Vorinostat Renders the Replication-Competent Latent Reservoir of Human Immunodeficiency Virus (HIV) Vulnerable to Clearance by CD8 T Cells

Latently human immunodeficiency virus (HIV)-infected cells are transcriptionally quiescent and invisible to clearance by the immune system. To demonstrate that the latency reversing agent vorinostat (VOR) induces a window of vulnerability in the latent HIV reservoir, defined as the triggering of viral antigen production sufficient in quantity and duration to allow for recognition and clearance of persisting infection, we developed a latency clearance assay (LCA). The LCA is a quantitative viral outgrowth assay (QVOA) that includes the addition of immune effectors capable of clearing cells expressing viral antigen. Here we show a reduction in the recovery of replication-competent virus from VOR exposed resting CD4 T cells following addition of immune effectors for a discrete period. TAKE HOME MESSAGE: VOR exposure leads to sufficient production of viral protein on the cell surface, creating a window of vulnerability within this latent reservoir in antiretroviral therapy (ART)-suppressed HIV-infected individuals that allows the clearance of latently infected cells by an array of effector mechanisms

Interval dosing with the HDAC inhibitor vorinostat effectively reverses HIV latency

BACKGROUND. The histone deacetylase (HDAC) inhibitor vorinostat (VOR) can increase HIV RNA expression in vivo within resting CD4+ T cells of aviremic HIV+ individuals. However, while studies of VOR or other HDAC inhibitors have reported reversal of latency, none has demonstrated clearance of latent infection. We sought to identify the optimal dosing of VOR for effective serial reversal of HIV latency

The Center for HIV/AIDS Vaccine Immunology (CHAVI) multi-site quality assurance program for cryopreserved Human Peripheral Blood Mononuclear Cells

The Center for HIV/AIDS Vaccine Immunology (CHAVI) consortium was established to determine the host and virus factors associated with HIV transmission, infection and containment of virus replication, with the goal of advancing the development of an HIV protective vaccine. Studies to meet this goal required the use of cryopreserved Peripheral Blood Mononuclear Cell (PBMC) specimens, and therefore it was imperative that a quality assurance (QA) oversight program be developed to monitor PBMC samples obtained from study participants at multiple international sites. Nine site-affiliated laboratories in Africa and the USA collected and processed PBMCs, and cryopreserved PBMC were shipped to CHAVI repositories in Africa and the USA for long-term storage. A three-stage program was designed, based on Good Clinical Laboratory Practices (GCLP), to monitor PBMC integrity at each step of this process. The first stage evaluated the integrity of fresh PBMCs for initial viability, overall yield, and processing time at the site-affiliated laboratories (Stage 1); for the second stage, the repositories determined post-thaw viability and cell recovery of cryopreserved PBMC, received from the site-affiliated laboratories (Stage 2); the third stage assessed the long-term specimen storage at each repository (Stage 3). Overall, the CHAVI PBMC QA oversight program results highlight the relative importance of each of these stages to the ultimate goal of preserving specimen integrity from peripheral blood collection to long-term repository storage

Aminobisphosphonates reactivate the latent reservoir in people living with HIV-1

Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure HIV-1 infection include “shock and kill” strategies to disrupt latency using small molecules or latency-reversing agents (LRAs) to induce expression of HIV-1 enabling cytotoxic immune cells to eliminate infected cells. The modest success of current LRAs urges the field to identify novel drugs with increased clinical efficacy. Aminobisphosphonates (N-BPs) that include pamidronate, zoledronate, or alendronate, are the first-line treatment of bone-related diseases including osteoporosis and bone malignancies. Here, we show the use of N-BPs as a novel class of LRA: we found in ex vivo assays using primary cells from ART-suppressed people living with HIV-1 that N-BPs induce HIV-1 from latency to levels that are comparable to the T cell activator phytohemagglutinin (PHA). RNA sequencing and mechanistic data suggested that reactivation may occur through activation of the activator protein 1 signaling pathway. Stored samples from a prior clinical trial aimed at analyzing the effect of alendronate on bone mineral density, provided further evidence of alendronate-mediated latency reversal and activation of immune effector cells. Decay of the reservoir measured by IPDA was however not detected. Our results demonstrate the novel use of N-BPs to reverse HIV-1 latency while inducing immune effector functions. This preliminary evidence merits further investigation in a controlled clinical setting possibly in combination with therapeutic vaccination

Breaking the Barriers to the Circular Economy

The Copernicus Institute of Sustainable Development, Utrecht University, the Netherlands and Deloitte have jointly carried out research on barriers to the Circular Economy (CE) in the European Union. For this research, a survey with 153 businesses, 55 government officials and expert interviews with forty-seven thought leaders on the circular economy from businesses, governments, academia and NGOs have been carried out. Two types of barriers emerged as main barriers Firstly, there are the cultural barriers of lacking consumer interest and awareness as well as a hesitant company culture. This finding is at odds with claims that the circular economy concept is hyped; rather, the concept may be a niche discussion among sustainable development professionals. Secondly, market barriers emerged as a core category of barriers, particularly low virgin material prices and high upfront investments costs for circular business models. Government intervention might be needed to overcome the market barriers which then may also help to overcome cultural barriers. Cultural barriers do also need to be overcome by circular start-ups. And, even though there is still no circular startup that has made global headlines, this may change soon

Barriers to the Circular Economy : Evidence From the European Union (EU)

