Treatment of HIV-1-infected individuals with a combination of anti-retroviral agents results in sustained suppression of HIV-1 replication, as evidenced by a reduction in plasma viral RNA to levels below the limit of detection of available assays. However, even in patients whose plasma viral RNA levels have been suppressed to below detectable levels for up to 30 months, replication-competent virus can routinely be recovered from patient peripheral blood mononuclear cells and from semen. A reservoir of latently infected cells established early in infection may be involved in the maintenance of viral persistence despite highly active anti-retroviral therapy. However, whether virus replication persists in such patients is unknown. HIV-1 cDNA episomes are labile products of virus infection and indicative of recent infection events. Using episome-specific PCR, we demonstrate here ongoing virus replication in a large percentage of infected individuals on highly active anti-retroviral therapy, despite sustained undetectable levels of plasma viral RNA. The presence of a reservoir of 'covert' virus replication in patients on highly active anti-retroviral therapy has important implications for the clinical management of HIV-1-infected individuals and for the development of virus eradication strategies.

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Antibody-dependent enhancement (ADE) of dengue virus infection occurs when neutralizing antibodies at sub-neutralizing concentrations or non-neutralizing antibodies form complexes with the virus. These virus-antibody complexes can then attach to a Fc7 receptor-bearing cell, via the Fc portion of the immunoglobulin, resulting in an increased number of infected cells. ADE may be responsible in part for the most severe clinical manifestations of dengue virus infection which include haemorrhage and shock. Three classes of human Fcy receptors exist, FcTRI, FcTRII and FcTRIII. In this study, we examined the effects of neuraminidase on ADE of dengue virus infection mediated by the lowaffinity FcTRII. K562 cells, which express only FcTRII, treated with neuraminidase resulted in augmentation of ADE of dengue virus infection by human anti-dengue antibodies. This augmented ADE of infection could be blocked by anti-FcTRII monoclonal antibody IV.3.Incubation of neuraminidase-treated K562 cells with IgG-coated human red blood cells resulted in an increase in the percentage of rosette formations compared with the untreated K562 cells. A bispecific antibody directed against FcTRII and dengue virus (IV. 3 × 2H2) enhanced virus infection. Neuraminidase also augmented ADE mediated by this antibody, but to a much lesser degree (by 50 %) compared with that seen using conventional human anti-dengue antibody (by 200 to 300%). Fluorescence-activated cell sorting analysis of neuraminidase-treated K562 ceils showed that the number of FcTRII-specific antibodies that bind to FcTRII increases by 15 to 20% after treatment with neuraminidase.These results indicate that neuraminidase augments ADE of dengue virus infection and that the augmented ADE is mediated through FcTRII.

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