From Expert Review of Vaccines
Mélanie Lambotin; Heidi Barth; Christiane Moog; François Habersetzer; Thomas F Baumert; Françoise Stoll-Keller; Samira Fafi-Kremer
Posted: 09/07/2012; Expert Rev Vaccines. 2012;11(7):791-804. © 2012 Expert Reviews Ltd.
Abstract and Introduction
Abstract
It is estimated that 4–5 million HIV-infected patients are coinfected with HCV. The impact of HIV on the natural course of HCV infection is deleterious. This includes a higher rate of HCV persistence and a faster rate of fibrosis progression. Coinfected patients show poor treatment outcome following standard HCV therapy. Although direct antiviral agents offer new therapeutic options, their use is hindered by potential drug interactions and toxicity in HIV-infected patients under HAART. Overtime, a large reservoir of HCV genotype 1 patients will accumulate in resource poor countries where the hepatitis C treatment is not easily affordable and HIV therapy remains the primary health issue for coinfected individuals. HCV vaccines represent a promising strategy as an adjunct or alternative to current HCV therapy. Here, the authors review the pathogenesis of hepatitis C in HIV-infected patients, with a focus on the impact of HIV on HCV-specific immune responses and discuss the challenges for vaccine development in HIV–HCV coinfection.
Introduction
HIV-1 and HCV may cause persistent infections with long-term high-level viremia in spite of a specific immune response.[1] Both infections progress silently over several years, leading to the destruction of the immune system in the case of HIV-1 and liver cirrhosis in the case of HCV. Unlike HIV infection, HCV is spontaneously cleared in 25% of cases and curable in more than 50% of patients when treated with interferon (IFN)-based combination therapies.[2,3] Coinfection is frequent because of the shared risk factors for viral transmission, as HCV and HIV are both transmitted through exposure to blood and sexual exposure, although with different efficiencies. Recent epidemiologic and clinical studies showed that the introduction of HAART has improved the survival of HIV-infected patients, while HCV-associated liver diseases have become a leading cause of death in the coinfected population. The standard treatment for HCV infection in HIV–HCV-coinfected patients is similar to that of HCV-monoinfected patients, although significant toxicity is associated with pegylated IFN-α and ribavirin in coinfected patients.[4] Therefore, the development of new therapeutic and preventive strategies against HCV in HIV-infected individuals has become a priority. This review summarizes the current knowledge on the pathogenesis of hepatitis C in HIV-infected patients, with a focus on the impact of HIV on HCV-specific immune responses and discusses the challenges for HCV vaccine development in HIV–HCV coinfection.
Epidemiology of HCV in HIV-infected Individuals
More than 170 million individuals are chronically infected with HCV and 34 million people are living with HIV.[201] It is estimated that 4–5 million HIV-infected patients are coinfected with HCV,[5] with a predominance of HCV genotype 1 (50–80%).[6–9] Population-based data on the global geographic distribution of HIV–HCV coinfection are largely unavailable. The prevalence of HCV coinfection among HIV patients is associated with HIV risk factors.[5] The incidence of HCV is higher among injection drug users (IDUs; 72–95%),[10,11] probably due to the high transmissibility of HCV through parenteral exposure, whereas only 10–15% of HIV-positive patients who are not IDUs are coinfected with HCV.[5] However, several studies reported a rapid and significant rise in the incidence of HCV infection in HIV-positive non-IDU men who have sex with men (MSM), suggesting a sexual transmission of HCV.[12–15] A longitudinal cohort study reported a tenfold increase in the incidence of HCV infections among HIV-positive MSM after the year 2000 in Amsterdam (from 0.18/100 to 0.87/100 people per year).[13,14] Similar data were reported in London, where the estimated annual HCV incidence in HIV-positive MSM increased by 20% on average each year between January 2002 and June 2006.[12,13] Unprotected and anal sex with multiple partners, along with the presence of sexually transmitted infections (e.g., syphilis), were reported in these populations, confirming the permucosal transmission of HCV infection.[16] By contrast, the incidence of HCV infection remains low in HIV-negative MSM, heterosexuals with multiple partners and individuals at risk for sexually transmitted infections,[17] suggesting that the HIV infection may increase the susceptibility to HCV infection and facilitate HCV sexual transmission. The increased vertical transmission of HCV was reported in mothers coinfected with HIV. A meta-analysis of observational studies demonstrated that the risk estimate (odds ratio) of HCV vertical transmission was 2.82 (95% CI: 1.78–4.45; p = 0.00001) from anti-HCV-positive/HIV-positive coinfected mothers as compared with anti-HCV-positive/HIV-negative mothers, suggesting that maternal HIV coinfection increased the risk of HCV vertical transmission.[18] For these reasons, raising awareness and increasing screening are essential for preventing the transmission of HCV in HIV-infected individuals, especially among MSM.
