A Protective Effect against HIV - Assignment Example

Summary Numerous studies have speculated that Hepatitis G virus (HGV) or GB virus C (GBV-C) is capable of lowering HIV viral loads and slowing the progression of HIV disease into full blown AIDS, thereby reducing the mortality due to HIV infection. But the exact immunologic mechanisms are not clear. In contrast, the few studies that were conducted in African patients revealed that there is no such beneficial effect conferred by GBV-C. Another study on pregnant Tanzanian women showed that GBV-C does not protect against perinatal HIV acquisition in infants Some of the possible mechanisms, suggested by studies, of how GBV-C inhibits HIV include: inducing chemokines, down-regulating HIV coreceptor(s), influencing cytokine profiles, and other undefined effects on the host lymphocytes. Another study pointed out that GBV-C coinfection might not be the reason for prolonged survival in HIV-positive patients but that GBV-C probably serves only as a marker of some other factor related to HIV disease progression. GBV-C positive patients also seem to maintain a strong T-helper 1 cytokine and T-helper 2 cytokine profile, showed better efficacy and better survival after HAART therapy. The latest study, which focused on identifying the specific protein responsible for the cellular effects of GBV-C, found that GBV-C NS5A protein; a nonstructural phosphoprotein in GBV-C is the viral protein, which is responsible for inhibiting HIV-1 replication. However, there are numerous questions, which are unanswered, and more studies are required before any definitive conclusions can be reached. Introduction Hepatitis G virus (HGV) or GB virus C (GBV-C) is a recently identified RNA virus, which does not cause any detectable liver disease, and in fact, actually replicates in the bone marrow and spleen. It was observed that a coinfection of GBV-C in HIV patients could slow HIV disease progression; reduce the mortality due to HIV infection, and lower HIV viral loads. However, the exact mechanism of how GBV-C inhibits HIV is still not clear. The aim of this study was to explore if there was any direct correlation of a protective effect against HIV due to coinfection with GBV-C, and if so, to know the possible immunologic mechanisms involved in the process. This study was chosen because an effective cure for HIV and AIDS has proven to be still elusive. By knowing how exactly GBV-C inhibits HIV, a possible therapeutic cure for AIDS would be possible. Hepatitis G virus (HGV) or GB virus C (GBV-C) virology Hepatitis G virus (HGV) or GB virus C (GBV-C) is a RNA virus, which was recently identified. HGV belongs to the Flaviviridae family (Nunnari et al., 2003). The virus has a positive-stranded, linear RNA genome (Sarrazin, Roth & Zeuzem, 1998). The Genome has 9400 nucleotides, which encodes exactly 2900 amino acids (Heathcode & Feld, 2006.) The genome encodes two structural glycoproteins, which constitute the virus envelope proteins E1 and E2. The exact composition of the nucleocapsid has not been defined (Maidana, Sabino & Kallas, 2005). The GBV-C genome sequence and organization are closely related to hepatitis C virus (Stapleton JT, 2003) but they share only 27% of nucleotide homology, and are thus clearly distinct (Heathcode & Feld, 2006). No core protein has been identified (Stapleton JT, 2003) but biophysical and electron microscopic evaluation suggests that GBV-C has a nucleocapsid structure, presumably with a core protein (Heathcode & Feld, 2006) GBV-C also has nonstructural proteins designated as NS1, NS2 etc. The NS5A protein is involved with the double-strand RNA protein kinase and NS5B serves as the RNA-dependent RNA polymerase. The GVB-C virus can be grown in cell culture (Heathcode & Feld, 2006.) The 5 ‘ untranslated region (UTR) of GVB-C has four highly conserved domains, which suggests an important role for this region in viral replication, gene expression or both (Alter, Umemura & Tanaka, 2003.) The virus can be classified into five genotypes: genotype 1 (predominant in West Africa), genotype 2 (Europe and USA), genotype 3 (Asia), genotype 4 (Southeast Asia), and genotype 5 (South Africa) (Maidana, Sabino & Kallas, 2005.) There appears to be no relationship between GBV-C infection and the presence of liver pathology. The majority of patients do not have any detectable evidence of liver disease (Sehgal & Sharma, 2002). This is probably because GBV-C grows in lymphocytes and not in hepatocytes (Stapleton JT, 2003). Available evidence suggests that GBV-C is a lymphotropic virus, which mainly replicates in the bone marrow and spleen (Canducci et al., 2003.) Transmission of the