Abstract The circular economy concept is much discussed in the European Union (EU), but only limited progress has been accomplished so far regarding its implementation. Most scholarly studies blame this on various technological barriers. Our work rebuts these studies. We present the first large-N-study on circular economy barriers in the EU (208 survey respondents, 47 expert interviews). We find that cultural barriers, particularly a lack of consumer interest and awareness as well as a hesitant company culture, are considered the main circular economy barriers by businesses and policy-makers. These are driven by market barriers which, in turn, are induced by a lack of synergistic governmental interventions to accelerate the transition towards a circular economy. Meanwhile, not a single technological barrier is ranked among the most pressing circular economy barriers, according to our research. Overall, our work suggests that circular economy is a niche discussion among sustainable development professionals at this stage. Significant efforts need to be undertaken for the concept to maintain its momentum

Study of Humoral Immunity to Commensal Oral Bacteria in Human Infants Demonstrates the Presence of Secretory Immunoglobulin A Antibodies Reactive with Actinomyces naeslundii Genospecies 1 and 2 Ribotypes

The mouths of three human infants were examined from birth to age 2 years to detect colonization of Actinomyces naeslundii genospecies 1 and 2. These bacteria did not colonize until after tooth eruption. The diversity of posteruption isolates was determined by ribotyping. Using immunoblotting and enzyme-linked immunosorbent assay, we determined the reactivity of secretory immunoglobulin A (SIgA) antibodies in saliva samples collected from each infant before and after colonization against cell wall proteins from their own A. naeslundii strains and carbohydrates from standard A. naeslundii genospecies 1 and 2 strains. A. naeslundii genospecies 1 and 2 carbohydrate-reactive SIgA antibodies were not detected in any saliva sample. However, SIgA antibodies reactive with cell wall proteins were present in saliva before these bacteria colonized the mouth. These antibodies could be almost completely removed by absorption with A. odontolyticus, a species known to colonize the human mouth shortly after birth. However, after colonization by A. naeslundii genospecies 1 and 2, specific antibodies were induced that could not be removed by absorption with A. odontolyticus. Cluster analysis of the patterns of reactivity of postcolonization salivary antibodies from each infant with antigens from their own strains showed that not only could these antibodies discriminate among strains but antibodies in saliva samples collected at different times showed different reactivity patterns. Overall, these data suggest that, although much of the salivary SIgA antibodies reactive with A. naeslundii genospecies 1 and 2 are directed against genus-specific or more broadly cross-reactive antigens, species, genospecies, and possibly strain-specific antibodies are induced in response to colonization

Barriers to the Circular Economy : Evidence From the European Union (EU)

Abstract The circular economy concept is much discussed in the European Union (EU), but only limited progress has been accomplished so far regarding its implementation. Most scholarly studies blame this on various technological barriers. Our work rebuts these studies. We present the first large-N-study on circular economy barriers in the EU (208 survey respondents, 47 expert interviews). We find that cultural barriers, particularly a lack of consumer interest and awareness as well as a hesitant company culture, are considered the main circular economy barriers by businesses and policy-makers. These are driven by market barriers which, in turn, are induced by a lack of synergistic governmental interventions to accelerate the transition towards a circular economy. Meanwhile, not a single technological barrier is ranked among the most pressing circular economy barriers, according to our research. Overall, our work suggests that circular economy is a niche discussion among sustainable development professionals at this stage. Significant efforts need to be undertaken for the concept to maintain its momentum

Clonal Diversity and Turnover of Streptococcus mitis bv. 1 on Shedding and Nonshedding Oral Surfaces of Human Infants during the First Year of Life

Streptococcus mitis bv. 1 is a pioneer colonizer of the human oral cavity. Studies of its population dynamics within parents and their infants and within neonates have shown extensive diversity within and between subjects. We examined the genetic diversity and clonal turnover of S. mitis bv. 1 isolated from the cheeks, tongue, and primary incisors of four infants from birth to 1 year of age. In addition, we compared the clonotypes of S. mitis bv. 1 isolated from their mothers' saliva collected in parallel to determine whether the mother was the origin of the clones colonizing her infant. Of 859 isolates obtained from the infants, 568 were unique clones. Each of the surfaces examined, whether shedding or nonshedding, displayed the same degree of diversity. Among the four infants it was rare to detect the same clone colonizing more than one surface at a given visit. There was little evidence for persistence of clones, but when clones were isolated on multiple visits they were not always found on the same surface. A similar degree of clonal diversity of S. mitis bv. 1 was observed in the mothers' saliva as in their infants' mouths. Clones common to both infant and mothers' saliva were found infrequently suggesting that this is not the origin of the infants' clones. It is unclear whether mucosal immunity exerts the environmental pressure driving the genetic diversity and clonal turnover of S. mitis bv. 1, which may be mechanisms employed by this bacterium to evade immune elimination

Breaking the Barriers to the Circular Economy

The Copernicus Institute of Sustainable Development, Utrecht University, the Netherlands and Deloitte have jointly carried out research on barriers to the Circular Economy (CE) in the European Union. For this research, a survey with 153 businesses, 55 government officials and expert interviews with forty-seven thought leaders on the circular economy from businesses, governments, academia and NGOs have been carried out. Two types of barriers emerged as main barriers Firstly, there are the cultural barriers of lacking consumer interest and awareness as well as a hesitant company culture. This finding is at odds with claims that the circular economy concept is hyped; rather, the concept may be a niche discussion among sustainable development professionals. Secondly, market barriers emerged as a core category of barriers, particularly low virgin material prices and high upfront investments costs for circular business models. Government intervention might be needed to overcome the market barriers which then may also help to overcome cultural barriers. Cultural barriers do also need to be overcome by circular start-ups. And, even though there is still no circular startup that has made global headlines, this may change soon