Preclinical Assessment of HIV Vaccines and Microbicides by Repeated Low-Dose Virus Challenges

BACKGROUND: Trials in macaque models play an essential role in the evaluation of biomedical interventions that aim to prevent HIV infection, such as vaccines, microbicides, and systemic chemoprophylaxis. These trials are usually conducted with very high virus challenge doses that result in infection with certainty. However, these high challenge doses do not realistically reflect the low probability of HIV transmission in humans, and thus may rule out preventive interventions that could protect against “real life” exposures. The belief that experiments involving realistically low challenge doses require large numbers of animals has so far prevented the development of alternatives to using high challenge doses. METHODS AND FINDINGS: Using statistical power analysis, we investigate how many animals would be needed to conduct preclinical trials using low virus challenge doses. We show that experimental designs in which animals are repeatedly challenged with low doses do not require unfeasibly large numbers of animals to assess vaccine or microbicide success. CONCLUSION: Preclinical trials using repeated low-dose challenges represent a promising alternative approach to identify potential preventive interventions

Dendritic Cells are preferentially targeted among hematolymphocytes by Modified Vaccinia Virus Ankara and play a key role in the induction of virus-specific T cell responses in vivo

<p>Abstract</p> <p>Background</p> <p>Modified Vaccinia Ankara (MVA) is a highly attenuated strain of vaccinia virus (VV) that has lost approximately 15% of the VV genome, along with the ability to replicate in most mammalian cells. It has demonstrated impressive safety and immunogenicity profile in both preclinical and clinical studies, and is being actively explored as a promising vaccine vector for a number of infectious diseases and malignancies. However, little is known about how MVA interacts with the host immune system constituents, especially dendritic cells (DCs), to induce strong immune responses despite its inability to replicate in vivo. Using <it>in vitro </it>and <it>in vivo </it>murine models, we systematically investigated the susceptibility of murine DCs to MVA infection, and the immunological consequences of the infection.</p> <p>Results</p> <p>Our data demonstrate that MVA preferentially infects professional antigen presenting cells, especially DCs, among all the subsets of hematolymphoid cells. In contrast to the reported blockage of DC maturation and function upon VV infection, DCs infected by MVA undergo phenotypic maturation and produce innate cytokine IFN-α within 18 h of infection. Substantial apoptosis of MVA-infected DCs occurs after 12 h following infection and the apoptotic DCs are readily phagocytosed by uninfected DCs. Using MHC class I – deficient mice, we showed that both direct and cross-presentation of viral Ags are likely to be involved in generating viral-specific CD8⁺T cell responses. Finally, DC depletion abrogated the T cell activation <it>in vivo</it>.</p> <p>Conclusion</p> <p>We present the first <it>in vivo </it>evidence that among hematolymphoid cells, DCs are the most susceptible targets for MVA infection, and DC-mediated Ag presentation is required for the induction of MVA-specific immune responses. These results provide important information concerning the mechanisms by which strong immune responses are elicited to MVA-encoded antigens and may inform efforts to further improve the immunogenicity of this already promising vaccine vector.</p

SIVsm Quasispecies Adaptation to a New Simian Host

Despite the potential for infectious agents harbored by other species to become emerging human pathogens, little is known about why some agents establish successful cross-species transmission, while others do not. The simian immunodeficiency viruses (SIVs), certain variants of which gave rise to the human HIV-1 and HIV-2 epidemics, have demonstrated tremendous success in infecting new host species, both simian and human. SIVsm from sooty mangabeys appears to have infected humans on several occasions, and was readily transmitted to nonnatural Asian macaque species, providing animal models of AIDS. Here we describe the first in-depth analysis of the tremendous SIVsm quasispecies sequence variation harbored by individual sooty mangabeys, and how this diverse quasispecies adapts to two different host species—new nonnatural rhesus macaque hosts and natural sooty mangabey hosts. Viral adaptation to rhesus macaques was associated with the immediate amplification of a phylogenetically related subset of envelope (env) variants. These variants contained a shorter variable region 1 loop and lacked two specific glycosylation sites, which may be selected for during acute infection. In contrast, transfer of SIVsm to its natural host did not subject the quasispecies to any significant selective pressures or bottleneck. After 100 d postinfection, variants more closely representative of the source inoculum reemerged in the macaques. This study describes an approach for elucidating how pathogens adapt to new host species, and highlights the particular importance of SIVsm env diversity in enabling cross-species transmission. The replicative advantage of a subset of SIVsm variants in macaques may be related to features of target cells or receptors that are specific to the new host environment, and may involve CD4-independent engagement of a viral coreceptor conserved among primates

Lipopolysaccharide Is a Potent Monocyte/Macrophage-specific Stimulator of Human Immunodeficiency Virus Type 1 Expression

Lipopolysaccharide (LPS) potently stimulates human immunodeficiency virus type 1-long terminal repeat (HIV-1-LTR) CAT constructs transfected into monocyte/macrophage-like cell lines but not a T cell line. This effect appears to be mediated through the induction of nuclear factor kappa B (NF-kappa B). Electrophoretic mobility shift assays demonstrate that LPS induces a DNA binding activity indistinguishable from NF-kappa B in U937 and THP-1 cells. LPS is also shown to dramatically increase HIV-1 production from a chronically infected monocyte/macrophage-like cloned cell line, U1, which produces very low levels of HIV-1 at baseline. The stimulation of viral production from this cell line occurs only if these cells are treated with granulocyte/macrophage colony-stimulating factor (GM-CSF) before treatment with LPS. This stimulation of HIV-1 production is correlated with an increase in the level of HIV-1 RNA and and activation of NF-kappa B. LPS is not able to induce HIV-1 production in a cloned T cell line. The effect of LPS on HIV-1 replication occurs at picogram per milliliter concentrations and may be clinically significant in understanding the variability of the natural history of HIV-1 infection