virus is through contaminated blood and/or blood products, intravenous drug use, from mother to child, sexual route, and possibly via close social contacts (Halasz, Weiland & Sallberg, 2001). Vertical and horizontal transmission have also been reported (Sarrazin, Roth & Zeuzem, 1998) The prevalence of GBV-C in the general population is 2% (Sarrazin, Roth & Zeuzem, 1998) and 20% to 24% among intravenous drug abusers and higher in patients with HIV-1 infection (Nunnari et al., 2003). In high-risk groups with coinfection, the prevalence can be as high as 15 to 20% (Pujol, et al., 1998.) The virus particles are of very low density, and based on this, it is possible that GBV-C associates with lipids in human serum. The virus binds and enters target cells by using the low-density lipoprotein receptor. Immunocompetent individuals commonly display GBV-C clearance with the development of antibodies against the envelope glycoprotein E2 (Maidana, Sabino & Kallas, 2005.) The reverse transcription polymerase chain reaction (RT PCR) helps in the detection of GBV-C/HGV infection. The presence of E2-specific antibodies indicates a recovery from GBV-C/HGV infection (Sarrazin, Roth & Zeuzem, 1998). GBV-C RNA can also be detected by nucleic acid amplification systems and by the use of branched chain DNA assays (Maidana, Sabino & Kallas, 2005.) Protective effect of GBV-C coinfection in HIV disease There have been several reports about the possible beneficial effect that GBV-C coinfection can slow HIV disease progression, reduce the mortality due to HIV infection, and lower HIV viral loads (Canducci et al., 2003.) Several longitudinal studies indicate that GBV-C infection slows down the progression of HIV disease to AIDS and eventually to death. The presence of GBV-C RNA in the serum is accompanied with a lower viral load. This influence of GBV-C on HIV infection could either be due to a direct inhibition of HIV replication or by the enhancement of the immune system to cope better with the HIV infection. However, the exact mechanism of how GBV-C inhibits the progression to AIDS and eventual death has to be clarified (Tillmann & Manns, 2001) Xiang et al., (2001), examined the role of coinfection with GBV-C on the survival of 362 HIV infected patients. They also evaluated cultures of peripheral-blood mononuclear cells with coinfection of both viruses to determine whether GBV-C infection alters replication in vitro. Fifty-six percent of patients who tested negative for GBV-C RNA died during the follow-up period, compared to only 28.5 percent of patients with GBV-C viremia; clearly showing that the mortality rate among the 218 HIV-infected patients without GBV-C coinfection was significantly higher than the 144 patients with GBV-C coinfection. GBV-C coinfection inhibited the replication of HIV virus in cultures of peripheral-blood mononuclear cells. This was measured by the detection of p24 antigen in culture supernatants. However, GBV-C coinfection did not alter the surface expression of HIV cellular receptors on peripheral-blood mononuclear cells (determined by flow cytometry). The study thus concluded that GBV-C coinfection in HIV infected patients could improve the survival rate. Factors like the lower mortality rate, slower progression to AIDS, and longer survival once AIDS has developed, in GBV-C coinfection in HIV infected patients, were found to be independent of age, HIV-1 load, HCV load, CD4+ and CD8+ T cell counts, and CC chemokine receptor 5 (CCR5) genotype. Additionally, it was also found that the serum levels of interleukin-2 (IL-2), IL-12, IL-4, and IL-10 were stable over a period of time in the GBV-C RNA-positive group. In case of the GBV-C RNA negative group, there was a decrease in IL-2 and IL-12 (approximately 85% and 83%, respectively), whereas IL-4 and IL-10 were found to be increased (by 654 and 395%, respectively), thereby preserving a TH1 cytokine response (Maidana, Sabino & Kallas, 2005.) In order to assess the relation between GBV-C infection and the progression of HIV disease, one study (Tillmann et al., 2001) prospectively followed 197 HIV-positive patients. Of the total 197 patients, 33 (16.8 %) tested positive for GBV-C RNA, 112 (56.9 %) had detectable antibodies against the GBV-C envelope protein E2, and 52 (26.4 %) had no marker of GBV-C infection. In addition, in order to find if there was any correlation between GBV-C viral load and both the CD4+ cell count and the HIV load, a quantitative branched-chain DNA (bDNA) assay was performed on 169 GBV-C-positive plasma samples. The results showed that the GBV-C RNA positive patients had both a slower progression to AIDS and longer survival rates (P Read More