Crosstalk between HIV and hepatitis C virus during co-infection

A number of research groups have sought to determine how HIV infection affects HCV in individuals that are co-infected. Multiple studies have identified elevated IP-10 (CXCL10) levels as a negative prognostic indicator for both HCV infection and HIV and HCV co-infection [12‐14]. Further, elevated IP-10 levels were associated with the poor response to interferon/ribavirin therapy noted above [15]. IP-10 is a CXC chemokine that binds to the CXCR3 immune system receptor present on a number of cells, including monocytes, natural killer cells and T-cells [16]. Binding of IP-10 to CXCR3 induces chemotaxis of stimulated cells to sites of infection or injury. It is thought that elevated IP-10 could recruit T-cells from the periphery and within the liver, mediating the damage seen in cirrhosis and hepatocellular carcinoma [17]. The mechanism by which elevated levels of IP-10 may affect HCV infection in individuals with HIV and HCV co-infection is not known.

Work by Qu et al., published in BMC Immunology, describes a potential molecular mechanism for the influence HIV has on HCV infection in individuals with HIV and HCV co-infection. Specifically, Qu et al. present findings describing a potential cause-and-effect relationship between HIV infection and increased HCV replication. HIV tat is shown to increase levels of IP-10 mRNA and protein and consequently enhance HCV replication. Importantly, IP-10 induction by tat is shown to be necessary and sufficient to increase HCV replication levels. Their data further demonstrate a synergism in the ability of HIV and HCV to induce IP-10: hepatocytes that were both infected with HCV and treated with HIV tat induced higher levels of IP-10 mRNA and protein than either HCV infection or treatment with HIV tat alone.

It is challenging for many to imagine a situation in which both HIV and HCV would find themselves in the same cell and thus in a position to affect the replication of one another. However, specialized immune cells, called peripheral blood mononuclear cells and Kupffer cells, are sites of infection for both HIV and HCV and the possibility exists that both HIV and HCV could find themselves in the same cell in an individual with a co-infection [18]. Experiments should be carried out to determine if tat-induced IP-10 can affect HCV replication in Kupffer cells and peripheral blood mononuclear cells. However, an interesting implication of the work presented by Qu et al. is that HIV does not need to be present in the same cell to exert an effect on HCV infection. Both tat [19] and IP-10 can act on cells distant from the site of HIV infection.

The work by Qu et al. poses many intriguing and important questions. Certainly it is important to determine the mechanisms by which HIV upregulates IP-10 expression and, more importantly, how IP-10 enhances HCV replication. CXCR3 receptor expression is not known to be expressed on hepatocytes [16]; thus, in the experiments described by Qu et al., IP-10 may be acting through an as yet unknown mechanism. Additionally, it was recently shown that induced IP-10 in patients with HCV infection was expressed in a truncated, antagonist form [20]. Cellular proteinases responsible for the conversion of IP-10 to its antagonist form are presumably absent in the experiments performed by Qu et al. It will be interesting to determine which form is important in individuals who are co-infected and whether the antagonistic IP-10 has a similar influence on HCV replication as found in the paper.

There are reports of a genotype-specific response to HCV treatments [15] and it will be necessary to determine whether IP-10's effect on HCV is genotype specific. Similar experiments will need to be performed using multiple genotypes. Further, these findings will need to be addressed in an in vivo setting, such as a humanized mouse or primate model, to assess the relevance of these findings to the pathogenesis of HIV and HCV co-infection. IP-10 is the only chemokine examined by Qu et al.; however, multiple chemokines are found to be differentially regulated in individuals with HCV-associated liver disease [17]. It will be important to determine if other chemokines are able to enhance HCV replication as shown in the paper by Qu et al.

An important consideration for HIV co-infection studies is whether the effect measured is due to HIV or whether the effect can be attributed to the immunodeficiency that defines AIDS [1]. The relationship between HIV and pathogens such as HCV in individuals with a co-infection is not simply one of opportunism, whereby the immunodeficiency caused by HIV creates a situation in which normally non-pathogenic organisms can cause disease. Rather, the direct or indirect interplay between pathogens in individuals with co-infection is presumed to alter the normal progression of the disease seen in individuals with a mono-infection. In the study by Qu et al., individuals who had progressed to AIDS (as determined by CD4 and CD8 counts) were included in the cohort to show a correlation between HIV, HCV and IP-10 levels. It will be important in future experiments to exclude individuals with an immunodeficiency as this confounds the interpretation of the effect of HIV infection on HCV viral load and IP-10 levels in those individuals. The low CD4 counts are likely responsible for some increase in HCV replication and, perhaps, the IP-10 levels reported. Still, the finding that upregulation of IP-10 expression by HIV tat can enhance the replication of HCV illuminates IP-10 and HIV tat as targets for therapeutic intervention in individuals co-infected with HIV and HCV.