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Background The rectum is particularly vulnerable to HIV transmission having only a single protective layer of columnar: epithelium overlying tissue rich in activated lymphoid cells; thus, unprotected anal intercourse in both women and men carries a higher risk of infection than other sexual routes. In the absence of effective prophylactic vaccines, increasing attention is being given to the use of microbicides and preventative antiretroviral (ARV) drugs. To prevent mucosal transmission of HIV, a microbicide/ARV should ideally act locally at and near the virus portal of entry. As part of an integrated rectal microbicide development programme, we have evaluated rectal application of the nucleotide reverse transcriptase (RT) inhibitor tenofovir (PMPA, 9-[(R)-2-(phosphonomethoxy) propyll adenine monohydrate), a drug licensed for therapeutic use, for protective efficacy against rectal challenge with simian immunodeficiency virus (SIV) in a well-established and standardised macaque model. Methods and Findings A total of 20 purpose-bred Indian rhesus macaques were used to evaluate the protective efficacy of topical tenofovir. Nine animals received 1 % tenofovir gel per rectum up to 2 h prior to virus challenge, four macaques received placebo gel, and four macaques remained untreated. In addition, three macaques were given tenofovir gel 2 h after virus challenge. Following intrarectal instillation of 20 median rectal infectious doses ([MID].sub.50]) of a noncloned, virulent stock Of [SIV.sub.mac251/32H], all animals were analysed for virus infection, by virus isolation from peripheral blood mononuclear cells (PBMC), quantitative proviral DNA load in PBMC, plasma viral RNA (vRNA) load by sensitive quantitative competitive (qc) RT-PCR, and presence of SIV-specific serum antibodies by ELISA. We report here a significant protective effect (p = 0.003; Fisher exact probability test) wherein eight of nine macaques given tenofovir per rectum up to 2 h priorto virus challenge were protected from infection (n=6) or had modified virus outcomes (n = 2), while all untreated macaques and three of four macaques given placebo gel were infected, as were two of three animals receiving tenofovir gel after challenge. Moreover, analysis of lymphoid tissues post mortem failed to reveal sequestration of SIV in the protected animals. We found a strong positive association between the concentration of tenofovir in the plasma 15 min after rectal application of gel and the degree of protection in the six animals challenged with virus at this time point. Moreover, colorectal explants from non-SIV challenged tenofovir-treated macaques were resistant to infection ex vivo, whereas no inhibition was seen in explants from the small intestine. Tissue-specific inhibition of infection was associated with the intracellular detection of tenofovir. Intriguingly, in the absence of seroconversion, Gag-specific gamma interferon (IFN-γ)-secreting T cells were detected in the blood of four of seven protected animals tested, with frequencies ranging from 144 spot forming cells (SFC)/[10.sup.6] PBMC to 261 spot forming cells (SFC)/[10.sup.6] PBMC. Conclusions These results indicate that colorectal pretreatment with ARV drugs, such as tenofovir, has potential as a clinically relevant strategy for the prevention of HIV transmission. We conclude that plasma tenofovir concentration measured 15 min after rectal administration may serve as a surrogate indicator of protective efficacy. This may prove to be useful in the design of clinical studies. Furthermore, in vitro intestinal explants served as a model for drug distribution in vivo and susceptibility to virus infection. The finding of T cell priming following exposure to virus in the absence of overt infection is provocative. Further studies would reveal if a combined modality microbicide and vaccination strategy is feasible by determining the full extent of local immune responses induced and their protective potential., Introduction The development of an effective vaccine against HIV is still thought to be a long-term endeavour; meanwhile the HIV pandemic continues relentlessly, fuelled primarily by sexual transmission. The relative [...]

Der schnelle Fortschritt in der Entwicklung von Lerntechnologien und die dadurch entstehende hohe Anzahl an didaktischen Möglichkeiten zur Vermittlung medien-gestützter Lehre stellen hohe Anforderungen an die multimediale Ausstattung der Unterrichtsräume dar. Im Zuge der Umbauarbeiten in Hörsälen an der Universität Innsbruck wurde ein Projekt initialisiert, das die Basis für die Umsetzung eines optimalen Unterrichtsraums bildet. Dabei konnten wertvolle Erfahrungen gesammelt werden, die in späterer Folge bei Unterrichtsraumadaptierungen einfließen. 13.01.2012 | Anton Tremetzberger (Innsbruck)

A study was undertaken to determine whether detectable levels of HIV-1 DNA or RNA remain in the gastrointestinal (GI) mucosal of HIV-1-infected, well suppressed subjects on highly active antiretroviral therapy (HAART) and also whether it was possible to identify the decay in those levels. It was observed that HIV-1 RNA was detected in mucosal biopsy specimens from only 20% of the subjects, mucosal HIV-1 DNA was detected in 80% of the subjects, while there was no evidence for decay of the HIV-1 DNA in either gut-associated lymphoid tissue (GALT) or peripheral blood mononuclear cells (PBMCs).

