Trispecific antibody targeting HIV-1 and T cells activates and eliminates latently-infected cells in HIV/SHIV infections.

Agents that can simultaneously activate latent HIV, increase immune activation and enhance the killing of latently-infected cells represent promising approaches for HIV cure. Here, we develop and evaluate a trispecific antibody (Ab), N6/αCD3-αCD28, that targets three independent proteins: (1) the HIV envelope via the broadly reactive CD4-binding site Ab, N6; (2) the T cell antigen CD3; and (3) the co-stimulatory molecule CD28. We find that the trispecific significantly increases antigen-specific T-cell activation and cytokine release in both CD4 <sup>+</sup> and CD8 <sup>+</sup> T cells. Co-culturing CD4 <sup>+</sup> with autologous CD8 <sup>+</sup> T cells from ART-suppressed HIV <sup>+</sup> donors with N6/αCD3-αCD28, results in activation of latently-infected cells and their elimination by activated CD8 <sup>+</sup> T cells. This trispecific antibody mediates CD4 <sup>+</sup> and CD8 <sup>+</sup> T-cell activation in non-human primates and is well tolerated in vivo. This HIV-directed antibody therefore merits further development as a potential intervention for the eradication of latent HIV infection

Vascular Endothelial Growth Factor Receptor-3 Directly Interacts with Phosphatidylinositol 3-Kinase to Regulate Lymphangiogenesis

Background Dysfunctional lymphatic vessel formation has been implicated in a number of pathological conditions including cancer metastasis, lymphedema, and impaired wound healing. The vascular endothelial growth factor (VEGF) family is a major regulator of lymphatic endothelial cell (LEC) function and lymphangiogenesis. Indeed, dissemination of malignant cells into the regional lymph nodes, a common occurrence in many cancers, is stimulated by VEGF family members. This effect is generally considered to be mediated via VEGFR-2 and VEGFR-3. However, the role of specific receptors and their downstream signaling pathways is not well understood. Methods and Results Here we delineate the VEGF-C/VEGF receptor (VEGFR)-3 signaling pathway in LECs and show that VEGF-C induces activation of PI3K/Akt and MEK/Erk. Furthermore, activation of PI3K/Akt by VEGF-C/VEGFR-3 resulted in phosphorylation of P70S6K, eNOS, PLCc1, and Erk1/2. Importantly, a direct interaction between PI3K and VEGFR-3 in LECs was demonstrated both in vitro and in clinical cancer specimens. This interaction was strongly associated with the presence of lymph node metastases in primary small cell carcinoma of the lung in clinical specimens. Blocking PI3K activity abolished VEGF-C-stimulated LEC tube formation and migration. Conclusions Our findings demonstrate that specific VEGFR-3 signaling pathways are activated in LECs by VEGF-C. The importance of PI3K in VEGF-C/VEGFR-3-mediated lymphangiogenesis provides a potential therapeutic target for the inhibition of lymphatic metastasis

Track A Basic Science

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138319/1/jia218438.pd

New member of the V1V2-directed CAP256-VRC26 lineage that shows increased breadth and exceptional potency.

CAPRISA, 2016.Abstract available in pdf

Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates

Background: Vaccines to prevent coronavirus disease 2019 (Covid-19) are urgently needed. The effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines on viral replication in both upper and lower airways is important to evaluate in nonhuman primates. Methods: Nonhuman primates received 10 or 100 μg of mRNA-1273, a vaccine encoding the prefusion-stabilized spike protein of SARS-CoV-2, or no vaccine. Antibody and T-cell responses were assessed before upper- and lower-airway challenge with SARS-CoV-2. Active viral replication and viral genomes in bronchoalveolar-lavage (BAL) fluid and nasal swab specimens were assessed by polymerase chain reaction, and histopathological analysis and viral quantification were performed on lung-tissue specimens. Results: The mRNA-1273 vaccine candidate induced antibody levels exceeding those in human convalescent-phase serum, with live-virus reciprocal 50% inhibitory dilution (ID50) geometric mean titers of 501 in the 10-μg dose group and 3481 in the 100-μg dose group. Vaccination induced type 1 helper T-cell (Th1)-biased CD4 T-cell responses and low or undetectable Th2 or CD8 T-cell responses. Viral replication was not detectable in BAL fluid by day 2 after challenge in seven of eight animals in both vaccinated groups. No viral replication was detectable in the nose of any of the eight animals in the 100-μg dose group by day 2 after challenge, and limited inflammation or detectable viral genome or antigen was noted in lungs of animals in either vaccine group. Conclusions: Vaccination of nonhuman primates with mRNA-1273 induced robust SARS-CoV-2 neutralizing activity, rapid protection in the upper and lower airways, and no pathologic changes in the lung. (Funded by the National Institutes of Health and others.)

