial role of GBV-C coinfection in HIV disease, and thus it is now possible, to a certain extent, to measure the protection attributes conferred by GBV-C. Although the mechanisms for the protective effect of GBV-C may involve modulation of coreceptor expression, enhanced cytotoxicity, or activation of innate immune components, the precise mechanism whereby the interaction between the viruses inside the cellular compartment is effected needs to be elucidated further. An especially interesting area of investigation would be the protection correlates and viral control attributes of exposed seronegative individuals, long-term nonprogressors and elite suppressors, and the association of GBV-C in these subsets of HIVinfected individuals. A greater understanding of the interactions between GBV-C and HIV-1 may point to therapeutic approaches to mimic the clinically protective effects of GBV-C in patients with HIV infection.
Disclosure No potential conflicts of interest relevant to this article were reported.
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