HIV vaccine availability does not guarantee uptake. Given suboptimal uptake of highly efficacious and already accessible vaccines in the United States, low vaccine coverage in the developing world, and the expectation that initial HIV vaccines will be only partially efficacious, the public health community will face formidable challenges in disseminating U.S. Food and Drug Administration (FDA)-approved HIV vaccines. HIV/AIDS stigma, fear of vaccine-induced HIV infection, social side effects of testing HIV-positive, and mistrust of government and research present additional obstacles to HIV vaccine dissemination. Increased risk behaviors because of HIV vaccine availability can undermine the effectiveness of partially efficacious vaccines in reducing HIV incidence. HIV vaccine efficacy trials also face significant challenges in recruitment of sufficient volunteers and possible increases in risk behaviors due to trial participation. Planning and designing interventions to facilitate successful recruitment for large-scale phase 3 efficacy trials is a vital step towards U.S. FDA-approved HIV vaccines. Rather than despair in the face of momentous HIV vaccine dissemination challenges, or presume unrealistically that vaccine uptake will ensue automatically and that risk behavior increases will not occur, let us deem the estimated 10-year window to an approved HIV vaccine as an opportunity to investigate and confront these challenges. A consumer research agenda founded on social marketing principles is needed to facilitate the design of empirically-based interventions tailored to the unique needs and preferences of specific segments of consumers. Social marketing interventions may increase future HIV vaccine uptake and clinical trial participation, and mitigate increases in HIV risk behaviors.

An attempt is made to characterize intestinal mucosal cytokine profiles in subjects with HIV-1 infection and their relation to muc os al viral load (MVL). Also, longitudinal data from two patients is included in whom it is possible to measure sequential tissue viral load and cytokine profiles after the initiation and withdrawal of antiretroviral therapy (ART).

Research examines the rationale of the patients to make decisions about the recommended treatments. The treatment decision model for chronic illness accounts for 57.8% of the variance in medication-taking intention, suggesting that relationship factors, health beliefs, and health status may influence the decision process.

Abstract Background The objective of this study is to identify the critical formulation parameters controlling distribution and function for the rectal administration of microbicides in humans. Four placebo formulations were designed with a wide range of hydrophilic characteristics (aqueous to lipid) and rheological properties (Newtonian, shear thinning, thermal sensitive and thixotropic). Aqueous formulations using typical polymers to control viscosity were iso-osmotic and buffered to pH 7. Lipid formulations were developed from lipid solvent/lipid gelling agent binary mixtures. Testing included pharmaceutical function and stability as well as in vitro and in vivo toxicity. Results The aqueous fluid placebo, based on poloxamer, was fluid at room temperature, thickened and became shear thinning at 37°C. The aqueous gel placebo used carbopol as the gelling agent, was shear thinning at room temperature and showed a typical decrease in viscosity with an increase in temperature. The lipid fluid placebo, myristyl myristate in isopropyl myristate, was relatively thin and temperature independent. The lipid gel placebo, glyceryl stearate and PEG-75 stearate in caprylic/capric triglycerides, was also shear thinning at both room temperature and 37°C but with significant time dependency or thixotropy. All formulations showed no rectal irritation in rabbits and were non-toxic using an ex vivo rectal explant model. Conclusions Four placebo formulations ranging from fluid to gel in aqueous and lipid formats with a range of rheological properties were developed, tested, scaled-up, manufactured under cGMP conditions and enrolled in a formal stability program. Clinical testing of these formulations as placebos will serve as the basis for further microbicide formulation development with drug-containing products.

Abstract Background Gene transfer to the gastrointestinal (GI) mucosa is a therapeutic strategy which could prove particularly advantageous for treatment of various hereditary and acquired intestinal disorders, including inflammatory bowel disease (IBD), GI infections, and cancer. Methods We evaluated vesicular stomatitis virus glycoprotein envelope (VSV-G)-pseudotyped lentiviral vectors (LV) for efficacy of gene transfer to both murine rectosigmoid colon in vivo and human colon explants ex vivo. LV encoding beta-galactosidase (LV-β-Gal) or firefly-luciferase (LV-fLuc) reporter genes were administered by intrarectal instillation in mice, or applied topically for ex vivo transduction of human colorectal explant tissues from normal individuals. Macroscopic and histological evaluations were performed to assess any tissue damage or inflammation. Transduction efficiency and systemic biodistribution were evaluated by real-time quantitative PCR. LV-fLuc expression was evaluated by ex vivo bioluminescence imaging. LV-β-Gal expression and identity of transduced cell types were examined by histochemical and immunofluorescence staining. Results Imaging studies showed positive fLuc signals in murine distal colon; β-Gal-positive cells were found in both murine and human intestinal tissue. In the murine model, β-Gal-positive epithelial and lamina propria cells were found to express cytokeratin, CD45, and CD4. LV-transduced β-Gal-positive cells were also seen in human colorectal explants, consisting mainly of CD45, CD4, and CD11c-positive cells confined to the LP. Conclusions We have demonstrated the feasibility of LV-mediated gene transfer into colonic mucosa. We also identified differential patterns of mucosal gene transfer dependent on whether murine or human tissue was used. Within the limitations of the study, the LV did not appear to induce mucosal damage and were not distributed beyond the distal colon.

Defining tissue and plasma‐specific prophylactic drug concentrations is central to pre‐exposure prophylaxis product development for sexual transmission of HIV‐1. Pharmacokinetic (PK) data from study RMP‐02/MTN‐006 comparing single dose oral tenofovir disoproxil fumarate with single and multiple dose rectal tenofovir (TFV) gel administration in HIV‐1 seronegative adults was used to construct a multicompartment plasma‐rectal tissue population PK model for TFV and tenofovir‐diphosphate (TFVdp) in plasma and rectal tissue. PK data were collected in five matrices: TFV (plasma, rectal tissue homogenate), TFVdp (peripheral blood mononuclear cells, rectal mononuclear cells (MMCs), rectal tissue homogenate). A viral growth compartment and a delayed effect compartment for p24 antigen expression measured from an ex vivo explant assay described HIV‐1 infection and replication. Using a linear PK/pharmacodynamic model, MMC TFVdp levels over 9,000 fmol/million cells in the explant assay provided apparent viral replication suppression down to 1%. Parameters were estimated using NONMEM version 7.4. [ABSTRACT FROM AUTHOR]