Drug Resistance Mutation Frequency of Single-Genome Amplification-Derived HIV-1 Polymerase Genomes in the Cerebrospinal Fluid and Plasma of HIV-1-Infected Individuals under Nonsuppressive Therapy.

HIV-1 evolution in the cerebrospinal fluid (CSF) and plasma may result in discordant drug resistance mutations (DRMs) in the compartments. Single-genome amplification (SGA) was used to generate partial HIV-1 polymerase genomes in paired CSF and plasma samples from 12 HIV-1-positive participants in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study who were classified as neurocognitively unimpaired or with various degrees of HIV-associated neurocognitive disorders (HAND). Subjects were viremic on combination antiretroviral therapy (cART).

VSV-Displayed HIV-1 Envelope Identifies Broadly Neutralizing Antibodies Class-Switched to IgG and IgA.

The HIV-1 envelope (Env) undergoes conformational changes during infection. Broadly neutralizing antibodies (bNAbs) are typically isolated by using soluble Env trimers, which do not capture all Env states. To address these limitations, we devised a vesicular stomatitis virus (VSV)-based probe to display membrane-embedded Env trimers and isolated five bNAbs from two chronically infected donors, M4008 and M1214.

Optical Control of Cytokine Production Using Photoswitchable Galactosylceramides.

α-Galactosylceramides are glycosphingolipids that show promise in cancer immunotherapy. After presentation by CD1d, they activate natural killer T cells (NKT), which results in the production of a variety of pro-inflammatory and immunomodulatory cytokines. Herein, we report the synthesis and biological evaluation of photochromic derivatives of KRN-7000, the activity of which can be modulated with light.

Cell-line-based assay for the toxicity/benefit analysis of lipopolysaccharides in plants.

There are many immune-boosting medicinal plants that can potently activate innate immune cells. Recent studies indicate that the active factors of some immune-boosting plants are lipopolysaccharides (LPSs) of plant-associated bacteria. However, little is currently known about the potential risk and benefit of LPSs in medicinal plants.

Islatravir for the treatment and prevention of infection with the human immunodeficiency virus type 1.

Purpose Of Review: To discuss the potential role of islatravir (ISL), a novel reverse transcriptase translocation inhibitor, in the treatment and prevention of human immunodeficiency virus type 1 (HIV-1) infection.

Recent Findings: Islatravir (4'-ethynyl-2-fluoro-2'-deoxyadenosine, MK-8591) is a long-acting first-in-class nucleoside reverse transcriptase translocation inhibitor with the potential for versatile dosing routes and dosing intervals. It demonstrated robust antiviral activity when dosed once daily and once weekly in HIV-1-infected individuals and SIV-infected rhesus macaques.

Functional Human CD141+ Dendritic Cells in Human Immune System Mice.

Background: For the purpose of studying functional human dendritic cells (DCs) in a humanized mouse model that mimics the human immune system (HIS), a model referred to as HIS mice was established.

Methods: Human immune system mice were made by engrafting NOD/SCID/IL2Rgammanull (NSG) mice with human hematopoietic stem cells (HSCs) following the transduction of genes encoding human cytokines and human leukocyte antigen (HLA)-A2.1 by adeno-associated virus serotype 9 (AAV9) vectors.

A Glycolipid Adjuvant, 7DW8-5, Enhances the Protective Immune Response to the Current Split Influenza Vaccine in Mice.

Vaccination is an effective strategy to control influenza disease. Adjuvants enhance the efficacy of vaccines, but few adjuvants are approved for human use, so novel, safe, and effective adjuvants are urgently needed. The glycolipid adjuvant 7DW8-5 has shown adjuvanticity to malaria vaccine; however, its adjuvant effect for seasonal influenza vaccine remains unknown.

Once-Weekly Oral Dosing of MK-8591 Protects Male Rhesus Macaques From Intrarectal Challenge With SHIV109CP3.

Background: MK-8591 (4'-ethynyl-2-fluoro-2'-deoxyadenosine [EFdA]) is a novel reverse transcriptase-translocation inhibitor.

Methods: We assessed MK-8591 as preexposure prophylaxis in the rhesus macaque model of intrarectal challenge with simian/human immunodeficiency virus (SHIV). In study 1, 8 rhesus macaques received 3.

Abundance of Plant-Associated Correlates with Immunostimulatory Activity of .

is a medicinal plant known for a variety of biological effects, including its ability to stimulate innate immune cells in humans. Recent studies indicate that the immunostimulatory activity of arises from microbe-associated molecular patterns (MAMPs) of plant-associated bacteria. However, it is unknown which bacterial taxa in are responsible for the production of immunostimulatory MAMPs.

An Asymmetric Opening of HIV-1 Envelope Mediates Antibody-Dependent Cellular Cytotoxicity.

The HIV-1 envelope glycoprotein (Env) (gp120-gp41) is the target for neutralizing antibodies and antibody-dependent cellular cytotoxicity (ADCC). HIV-1 Env is flexible, sampling different conformational states. Before engaging CD4, Env adopts a closed conformation (State 1) that is largely antibody resistant.

A Potent CD1d-binding Glycolipid for iNKT-Cell-based Therapy Against Human Breast Cancer.

Background/aim: Invariant natural killer T-cells (iNKT) stimulated by CD1d-binding glycolipids have been shown to exert antitumor effects by a number of studies in a mouse model. Breast cancer is a devastating disease, with different types of breast cancer recurring locally or distant as metastatic/advanced disease following initial treatment. The aim of this study was to examine the tumoricidal effect of a CD1d-binding glycolipid, called 7DW8-5, against a highly invasive human breast cancer cell line both in vitro and in vivo.