Natural History of HCV Infection in HIV-coinfected Patients
HIV infection has deleterious effects on the natural history of HCV infection. After primary infection, approximately 25–30% of HCV-monoinfected patients spontaneously clear HCV, in comparison with only 15% of HIV–HCV coinfected patients.[19] A prospective longitudinal study conducted involving 112 HIV–HCV coinfected patients showed that spontaneous HCV clearance was associated with a rapid decline in viral load, being 2.2 log10 within 100 days versus 0.03 log10 in the case of HCV persistence (hazard ratio: 1.78; p < 0.0001) and high CD4+ T-cell count.[19] These data suggest that although coinfected individuals usually have persistent HCV infection, some are able to generate immunity against HCV and spontaneously clear the virus, indicating that HIV infection does not preclude vaccine-induced HCV-specific immunity.[2]
During chronic HCV infection, HIV–HCV-coinfected patients exhibit a higher HCV RNA load and more rapid progression to cirrhosis compared with HCV-monoinfected patients. Moreover, an increased number of end-stage liver complications were found in coinfected patients over the last decade.[20] In the French Germivic study, the rate of deaths related to HCV liver disease increased from 2 to 17% between 1995 and 2005.[21]
The course of HIV-1 infection varies from one individual to another, ranging from spontaneous control of viral load without HAART to rapid depletion of CD4+ T cells and progression to AIDS. The patients (1–5%) who are able to maintain very low levels of plasma viral loads over long periods of time without antiretroviral therapy are known as 'HIV controllers' (normally <1000 HIV-1 RNA copies/ml) or 'elite controllers' (<50 HIV-1 RNA copies/ml). The mechanisms by which elite controllers naturally control HIV infection are not yet completely understood. Several studies showed that these patients exhibit an unusually robust HIV-specific T-cell response.[22–24] However, the role of humoral immunity in the control of HIV replication is less clear, as neutralizing antibodies were found to be low in elite controllers. Moreover, non-neutralizing inhibitory antibodies were detected in elite controllers, these being correlated with low viral load or sustained CD4+ T-cell counts.[25] Recently, a link between the natural control of HIV infection and improved control of HCV replication was suggested in two studies. An increased spontaneous clearance of HCV was reported in a cohort of African–American HIV controllers infected with HCV genotype 1,[26] while a Spanish study suggested that Caucasian HIV controllers could better control HCV replication in terms of lower HCV viral load levels.[27] However, the limitations of these studies include their low patient numbers and cross-sectional designs. In 2002, Alatrakchi et al. compared T-cell responses to HIV and HCV in HIV-infected long-term nonprogressors (defined in this study as individuals with a lack of disease progression and low HIV replication levels).[28] These authors showed that, in addition to high Th1 cell frequencies directed against HIV-p24, long-term nonprogressors displayed significantly (p < 0.05) higher frequencies of Th1 cells against HCV as compared with HIV-positive progressors coinfected with HCV and HIV-negative HCV-infected patients. Immunological mechanisms by which HIV controllers partially control HCV infection deserve further investigations in order to develop future therapeutic strategies for HIV–HCV-coinfected patients.
