Megan Crane

Immunopathogenesis of hepatic flare in HIV/hepatitis b virus (Hbv)-coinfected individuals after the initiation of Hbv-active antiretroviral therapy

BACKGROUND The pathogenesis of and risk factors for hepatic flare (HF) after the initiation of hepatitis B virus (HBV)-active antiretroviral therapy (ART) in HIV/HBV-coinfected individuals is not well understood. METHODS We studied HF in ART-naive HIV/HBV-coinfected individuals in Thailand (n = 36) who were beginning HBV-active ART as part of a prospective clinical trial. HF was defined as an alanine aminotransferase (ALT) level>5 times the upper limit of normal or >200 IU/L higher than that at baseline. Immune mediators (interleukin [IL]-18, IL-2, IL-6, IL-8, IL-10, soluble CD26 [sCD26], sCD30, sCD8, CXCL-10, CCL-2, tumor necrosis factor-alpha, interferon [IFN]-gamma, and IFN-alpha) and activated NK cells were quantified. RESULTS HBV DNA and ALT levels at baseline were higher in patients with HF (n=8) than in patients without HF (n=28) (P=.01). After the initiation of ART, CXCL-10 levels remained elevated in patients with HF but decreased in patients without HF (P<.01). sCD30 levels increased and were significantly higher at week 8 in patients with HF (P<.05). There was a positive correlation between levels of ALT and levels of CXCL-10, sCD30, CCL-2, and IL-18 at week 8 (the time of peak ALT level) but not at other time points. CONCLUSION Elevated HBV DNA and ALT levels before the initiation of HBV-active ART are risk factors for HF. The pathogenesis of HF after the initiation of HBV-active ART is probably consistent with immune restoration disease.

HIV and co-infections

Despite significant reductions in morbidity and mortality secondary to availability of effective combination anti‐retroviral therapy (cART), human immunodeficiency virus (HIV) infection still accounts for 1.5 million deaths annually. The majority of deaths occur in sub‐Saharan Africa where rates of opportunistic co‐infections are disproportionately high. In this review, we discuss the immunopathogenesis of five common infections that cause significant morbidity in HIV‐infected patients globally. These include co‐infection with Mycobacterium tuberculosis, Cryptococcus neoformans, hepatitis B virus, hepatitis C virus, and Plasmodium falciparum. Specifically, we review the natural history of each co‐infection in the setting of HIV, the specific immune defects induced by HIV, the effects of cART on the immune response to the co‐infection, the pathogenesis of immune restoration disease (IRD) associated with each infection, and advances in the areas of prevention of each co‐infection via vaccination. Finally, we discuss the opportunities and gaps in knowledge for future research.

Coinfection of Hepatic Cell Lines with Human Immunodeficiency Virus and Hepatitis B Virus Leads to an Increase in Intracellular Hepatitis B Surface Antigen

ABSTRACT Liver-related mortality is increased in the setting of HIV-hepatitis B virus (HBV) coinfection. However, interactions between HIV and HBV to explain this observation have not been described. We hypothesized that HIV infection of hepatocytes directly affects the life cycle of HBV. We infected human hepatic cell lines expressing HBV (Hep3B and AD38 cells) or not expressing HBV (Huh7, HepG2, and AD43 cells) with laboratory strains of HIV (NL4-3 and AD8), as well as a vesicular stomatitis virus (VSV)-pseudotyped HIV expressing enhanced green fluorescent protein (EGFP). Following HIV infection with NL4-3 or AD8 in hepatic cell lines, we observed a significant increase in HIV reverse transcriptase activity which was infectious. Despite no detection of surface CD4, CCR5, and CXCR4 by flow cytometry, AD8 infection of AD38 cells was inhibited by maraviroc and NL4-3 was inhibited by AMD3100, demonstrating that HIV enters AD38 hepatic cell lines via CCR5 or CXCR4. High-level infection of AD38 cells (50%) was achieved using VSV-pseudotyped HIV. Coinfection of the AD38 cell line with HIV did not alter the HBV DNA amount or species as determined by Southern blotting or nucleic acid signal amplification. However, coinfection with HIV was associated with a significant increase in intracellular HBsAg when measured by Western blotting, quantitative HBsAg, and fluorescence microscopy. We conclude that HIV infection of HBV-infected hepatic cell lines significantly increased intracellular HBsAg but not HBV DNA synthesis and that increased intrahepatic HBsAg secondary to direct infection by HIV may contribute to accelerated liver disease in HIV-HBV-coinfected individuals.