Satisfaction and acceptability of cabotegravir long-acting injectable suspension for prevention of HIV: Patient perspectives from the ECLAIR trial.

Background: Cabotegravir (GSK1265744) is an integrase strand transfer inhibitor in development as a long-acting (LA) intramuscular injectable suspension for HIV-1 pre-exposure prophylaxis (PrEP).

Objective: We report participant outcomes from the phase IIa ECLAIR study related to tolerability, acceptability, and satisfaction of cabotegravir LA.

Methods: The ECLAIR study (ClinicalTrials.

Development of a novel mechanism-based glycolipid adjuvant for vaccination.

The inability to elicit strong and durable cellular responses is a major obstacle in the development of successful vaccines, in particular those against malaria. In this regard, the generation of novel adjuvants that will potently boost cell-mediated immunity induced by candidate vaccines is helpful. We and others have found a glycolipid, called α-galactosylceramide (α-GalCer), which could be presented on CD1d expressed by antigen-presenting cells (APCs) and stimulate natural killer T (NKT) cells.

Gp120 V5 Is Targeted by the First Wave of Sequential Neutralizing Antibodies in SHIV-Infected Rhesus Macaques.

Simian-human immunodeficiency virus (SHIV) infection provides a relevant animal model to study HIV-1 neutralization breadth. With previously identified SHIV infected rhesus macaques that did or did not develop neutralization breadth, we characterized the transmitted/founder viruses and initial autologous/homologous neutralizing antibodies in these animals. The plasma viral load and blood CD4 count did not distinguish macaques with and without breadth, and only one tested homologous envelope clone revealed a trend for macaques with breadth to favor an early homologous response.

Human Immune System Mice for the Study of Human Immunodeficiency Virus-Type 1 Infection of the Central Nervous System.

Immunodeficient mice transplanted with human cell populations or tissues, also known as human immune system (HIS) mice, have emerged as an important and versatile tool for the study of human immunodeficiency virus-type 1 (HIV-1) pathogenesis, treatment, and persistence in various biological compartments. Recent work in HIS mice has demonstrated their ability to recapitulate critical aspects of human immune responses to HIV-1 infection, and such studies have informed our knowledge of HIV-1 persistence and latency in the context of combination antiretroviral therapy. The central nervous system (CNS) is a unique, immunologically privileged compartment susceptible to HIV-1 infection, replication, and immune-mediated damage.

5' Rapid Amplification of cDNA Ends and Illumina MiSeq Reveals B Cell Receptor Features in Healthy Adults, Adults With Chronic HIV-1 Infection, Cord Blood, and Humanized Mice.

Using 5' rapid amplification of cDNA ends, Illumina MiSeq, and basic flow cytometry, we systematically analyzed the expressed B cell receptor (BCR) repertoire in 14 healthy adult PBMCs, 5 HIV-1+ adult PBMCs, 5 cord blood samples, and 3 HIS-CD4/B mice, examining the full-length variable region of μ, γ, α, κ, and λ chains for V-gene usage, somatic hypermutation (SHM), and CDR3 length. Adding to the known repertoire of healthy adults, Illumina MiSeq consistently detected small fractions of reads with high mutation frequencies including hypermutated μ reads, and reads with long CDR3s. Additionally, the less studied IgA repertoire displayed similar characteristics to that of IgG.

A Neutralizing Antibody Recognizing Primarily N-Linked Glycan Targets the Silent Face of the HIV Envelope.

Virtually the entire surface of the HIV-1-envelope trimer is recognized by neutralizing antibodies, except for a highly glycosylated region at the center of the "silent face" on the gp120 subunit. From an HIV-1-infected donor, #74, we identified antibody VRC-PG05, which neutralized 27% of HIV-1 strains. The crystal structure of the antigen-binding fragment of VRC-PG05 in complex with gp120 revealed an epitope comprised primarily of N-linked glycans from N262, N295, and N448 at the silent face center.

Modeling the effect of boost timing in murine irradiated sporozoite prime-boost vaccines.

Vaccination with radiation-attenuated sporozoites has been shown to induce CD8+ T cell-mediated protection against pre-erythrocytic stages of malaria. Empirical evidence suggests that successive inoculations often improve the efficacy of this type of vaccines. An initial dose (prime) triggers a specific cellular response, and subsequent inoculations (boost) amplify this response to create a robust CD8+ T cell memory.

Expanding the Menu of HIV Prevention Options: A Qualitative Study of Experiences with Long-Acting Injectable Cabotegravir as PrEP in the Context of a Phase II Trial in the United States.

Adherence challenges with oral pre-exposure prophylaxis have stimulated interest in alternate modes of administration including long-acting injections. We conducted 30 in-depth interviews with 26 male trial participants and 4 clinical providers in a Phase IIa study (ÉCLAIR) evaluating the use of long-acting cabotegravir (CAB-LA) injections in New York and San Francisco. Interviews exploring attitudes and experiences with CAB-LA were audiotaped, transcribed, and analyzed using thematic content analysis.

Inhibiting the Plasmodium eIF2α Kinase PK4 Prevents Artemisinin-Induced Latency.

Artemisinin and its derivatives (ARTs) are frontline antimalarial drugs. However, ART monotherapy is associated with a high frequency of recrudescent infection, resulting in treatment failure. A subset of parasites is thought to undergo ART-induced latency, but the mechanisms remain unknown.

A potent malaria vaccine based on adenovirus with dual modifications at Hexon and pVII.

Adenovirus (Ad) is thought to be one of the most promising platforms for a malaria vaccine targeted against its liver stages, because of its ability to induce a strong T-cell response against a transgene. However, a further improvement of this platform is needed in order to elicit another arm of the immunity, i.e.