International AIDS Society global scientific strategy: towards an HIV cure 2016

Antiretroviral therapy is not curative. Given the challenges in providing lifelong therapy to a global population of more than 35 million people living with HIV, there is intense interest in developing a cure for HIV infection. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. This Perspective summarizes the group's strategy

Enhancement of physicochemical stability and reduction in enzyme and microbial activity of apple juice by hydrodynamic cavitation processing

Conventional thermally processed apple juices are nutritionally depleted because the heat sensitivity degrades the bioactive compounds that comprise them. This study proposed a non-thermal technique, hydrodynamic cavitation (HC), to preserve the nutritional content and prevent the loss of bioactive components in apple juice. In addition, the effect of hydrodynamic cavitation on the physicochemical, nutrition, and enzyme inactivation of freshly expressed apple juice has been studied. The design expert software has been used for process optimization, while fuzzy logic was applied for sensory. Hydrodynamic cavitation has been used on freshly extracted apple juice with inlet pressure in the range of (34.47–103.421 kPa) for a treatment time of (0–30 min). The apple juice was treated thermally at 90 °C for 2.5 min to compare the cavitation results. The settling of particles in the cavitation sample was 7%, which was lower than the heat-treated sample (10%) and untreated control sample (39%) and had a noticeable effect on the cloud value and stability of the apple juice. The HC treatment reduces the particle size of fresh apple juice from 8934.09 nm to 1112 nm, resulting in a homogenizing effect, a decrease in viscosity, and improved juice stability. Hydrodynamic cavitation reduced the antioxidant activity from 0.4987 mg GAE mL−1 (control) to 0.3951 mg GAE mL−1 yet retained better activity than the heat-treated apple juice (0.3489 ± 0.34 mg GAE mL−1) with microbial log reduction of 0.9 at 103.42 kPa treated for 30 min. After 15 days of storage at 4 °C, HC-treated juice had higher quality features and nutrient retention than heat-treated apple juice

Molecular Interface Engineering via Triazatruxene-Based Moieties/NiOx as Hole-Selective Bilayers in Perovskite Solar Cells for Reliability

Interface engineering is an effective approach to decrease nonradiative recombination and the energy barrier at the perovskite/hole transporting layer (HTL) interfaces. To overcome such limitations, an organic semiconductor (DTT-EHDI 2) is proposed, which is, composed of dithienothiophene (DTT) as the core and a planar triazatruxene incorporating an alkyl chain as the side group. This is noted to be an effective interfacial layer for inverted planar perovskite solar cells (PSCs). The altered interface effectively minimizes the detrimental charge recombination and tailors the photoinduced charge transfer dynamics at the interface of the inorganic HTL/perovskite. The π-conjugation in DTT-EHDI 2 induces high hole mobility and electrical conductivity via electron-donating properties and strong π–π intermolecular interaction. The synergetic approach leads to a substantial performance enhancement in dopant-free DTT-EHDI 2-based inverted planar PSCs, achieving 18.15% power conversion efficiency with negligible hysteresis effect. The present approach provides an effective direction of the cost-effective thiophene derivative as an interfacial agent to escalate the optoelectronic performances in photovoltaics. © 2022 Wiley-VCH GmbHThis work received funding from the European Union H2020 Programme under a European Research Council Consolidator grant (MOLEMAT, 726360) and PARASOL (RTI2018-102292-B-I00) and ARISE (PID2019-111774RB-100) from the Spanish Ministry of Science and Innovation.Peer reviewe