Immunological Determinants of HCV Clearance
There is strong evidence that vigorous and sustained CD4+ and CD8+ T-cell responses against multiple HCV epitopes are associated with the spontaneous clearance of HCV infection.[29] Patients who cleared HCV infection were shown to exhibit strong HCV-specific CD4+ T-cell responses during the acute phase of infection.[30–33] By contrast, these responses were barely detectable in patients who subsequently developed persistent HCV infection.[34,35] The relevance of the CD4+ T-cell response was also demonstrated in selective depletion experiments in HCV-infected chimpanzees. CD4+ T-cell depletion suppressed protective CD8+ T-cell immunity upon rechallenge, leading to HCV persistence.[36] CD8+ T cells are the major effector cells of the antiviral response within the infected liver. The accumulation of HCV-specific CD8+ T cells in the liver coincides with the onset of liver disease and a rapid decline of viremia.[37] There is also mounting evidence that neutralizing antibody responses contribute to HCV clearance and protection. Recent data obtained from a well-characterized homogenous cohort of patients exposed to a single inoculum of HCV demonstrated a direct correlation between HCV clearance during acute infection and the rapid induction of neutralizing antibodies.[38,39] Furthermore, in vitro neutralization of the virus inoculum protected chimpanzees from HCV infection.[40,41] In contrast to antibody titers that decline to undetectable levels in many patients after HCV clearance, HCV-specific memory T cells remain detectable for decades in the blood and liver.[42,43] However, the occurrence of multiple episodes of HCV reinfection among individuals who are repeatedly exposed to HCV through injection drug use indicates that HCV-specific memory T cells are not sufficient to prevent HCV infection.[44] Although this data suggests that sterilizing immunity is difficult to achieve, the reduced risk of developing persistent infection upon viral re-exposure in frequently exposed individuals and chimpanzees[45] indicates that the immune system is able to develop a certain degree of protective immunity against HCV.[46–50] Thus, the goal of current vaccine strategies is to maximize the HCV-specific immunity by stimulating strong and cross-reactive CD4+ and CD8+ T cells as well as neutralizing antibodies to increase the likelihood of HCV clearance and thereby reducing the risk of developing chronic hepatitis C.
Approximately 60–80% of HCV-infected patients are not able to clear the infection and so develop chronic hepatitis. Viral- and host-specific factors appear to contribute to viral evasion and the failure of the immune system to control HCV infection.[29] First, HCV has a high rate of replication and lacks a proofreading function, thus allowing HCV to continuously escape the emerging cytotoxic CD8+ T-cell response and neutralizing antibody responses during chronic infection. Second, HCV-specific CD8+ T cells become functionally exhausted during chronic HCV infection, probably due to the constant HCV antigen stimulation. Third, HCV infection induces regulatory CD4+ T cells (Tregs), which are able to suppress HCV-specific effector T cells. It should be noted that in the case of HCV infection, the adaptive immune response induction is delayed for several weeks, which may be accounted for, by the tolerogenic environment of the liver[51] and the fact that HCV has developed successful strategies to attenuate the host type I IFN-mediated innate response. IFNs not only exhibit potent antiviral activity but also induce adaptive immune responses. The genetic background of the host also has a significant impact on the outcome of HCV infection. The HLA class I allele B27 and class II allele DR11 were found to be associated with HCV clearance,[52,53] suggesting the presence of protective HLA alleles. Of note, IL-28B polymorphisms, recently identified to be strongly associated with HCV treatment outcome, were shown to be significantly associated with spontaneous HCV clearance.[54,55]
Once HCV persistence is established, spontaneous clearance without any therapy is a rare event.[56] There have been reports of HCV clearance in the case of chronic infection after superinfection with other hepatitis viruses, such as hepatitis A, B or D,[57–60] suggesting that heterologous T-cell immunity triggered HCV-specific immune responses.[61] Preliminary insights into the immunological mechanisms leading to HCV clearance in the case of chronic HCV infection have been gained in a longitudinal study performed on a patient who spontaneously recovered from chronic HCV infection without any evidence of virus superinfection. In this report, HCV clearance was first associated with the appearance of neutralizing antibodies, followed by the reconstitution of HCV-specific T-cell immunity.[62] These findings support the immunotherapy of chronic infections as they suggest that T-cell dysfunction is reversible and capable of clearing the infection.
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