Different measures applied to the same patient suggest different levels of adherence. Adherence may be underestimated by MEMS and overestimated by pill count and interview. A summary measure combining several measures is more strongly related to a clinical response, but more practical measurement methods are needed for clinical use.

Nearly all patients' adherence levels were suboptimal, demonstrating the critical need for programs to assist patients with medication taking. Interventions that assess and treat substance abuse and incorporate adherence aids may be particularly helpful and warrant further study.

The proteolytic processing sites of the human immunodeficiency virus type 1 (HIV-1) Gag precursor are cleaved in a sequential manner by the viral protease. We investigated the factors that regulate sequential processing. When full-length Gag protein was digested with recombinant HIV-1 protease in vitro, four of the five major processing sites in Gag were cleaved at rates that differ by as much as 400-fold. Three of these four processing sites were cleaved independently of the others. The CA/p2 site, however, was cleaved approximately 20-fold faster when the adjacent downstream p2/NC site was blocked from cleavage or when the p2 domain of Gag was deleted. These results suggest that the presence of a C-terminal p2 tail on processing intermediates slows cleavage at the upstream CA/p2 site. We also found that lower pH selectively accelerated cleavage of the CA/p2 processing site in the full-length precursor and as a peptide primarily by a sequence-based mechanism rather than by a change in protein conformation. Deletion of the p2 domain of Gag results in released virions that are less infectious despite the presence of the processed final products of Gag. These findings suggest that the p2 domain of HIV-1 Gag regulates the rate of cleavage at the CA/p2 processing site during sequential processing in vitro and in infected cells and that p2 may function in the proper assembly of virions.

Objectives. The purpose of this study was to determine the effect of release from prison and subsequent re-incarceration on the viral loads of HIV-infected individuals receiving highly active antiretroviral therapy (HAART). Methods. Fifteen re-incarcerated HIV-infected prisoners on HAART were identified from a retrospective cohort of HIV-infected prison inmates released from January 1, 1997, to August 31, 1999. The re-incarcerated prisoners were matched (1:2) to 30 HIV-infected incarcerated prisoners on HAART who remained incarcerated during the re-incarcerated participants' release time period. The outcomes measured were plasma HIV RNA levels, CD4+ lymphocyte counts, percentage of re-incarcerated and incarcerated participants with plasma HIV RNA levels <400 copies/mL, and the median change in plasma HIV RNA levels of the re-incarcerated and incarcerated participants at the end of the study. Results. At the beginning of the study, 8/15 re-incarcerated participants had plasma HIV RNA levels <400 copies/mL, compared with 15/30 incarcerated participants. At the end of the study, only three of those eight re-incarcerated participants had plasma HIV RNA levels <400 copies/mL, compared with 14/15 incarcerated participants ( p=0.0086). The median change in plasma HIV RNA levels of the re-incarcerated participants was 1.29 log10 copies/mL (interquartile range 0.04 to 1.70), compared with −0.03 log10 copies/mL (interquartile range −0.65 to 0.09) in the incarcerated participants ( p=0.0183). Conclusions. Release from prison was associated with a deleterious effect on virological and immunological outcomes. These data suggest that comprehensive discharge planning efforts are required to make certain that HIV-infected inmates receive access to quality care following incarceration.

Processing of the GagPol polyprotein precursor of human immunodeficiency virus type 1 (HIV-1) is a critical step in viral assembly and replication. The HIV-1 protease (PR) is translated as part of GagPol and is both necessary and sufficient for precursor processing. The PR is active only as a dimer; enzyme activation is initiated when the PR domains in two GagPol precursors dimerize. The precise mechanism by which the PR becomes activated and the subsequent initial steps in precursor processing are not well understood. However, it is clear that processing is initiated by the PR domain that is embedded within the precursor itself. We have examined the earliest events in precursor processing using an in vitro assay in which full-length GagPol is cleaved by its embedded PR. We demonstrate that the embedded, immature PR is as much as 10,000-fold less sensitive to inhibition by an active-site PR inhibitor than is the mature, free enzyme. Further, we find that different concentrations of the active-site inhibitor are required to inhibit the processing of different cleavage sites within GagPol. Finally, our results indicate that the first cleavages carried out by the activated PR within GagPol are intramolecular. Overall, our data support a model of virus assembly in which the first cleavages occur in GagPol upstream of the PR. These intramolecular cleavages produce an extended form of PR that completes the final processing steps accompanying the final stages of particle assembly by an intermolecular mechanism.

The CD8+ T-cell response is central to control and eventual elimination of persistent viral infections. Although it might be expected that CD8+ T-cell activation would be associated with a better clinical outcome during viral infections, in long-term HIV-1 infection, high levels of CD8+ T-cell activation are instead associated with faster disease progression. In this study, cell surface expression of CD38, a flow cytometric marker of T-cell activation of CD8+ T cells, had predictive value for HIV-1 disease progression that was in part independent of the predictive value of plasma viral burden and CD4+ T-cell number. Measurements of CD38 antigen expression on CD8+ T cells in HIV-1-infected patients may be of value for assessing prognosis and the impact of therapeutic interventions. The pathogenetic reason why CD8+ T-cell activation is associated with poor outcome in HIV-1 disease remains unknown. Possibly CD8+ T-cell activation contributes to immunologic exhaustion, hyporesponsiveness of T cells to their cognate antigens, or perturbations in the T-cell receptor repertoire.

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Inhibitors of the human immunodeficiency virus type 1 (HIV-1) protease represent a promising addition to the available agents used to inhibit virus replication in a therapeutic setting. HIV-1 is capable of generating phenotypic variants in the face of a variety of selective pressures. The potential to generate variants with reduced sensitivity to a protease inhibitor was examined by selecting for virus growth in cell culture in the presence ofthe protease inhibitor A-77003. Virus variants grew out in the presence of the inhibitor, and these variants encoded proteases with reduced sensitivity to the inhibitor. Variants were identified that encoded changes in each of the three subsites of the protease that interact with the inhibitor. HIV-1 displays significant potential for altering its interaction with this protease inhibitor, suggesting the need for multiple protease inhibitors with varying specificities.