Immune response to immunostimulatory complexes (ISCOMs) prepared from human immunodeficiency virus type 1 (HIV-1) or the HIV-1 external envelope glycoprotein (gp120)

In mice, immunostimulatory complexes (ISCOMs) prepared from HIV-1 B external envelope glycoprotein (gp120) induced 10-fold higher antibody titres than gp120 emulsified in depot adjuvant, as measured by enzyme-linked immunosorbent assay (ELISA). Rhesus monkeys immunized with gp120 ISCOMs produced precipitating and virus neutralizing antibody titres equivalent to those seen in HIV-infected chimpanzees and humans. After multiple immunizations with HIV-1 B gp120 ISCOMs, a rhesus monkey developed a neutralizing response to the HIV-1 isolates RF and MN, but not to the CC isolate. Antisera from ISCOM-immunized rhesus monkeys recognized gp120 on the membranes of HIV-1 B-infected H9 cells, indicating the preservation of epitope structure in the ISCOMs matrix.     

Monocyte and iscom enhancement of cell-mediated response to cytomegalovirus

Cell-mediated and humoral responses to cytomegalovirus were studied in a monkey model. Repeated low doses of virus antigen gave poor reactivities in both respects. High antigen doses gave a good humoral IgG response. When autologous monocytes were incubated with the CMV antigen as the immunizing injection, the specific cellular response to CMV antigen increased. The monocytes themselves did not contribute to the in vitro specific proliferation response. When iscoms were the carrier particles for CMV antigens, cellular response was even more strongly enhanced. In immunization schedules where specific cellular responses are important, we suggest that autologous monocytes or iscoms may be employed as antigen carriers.     

HIV-1 vaccine-induced immune responses which correlate with protection from SHIV infection: compiled preclinical efficacy data from trials with ten different HIV-1 vaccine candidates

The specific immune mechanisms necessary and/or sufficient to elicit HIV-vaccine protection remain undefined. Utilising the SHIV rhesus macaque model the immunogenicity as well as the efficacy of ten different HIV-1 vaccine candidates was evaluated. Comparison of the immune responses induced, with the ability of the vaccine to protect from SHIV infection provided a means to determine which type of immune responses were necessary for protection. Vaccine candidates included VLPs, DNA, subunit protein with novel adjuvant formulations, ISCOMs and pox-virus vectors. Protection from SHIV infection was achieved in approximately half of the animals which received a primary intravenous cell-free challenge. The presence of CTL in the absence of other effector responses did not correlate with protection from this route and type of challenge. Virus neutralising antibodies (Nab) appeared to be necessary but alone were insufficient for protection. If Ag-specific IFN-gamma and/or IL-4 as well as lymphoproliferative (LP) responses were found with the lack of a detectable IL-2 response, then protection was not observed. Immunity correlated with the magnitude of Nab responses, beta-chemokines and as well as balanced, qualitative T-helper responses.     

The CINOD, AZD3582, exhibits an improved gastrointestinal safety profile compared with naproxen in healthy volunteers

COX-inhibiting nitric oxide donators (CINODs) are a new class of drugs in development for the treatment of acute and chronic pain. They comprise a COX-inhibiting moiety linked to a nitric-oxide-donating component and are designed to provide an innovative mechanism of action of balanced COX inhibition and controlled nitric oxide donation. Through these pathways, CINODs should provide analgesic and anti-inflammatory efficacy, while offering gastrointestinal safety through the tissue-protective effects of nitric oxide donation. AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] is the first agent in the CINOD class to enter extensive clinical development. Pre-clinical studies demonstrate that AZD3582 has a superior gastrointestinal safety profile to naproxen, while demonstrating analgesic and anti-inflammatory efficacy. In healthy human volunteers, AZD3582 caused little gastrointestinal damage compared with equimolar doses of naproxen. Studies to evaluate the longer-term gastrointestinal safety of AZD3582, alongside its efficacy in alleviating chronic and acute pain, are ongoing.     

COX-inhibiting nitric oxide donators (CINODs) -- a new paradigm in the treatment of pain and inflammation

The clinical utility of non-selective non-steroidal anti-inflammatory drugs (NSAIDs) for pain relief is tempered by their propensity to cause gastrointestinal toxicity. Cyclooxygenase (COX)-inhibiting nitric oxide donators (CINODs) are a new class of drugs designed to provide analgesic efficacy through COX inhibition and gastrointestinal safety through the protective effects of controlled nitric oxide donation. Pre-clinical studies assessing the pharmacology, efficacy and gastrointestinal safety of AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] support this concept. Based on these studies, AZD3582 was the first CINOD to enter clinical development for the treatment of acute and chronic pain. The potential clinical utility of this new class is illustrated by a study of AZD3582 in healthy volunteers in which it caused significantly less acute gastrointestinal toxicity than an equimolar dose of naproxen. The results of the animal studies and the initial clinical study warrant long-term tolerability studies of AZD3582 along with evaluation of its anti-inflammatory and analgesic effects in humans.     

