Publications

T-cell activation has long been considered a central mediator of HIV pathogenesis. High T-cell activation levels predict more rapid disease progression in untreated patients and decreased treatment-mediated CD4+ T-cell gains during antiretroviral therapy, independent of plasma HIV RNA levels, and may be the primary feature distinguishing pathogenic from nonpathogenic primate models of HIV infection. Studies in animal models and individuals with HIV infection continue to enhance our understanding of how T-cell activation causes immunodeficiency during HIV infection. The goal of these studies is to identify specific mechanisms that can be targeted by novel immune-based therapies for patients who have thus far been unable to recover normal immune function despite years of antiretroviral therapy. Although most immune-based therapies targeting T-cell activation have been unsuccessful to date, recent scientific developments have focused attention on specific pathways that may be exploited by future generations of immune-based therapies.

Four new compounds, belonging to the tetranortriterpenoid family, named dysoxylins A-D (1-4), isolated from Dysoxylum gaudichaudianum, were found to exhibit potent antiviral activity against respiratory syncytial virus (RSV). These structures were determined by NMR spectroscopy and mass spectrometry and were shown to have anti-RSV EC50 activities in the range 1.0-4.0 microg/mL in cytopathic effect inhibition and plaque reduction assays.

Prior studies have indicated that dehydroepiandrosterone (DHEA) may have immunomodulatory properties as well as positive effects on mood, quality of life, and body composition. Preliminary data suggest that DHEA inhibits expression of human immunodeficiency virus 1 (HIV) in latently infected cells; thus, it might be a potential adjunct to currently available antiretroviral therapy. The objective was to determine DHEA's impact on latent HIV infection, persistent viral replication, immunity, and nonimmune aspects of health restoration. A randomized, double-blind, placebo-controlled 24-week outpatient intervention included 40 subjects with suppressed HIV viremia on a stable antiretroviral regimen. Participants were randomized with equal probability to receive either DHEA or placebo for 12 weeks, followed by open-label DHEA for an additional 12 weeks. Intensive virologic monitoring included plasma viral load assays (lower limits of detection 50 copies/ml and 2.5 copies/ml) and quantitative cultures of replication-competent virus reservoirs in blood cells. A full battery of immunologic measurements was performed. Measurements of hormones, body weight, and body composition were obtained. Quality of life was assessed using validated questionnaires. DHEA was bioavailable as ascertained by increased levels of DHEA, DHEA(S), and androstenedione in recipients' plasma compared to the control group. The titers of infectious HIV culturable from blood trended upward in the DHEA arm although there was no significant change in plasma HIV RNA level. No significant immune effects were observed with DHEA. There appeared to be no benefit with regard to lean muscle mass or bone density in the DHEA recipients. DHEA treatment had a positive impact on overall quality of life. DHEA supplementation in fully suppressed HIV patients was associated with an improvement in quality of life but appeared to have no beneficial antiviral, immunomodulatory, hormonal, or body composition effects, suggesting that it not be routinely used as an adjunctive therapy in this population.

Many antiretroviral drugs continue to exert an anti-human immunodeficiency virus (HIV) benefit in the presence of drug resistance mutations. The degree to which enfuvirtide exerts continued antiviral activity in the presence of incomplete viral suppression has not been defined. To address this question, 25 subjects interrupted enfuvirtide while remaining on a stable background regimen. Enfuvirtide interruption was associated with an immediate but limited increase in plasma HIV-1 RNA levels. Enfuvirtide resistance waned rapidly in the absence of drug pressure and was no longer detectable by week 16 in most individuals. These data indicate that enfuvirtide has measurable antiviral activity in the setting of incomplete viral suppression. Although enfuvirtide resistance mutations are associated with significant fitness defects in vivo, the clinical significance of these mutations remains undefined.