Temporal analysis of early immune responses in patients with acute hepatitis B virus infection.

BACKGROUND & AIMS: Hepatitis B virus (HBV) causes more than 1 million deaths annually from immune-mediated liver damage. The long incubation period has been difficult to study; by the time most patients present, massive viremia and the majority of viral clearance have already occurred. The aim of this study was to investigate the contribution of innate and adaptive immune mechanisms in early acute HBV through access to an unusual cohort of patients sampled in the preclinical phase and followed up to resolution of their infection. METHODS: Twenty-one patients with acute HBV were studied, 8 of them from before the peak of viremia. Circulating innate cytokines were quantitated by enzyme-linked immunosorbent assay and natural killer (NK) and T-cell effector function by flow cytometry. Results were correlated with temporal changes in viral load, serology, and liver inflammation and compared with healthy controls. RESULTS: Type I interferon (IFN) remained barely detectable throughout, with concentrations no higher than those found in healthy controls. Similarly, interleukin-15 and IFN-lambda1 were not induced during peak viremia. NK cell activation and capacity for IFN-gamma production were reduced at peak viremia. Early functional HBV-specific CD4 and CD8 T-cell responses were attenuated as viral load increased and recovered again as infection resolved. The transient inhibition of NK and T-cell responses coincided with a surge in the immunosuppressive cytokine interleukin-10 accompanying HBV viremia. CONCLUSIONS: The early stages of acute HBV are characterized by induction of interleukin-10 rather than type I IFN, accompanied by a temporary attenuation of NK and T-cell responses.

Role of darunavir in the management of HIV infection.

There is an ongoing need for potent antiretroviral therapies to deal with the increasing pool of treatment-experienced patients with multiple drug resistance. The last few years have seen the arrival of 2 new and very potent protease inhibitors - darunavir and tipranavir - alongside 2 whole new classes of anti-HIV agents - the integrase inhibitors and chemokine receptor CCR5 antagonists. This review focuses on the role of darunavir in managing HIV infection, with an emphasis on darunavir's exceptional resistance profile and related clinical effectiveness, pharmacokinetics, tolerability and toxicity data. Darunavir in combination with the pharmacokinetic booster ritonavir has proved to be very effective in the treatment of highly treatment-experienced HIV patients with multiple drug resistance. The favorable tolerability and toxicity profile alongside the drug's high genetic barrier to the development of resistance prompted approval of darunavir for HIV-treatment naïve patients. Furthermore, the paradigm of treating HIV with a combination of anti-HIV agents is currently being challenged by ongoing darunavir monotherapy trials and these preliminary data will be discussed.

Effect of HIV infection and antiretroviral therapy on hepatitis B virus (HBV)-specific T cell responses in patients who have resolved HBV infection.

Coinfection with hepatitis B virus (HBV) is a common occurrence in human immunodeficiency virus (HIV)-positive patients and an increasing cause of morbidity and mortality. The CD8(+) T cell response is critical for long-term control of HBV in patients resolving acute infection. Here, we examine the effect of HIV on HBV-specific CD8(+) T cell responses in patients who have resolved HBV infection. A cross-sectional study showed a reduction in HBV-specific CD8(+) T cell responses in HIV-positive, HBV-immune patients, compared with those in HIV-negative, HBV-immune patients. A longitudinal study of a subgroup of patients examined whether this attrition could be reversed by effective antiretroviral therapy. The introduction of highly active antiretroviral therapy (HAART) resulted in reconstitution of some HBV-specific CD4(+) and CD8(+) T cell responses, in association with restoration of CD4(+) T cell counts. These data provide a mechanism to account for the observed impairment of control of HBV infection in the setting of HIV infection and support the ability of HAART to reconstitute functionally active T cell responses.

Reconstitution of hepatitis B virus (HBV)-specific T cell responses with treatment of human immunodeficiency virus/HBV coinfection.

Liver-related mortality is an increasing problem in human immunodeficiency virus (HIV)/hepatitis B virus (HBV)-coinfected patients receiving highly active antiretroviral therapy (HAART). In HIV-negative patients, HBV chronicity is associated with a reduction in specific T cell responses that can be partially restored by treatment with lamivudine. We studied 5 HIV/HBV-coinfected patients treated with HAART, either with or without addition of a drug with specific anti-HBV activity. Our data show that reconstitution of some HBV-specific T cell responses can also occur in HIV-positive patients after a reduction in HBV load. This potential to recover T cell responses, which has been thought to be critical for HBV control, provides support for the addition of anti-HBV therapy in the treatment of HIV/HBV-coinfected patients.

Greater CD8+ TCR heterogeneity and functional flexibility in HIV-2 compared to HIV-1 infection.

Virus-specific CD8(+) T cells are known to play an important role in the control of HIV infection. In this study we investigated whether there may be qualitative differences in the CD8(+) T cell response in HIV-1- and HIV-2-infected individuals that contribute to the relatively efficient control of the latter infection. A molecular comparison of global TCR heterogeneity showed a more oligoclonal pattern of CD8 cells in HIV-1- than HIV-2-infected patients. This was reflected in restricted and conserved TCR usage by CD8(+) T cells recognizing individual HLA-A2- and HLA-B57-restricted viral epitopes in HIV-1, with limited plasticity in their response to amino acid substitutions within these epitopes. The more diverse TCR usage observed for HIV-2-specific CD8(+) T cells was associated with an enhanced potential for CD8 expansion and IFN-gamma production on cross-recognition of variant epitopes. Our data suggest a mechanism that could account for any possible cross-protection that may be mediated by HIV-2-specific CD8(+) T cells against HIV-1 infection. Furthermore, they have implications for HIV vaccine development, demonstrating an association between a polyclonal, virus-specific CD8(+) T cell response and an enhanced capacity to tolerate substitutions within T cell epitopes.