A ferritin-based COVID-19 nanoparticle vaccine that elicits robust, durable, broad-spectrum neutralizing antisera in non-human primates

While the rapid development of COVID-19 vaccines has been a scientific triumph, the need remains for a globally available vaccine that provides longer-lasting immunity against present and future SARS-CoV-2 variants of concern (VOCs). Here, we describe DCFHP, a ferritin-based, protein-nanoparticle vaccine candidate that, when formulated with aluminum hydroxide as the sole adjuvant (DCFHP-alum), elicits potent and durable neutralizing antisera in non-human primates against known VOCs, including Omicron BQ.1, as well as against SARS-CoV-1. Following a booster ~one year after the initial immunization, DCFHP-alum elicits a robust anamnestic response. To enable global accessibility, we generated a cell line that can enable production of thousands of vaccine doses per liter of cell culture and show that DCFHP-alum maintains potency for at least 14 days at temperatures exceeding standard room temperature. DCFHP-alum has potential as a once-yearly (or less frequent) booster vaccine, and as a primary vaccine for pediatric use including in infants

Stress-related psychological symptoms contribute to axial pain persistence after motor vehicle collision

Posttraumatic stress disorder (PTSD) symptoms and pain after traumatic events such as motor vehicle collision (MVC) have been proposed to be mutually promoting. We performed a prospective multicenter study that enrolled 948 individuals who presented to the emergency department within 24 hours of MVC and were discharged home after evaluation. Follow-up evaluations were completed 6 weeks, 6 months, and 1 year after MVC. Path analysis results supported the hypothesis that axial pain after MVC consistently promotes the maintenance of hyperarousal and intrusive symptoms, from the early weeks after injury through 1 year. In addition, path analysis results supported the hypothesis that one or more PTSD symptom clusters had an influence on axial pain outcomes throughout the year after MVC, with hyperarousal symptoms most influencing axial pain persistence in the initial months after MVC. The influence of hyperarousal symptoms on pain persistence was only present among individuals with genetic vulnerability to stress-induced pain, suggesting specific mechanisms by which hyperarousal symptoms may lead to hyperalgesia and allodynia. Further studies are needed to better understand the specific mechanisms by which pain and PTSD symptoms enhance one another after trauma, and how such mechanisms vary among specific patient subgroups, to better inform the development of secondary preventive interventions

Color coherent phenomena on nuclei and the QCD evolution equation

We review the phenomenon of color coherence in quantum chromodynamics (QCD), its implications for hard and soft processes with nuclei, and its experimental manifestations. The relation of factorization theorems in QCD with color coherence phenomena in deep inelastic scattering (DIS) and color coherence phenomena in hard exclusive processes is emphasized. Analyzing numerically the QCD evolution equation for conventional and skewed parton densities in nuclei, we study the onset of generalized color transparency and nuclear shadowing of the sea quark and gluon distributions in nuclei as well as related phenomena. Such novel results as the dependence of the effective coherence length on $Q^2$ and general trends of the QCD evolution are discussed. The limits of the applicability of the QCD evolution equation at small Bjorken $x$ are estimated by comparing the inelastic quark-antiquark- and two gluon-nucleon (nucleus) cross sections, calculated within the DGLAP approximation, with the dynamical boundaries, which follow from the unitarity of the $S$ matrix for purely QCD interactions. We also demonstrate that principles of color coherence play an important role in the processes of soft diffraction off nuclei.Comment: 58 pages, 19 figures, Revtex. Minor editor's changes, final version published in J.Phys. G27 (2001) R23-6

Deriving effective models for multiscale systems via evolutionary GammaGamma-convergence

We discuss possible extensions of the recently established theory of evolutionary Gamma convergence for gradient systems to nonlinear dynamical systems obtained by perturbation of a gradient systems. Thus, it is possible to derive effective equations for pattern forming systems with multiple scales. Our applications include homogenization of reaction-diffusion systems, the justification of amplitude equations for Turing instabilities, and the limit from pure diffusion to reaction-diffusion. This is achieved by generalizing the Gamma-limit approaches based on the energy-dissipation principle or the evolutionary variational estimate

A Future Large-Aperture UVOIR Space Observatory: Key Technologies and Capabilities

We present the key technologies and capabilities that will enable a future, large-aperture ultravioletopticalinfrared (UVOIR) space observatory. These include starlight suppression systems, vibration isolation and control systems, lightweight mirror segments, detector systems, and mirror coatings. These capabilities will provide major advances over current and near-future observatories for sensitivity, angular resolution, and starlight suppression. The goals adopted in our study for the starlight suppression system are 10-10 contrast with an inner working angle of 20 milliarcsec and broad bandpass. We estimate that a vibration and isolation control system that achieves a total system vibration isolation of 140 dB for a vibration-isolated mass of 5000 kg is required to achieve the high wavefront error stability needed for exoplanet coronagraphy. Technology challenges for lightweight mirror segments include diffraction-limited optical quality and high wavefront error stability as well as low cost, low mass, and rapid fabrication. Key challenges for the detector systems include visible-blind, high quantum efficiency UV arrays, photon counting visible and NIR arrays for coronagraphic spectroscopy and starlight wavefront sensing and control, and detectors with deep full wells with low persistence and radiation tolerance to enable transit imaging and spectroscopy at all wavelengths. Finally, mirror coatings with high reflectivity ( 90), high uniformity ( 1) and low polarization ( 1) that are scalable to large diameter mirror substrates will be essential for ensuring that both high throughput UV observations and high contrast observations can be performed by the same observatory