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Previous data have indicated that the development of resistance to amprenavir, an inhibitor of the human immunodeficiency virus type 1 protease, is associated with the substitution of valine for isoleucine at residue 50 (I50V) in the viral protease. We present further findings from retrospective genotypic and phenotypic analyses of plasma samples from protease inhibitor-naïve and nucleoside reverse transcriptase inhibitor (NRTI)-experienced patients who experienced virological failure while participating in a clinical trial where they had been randomized to receive either amprenavir or indinavir in combination with NRTIs. Paired baseline and on-therapy isolates from 31 of 48 (65%) amprenavir-treated patients analyzed demonstrated the selection of protease mutations. These mutations fell into four distinct categories, characterized by the presence of either I50V, I54L/I54M, I84V, or V32I؉I47V and often included accessory mutations, commonly M46I/L. The I50V and I84V genotypes displayed the greatest reductions in susceptibility to amprenavir, although each of the amprenavir-selected genotypes conferred little or no cross-resistance to other protease inhibitors. There was a significant association, for both amprenavir and indinavir, between preexisting baseline resistance to NRTIs subsequently received during the study and development of protease mutations (P ‫؍‬ 0.014 and P ‫؍‬ 0.031, respectively). Our data provide a comprehensive analysis of the mechanisms by which amprenavir resistance develops during clinical use and present evidence that resistance to concomitant agents in the treatment regimen predisposes to the development of mutations associated with protease inhibitor resistance and treatment failure.

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This study examines the role of immune defence mechanisms in herpes simplex virus (HSV) infections in atopic eczema and whether impairment of these mechanisms explains the susceptibility of some children with atopic eczema to cutaneous HSV infections. Ten children with eczema herpeticum and 13 with atopic eczema and recurrent HSV infection affecting multiple skin sites were studied, together with relevant control groups. In all children with atopic eczema, in vitro lymphoproliferation in response to stimulation with concanavalin A (Con A) was significantly decreased and natural killer (NK) cells (CD16 + 56) were reduced compared with non-atopic controls. IL-2 receptors, a marker for lymphocyte activation, were decreased during the acute phase of eczema herpeticum, and for 1 month thereafter. A positive stimulation index (> 3) to HSV antigen, and high HSV IgG antibody titres measured by ELISA, Western blotting and neutralization assay, were seen in children with eczema herpeticum by 6 weeks, and also in children with atopic eczema and recurrent HSV infections. No evidence of an HSV-specific immune defect (either cell-mediated or humoral) was found in atopic eczema. Impairment of cell-mediated immunity in atopic eczema was suggested by the reduced response to Con A. It is likely that reduced numbers of circulating NK cells and a decrease in IL-2 receptors during early eczema herpeticum contribute to the susceptibility of children with atopic eczema to cutaneous HSV infections.