Human immunodeficiency virus infection and the liver

Liver disease in human immunodeficiency virus (HIV)-infected individuals encompasses the spectrum from abnormal liver function tests, liver decompensation, with and without evidence of cirrhosis on biopsy, to non-alcoholic liver disease and its more severe form, non-alcoholic steatohepatitis and hepatocellular cancer. HIV can infect multiple cells in the liver, leading to enhanced intrahepatic apoptosis, activation and fibrosis. HIV can also alter gastro-intestinal tract permeability, leading to increased levels of circulating lipopolysaccharide that may have an impact on liver function. This review focuses on recent changes in the epidemiology, pathogenesis and clinical presentation of liver disease in HIV-infected patients, in the absence of co-infection with hepatitis B virus or hepatitis C virus, with a specific focus on issues relevant to low and middle income countries.

Lipopolysaccharide, Immune Activation, and Liver Abnormalities in HIV/Hepatitis B Virus (HBV)–Coinfected Individuals Receiving HBV-Active Combination Antiretroviral Therapy

We investigated the relationship between microbial translocation, immune activation, and liver disease in human immunodeficiency virus (HIV)/hepatitis B virus (HBV) coinfection. Lipopolysaccharide (LPS), soluble CD14, CXCL10, and CCL-2 levels were elevated in patients with HIV/HBV coinfection. Levels of LPS, soluble CD14, and CCL-2 declined following receipt of HBV-active combination antiretroviral therapy (cART), but the CXCL10 level remained elevated. No markers were associated with liver disease severity on liver biopsy (n = 96), but CXCL10, interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor α, and interferon γ (IFN-γ) were all associated with elevated liver enzyme levels during receipt of HBV-active cART. Stimulation of hepatocyte cell lines in vitro with IFN-γ and LPS induced a profound synergistic increase in the production of CXCL10. LPS may contribute to liver disease via stimulating persistent production of CXCL10.

No Increase in Hepatitis B Virus (HBV)-Specific CD8+ T Cells in Patients with HIV-1-HBV Coinfections following HBV-Active Highly Active Antiretroviral Therapy

ABSTRACT Following treatment of hepatitis B virus (HBV) monoinfection, HBV-specific T-cell responses increase significantly; however, little is known about the recovery of HBV-specific T-cell responses following HBV-active highly active antiretroviral therapy (HAART) in HIV-HBV coinfected patients. HIV-HBV coinfected patients who were treatment naïve and initiating HBV-active HAART were recruited as part of a prospective cohort study in Thailand and followed for 48 weeks (n = 24). Production of gamma interferon (IFN-γ) and tumor necrosis factor α (TNF-α) in both HBV- and HIV-specific CD8+ T cells was quantified using intracellular cytokine staining on whole blood. Following HBV-active HAART, the median (interquartile range) log decline from week 0 to week 48 for HBV DNA was 5.8 log (range, 3.4 to 6.7) IU/ml, and for HIV RNA it was 3.1 (range, 2.9 to 3.5) log copies/ml (P < 0.001 for both). The frequency of HIV Gag-specific CD8+ T-cell responses significantly decreased (IFN-γ, P < 0.001; TNF-α, P = 0.05). In contrast, there was no significant change in the frequency (IFN-γ, P = 0.21; TNF-α, P = 0.61; and IFN-γ and TNF-α, P = 0.11) or magnitude (IFN-γ, P = 0.13; TNF-α, P = 0.13; and IFN-γ and TNF-α, P = 0.13) of HBV-specific CD8+ T-cell responses over 48 weeks of HBV-active HAART. Of the 14 individuals who were HBV e antigen (HBeAg) positive, 5/14 (36%) lost HBeAg during the 48 weeks of follow-up. HBV-specific CD8+ T cells were detected in 4/5 (80%) of patients prior to HBeAg loss. Results from this study show no sustained change in the HBV-specific CD8+ T-cell response following HBV-active HAART. These findings may have implications for the duration of treatment of HBV in HIV-HBV coinfected patients, particularly in HBeAg-positive disease.

Hepatitis virus immune restoration disease of the liver.