β-Chemokines and neutralizing antibody titers correlate with sterilizing immunity generated in HIV-1 vaccinated macaques

One of the obstacles to AIDS vaccine development is the variability of HIV-1 within individuals and within infected populations, enabling viral escape from highly specific vaccine induced immune responses. An understanding of the different immune mechanisms capable of inhibiting HIV infection may be of benefit in the eventual design of vaccines effective against HIV-1 variants. To study this we first compared the immune responses induced in Rhesus monkeys by using two different immunization strategies based on the same vaccine strain of HIV-1. We then utilized a chimeric simian/HIV that expressed the envelope of a dual tropic HIV-1 escape variant isolated from a later time point from the same patient from which the vaccine strain was isolated. Upon challenge, one vaccine group was completely protected from infection, whereas all of the other vaccinees and controls became infected. Protected macaques developed highest titers of heterologous neutralizing antibodies, and consistently elevated HIV-1-specific T helper responses. Furthermore, only protected animals had markedly increased concentrations of RANTES, macrophage inflammatory proteins 1α and 1β produced by circulating CD8⁺ T cells. These results suggest that vaccine strategies that induce multiple effector mechanisms in concert with β-chemokines may be desired in the generation of protective immune responses by HIV-1 vaccines.     

Book Reviews

Abstract

Objective: Monitoring of ongoing psychotherapy is of crucial importance in improving the quality of mental health care by detecting therapies being off track, which requires that the instrument used is psychometrically sound. This study investigates the psychometric properties of the Norwegian version of the Outcome Questionnaire 45.2 (OQ-45) and situates the results in an international context.Method: Data from one non-clinical sample (N = 338) and one clinical sample (N = 560) were compared to international samples investigating reliability, cut-offs, and factor structure. Results: The results show adequate reliability and concurrent validity. Conclusions: The means, clinical cut-offs, and the reliable change index vary across countries. However, the means of the OQ-45 for nonclinical samples correlate highly with external values of national well-being, indicating that the OQ-45 is a valid instrument internationally. The factor analyses in the present study do not confirm the hypothesized factor structure of the OQ-45, but are similar to the results internationally.     

Human modification of global water vapor flows from the land surface

It is well documented that human modification of the hydrological cycle has profoundly affected the flow of liquid water across the Earth's land surface. Alteration of water vapor flows through land-use changes has received comparatively less attention, despite compelling evidence that such alteration can influence the functioning of the Earth System. We show that deforestation is as large a driving force as irrigation in terms of changes in the hydrological cycle. Deforestation has decreased global vapor flows from land by 4% (3,000 km(3)/yr), a decrease that is quantitatively as large as the increased vapor flow caused by irrigation (2,600 km(3)/yr). Although the net change in global vapor flows is close to zero, the spatial distributions of deforestation and irrigation are different, leading to major regional transformations of vapor-flow patterns. We analyze these changes in the light of future land-use-change projections that suggest widespread deforestation in sub-Saharan Africa and intensification of agricultural production in the Asian monsoon region. Furthermore, significant modification of vapor flows in the lands around the Indian Ocean basin will increase the risk for changes in the behavior of the Asian monsoon system. This analysis suggests that the need to increase food production in one region may affect the capability to increase food production in another. At the scale of the Earth as a whole, our results emphasize the need for climate models to take land-use change, in both land cover and irrigation, into account.     

Human (HLA-A and HLA-B) and murine (H-2K and H-2D) histocompatibility antigens are cell surface receptors for Semliki Forest virus.

The proteins coded for by the HLA-A and HLA-B loci in man and the H-2K and H-2D loci in mice were identified as cell surface receptors for Semliki Forest virus. This conclusion is based on the following observations: (i) Water-soluble octamers of viral coat proteins inhibit the complement-dependent cytotoxicity of antibodies directed against H-2K and H-2D antigens in mouse cells. (ii) Isolated detergent-soluble HLA-A and HLA-B antigens reconstituted in lipid vesicles inhibit the binding of viral proteins to human cells (as do the water-soluble antigens to a lesser extent). (iii) Reconstituted HLA-A and HLA-B vesicles interact in solution with Semliki Forest virus (or with vesicles containing viral spike proteins), as demonstrated by coprecipitation with antisera. (iv) Complexes between viral spoke proteins and HLA-A and HLA-B antigens or H-2K and H-2D antigens can be isolated from the cell surface by utilizing affinity chromatography or immunoprecipitation.