Interactions Between HIV and HCV in Hemophiliacs

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The human immunodeficiency virus type 1 (HIV-1) frequently infected hemophiliacs who received non-heat-treated clotting factor concentrates prior to 1985. In addition, these individuals were universally infected by hepatitis C virus (HCV) with >80% remaining chronically infected by this agent. Thus, hemophiliacs represent an important population for studies of the natural history of these chronic viral infections. Moreover, the high rate of co-infection makes it an ideal group for assessing the interaction between the viruses and the relationship between viral-specific immune responses and clinical progression. Although the hemophiliac population is unique, co-infection by these chronic viral pathogens is becoming increasingly common, particularly amongst intravenous drug users, who account for approximately 25% of the epidemic in the United States. We have investigated issues related to HIV-1 and HCV immunopathogenesis by studying children and adolescents enrolled in the Hemophilia Growth and Development Study (HGDS). The HGDS enrolled 333 hemophiliacs between 1989 and 1990 and followed them for 7-8 years. This multicenter, United States study represents a well-characterized, prospectively followed cohort of HCV-infected hemophiliacs, of whom 207 are HIV-1 co-infected. However, it was not known how HCV coinfection affects the natural history of HIV-1 progression. A total of 332 hemophiliacs had 1-8 repeated annual HCV RNA measurements between baseline and 7 years of follow-up. CD4+ cells and plasma HCV RNA were measured annually in all subjects, and plasma HIV RNA was measured annually in the HIV-infected subjects. HIV and HCV RNA levels were quantified using second generation Chiron bDNA assays. Not unexpectedly, we found that baseline HCV RNA was higher in HIV-infected children than in uninfected groups (p=0.0001). There were significant correlations between baseline CD4+ cell number, HIV RNA and HCV RNA: higher absolute CD4+ T cells were correlated with lower HCV RNA while higher HCV RNA was strongly correlated with high HIV viral load. We found a significant association between HCV viral load and rate of progression to AIDS: after controlling for HIV RNA, CD4+ T cells, and antiviral therapy, for every 10-fold increase in baseline HCV RNA, there was a 1.60 increase in the relative hazard for progression to AIDS. We also observed that HCV clearance rates are significantly lower in children with HIV coinfection. This study demonstrates that HCV is an independent predictor of HIV clinical progression and suggests that therapeutic interventions to lower HCV viral load should be investigated in coinfected patients. We are now investigating the role of viral-specific immunologic responses in controlling HIV-1 and HCV replication and how these responses are regulated by the immune system. Genetic polymorphisms that affect T cell differention may influence Th1/Th2 balance and the effectiveness of the immune system in mounting a cytotoxic response to specific HIV-1 and HCV epitopes. We have identified single nucleotide polymorphisms in regulatory or noncoding regions of cytokines known to have a role in determining Th1/Th2 states. These will be analyzed for associations with specific immune responses to viral peptides.