Purpose of reviewCo-infection of HIV with hepatitis B virus or hepatitis C virus is common. Hepatotoxicity (grade 3 or 4 transaminitis) after highly active antiretroviral therapy occurs more frequently in either hepatitis B virus or hepatitis C virus co-infection. The cause of abnormal alanine aminotransferase following the initiation of highly active antiretroviral therapy is often multifactorial, and may include immune restoration disease. Since the widespread use of highly active antiretroviral therapy, liver disease secondary to viral hepatitis has become one of the most common causes of death in HIV infected individuals. A better understanding of the immunopathogenesis, diagnosis and treatment of hepatitis immune restoration disease is urgently needed, therefore. Recent findingsOur current understanding of the immunopathogenesis of hepatitis immune restoration disease is limited but it is likely that hepatic damage is secondary to recruitment of both antigen-specific and nonantigen-specific mononuclear cells to the liver, possibly mediated by IFN-γ. HIV–hepatitis B virus co-infected individuals with low CD4+ T-cells and elevated hepatitis B virus DNA and alanine aminotransferase prior to initiation of highly active antiretroviral therapy are at increased risk of hepatitis B virus immune restoration disease. Risk factors for hepatitis C virus immune restoration disease are less well defined. Although clinical deterioration can occur, hepatitis immune restoration disease has also been associated with successful clearance of both hepatitis B virus and hepatitis C virus. SummaryFurther randomized clinical trials are needed to develop improved management strategies for hepatitis immune restoration disease.

HIV Infection and TLR Signalling in the Liver.

Despite the availability of effective combination antiretroviral therapy (cART), liver disease is one of the leading causes of morbidity and mortality in Human Immunodeficiency Virus (HIV)-infected individuals, specifically, in the presence of viral hepatitis coinfection. HIV, a single stranded RNA virus, can bind to and activate both Toll-like receptor (TLR)7 and TLR8 in circulating blood mononuclear cells, but little is known about the effect of HIV on TLRs expressed in the liver. HIV can directly infect cells of the liver and HIV-mediated depletion of CD4+ T-cells in the gastrointestinal tract (GI tract) results in increased circulating lipopolysaccharide (LPS), both of which may impact on TLR signaling in the liver and subsequent liver disease progression. The potential direct and indirect effects of HIV on TLR signaling in the liver will be explored in this paper.

HIV-hepatitis B virus coinfection: epidemiology, pathogenesis, and treatment

&NA; HIV infection has a significant impact on the natural history of chronic hepatitis B virus (HBV) infection, with increased levels of HBV DNA, accelerated progression of liver disease and increased liver-associated mortality compared with HBV monoinfection. Widespread uptake and early initiation of HBV-active antiretroviral therapy has substantially improved the natural history of HIV–HBV coinfection but the prevalence of liver disease remains elevated in this population. In this paper, we review recent studies examining the natural history and pathogenesis of liver disease and seroconversion in HIV–HBV coinfection in the era of HBV-active antiretroviral therapy and the effects of HIV directly on liver disease. We also review novel therapeutics for the management of HBV with a particular emphasis on clinical strategies being developed for an HBV cure and an HIV cure and their impact on HIV–HBV coinfected individuals.

Extremely prolonged HIV seroconversion associated with an MHC haplotype carrying disease susceptibility genes for antibody deficiency disorders.

Severe immunodeficiency during primary human immunodeficiency virus (HIV) infection is unusual. Here, we characterized viral and immunological parameters in a subject presenting with Pneumocystis jirovecii pneumonia in the setting of prolonged primary HIV illness and delayed seroconversion. HIV antibody was only detected by enzyme-linked immunosorbent assay 12 months after presentation, and Western blot profiles remain indeterminate. Isolated virus was of R5 phenotype, exhibited poor viral fitness, but was otherwise unremarkable. Analysis of HIV antibody isotypes showed failure to mount a detectable HIV IgG response over nearly 2 years of infection, in particular IgG(1)- and IgG(3)-specific responses, despite normal responses to common infections and vaccines. Genetic analysis demonstrated homozygosity for part of an MHC haplotype containing susceptibility genes for common variable immunodeficiency (CVID) syndrome and other antibody deficiency disorders. Thus, a primary disorder of specific antibody production may explain exceptionally slow antibody development in an otherwise severe seroconversion illness. This highlights the need for multiparameter testing, in particular use of a fourth generation HIV test, for confirming HIV infection and underscores the importance of host factors in HIV pathogenesis.