Featured
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| Open AccessFirst-in-human immunoPET imaging of HIV-1 infection using 89Zr-labeled VRC01 broadly neutralizing antibody
Here, the authors apply positron emission tomography (PET) imaging to visualize HIV tissue-wide burden in infected individuals using a radiolabeled broadly neutralizing antibody, 89Zr-VRC01, and show that PET tracer lymph node uptake positively correlates with HIV protein levels measured directly from cells obtained from these tissues. This strategy may allow non-invasive characterization of residual HIV infection in the setting of therapeutic interventions.
- Denis R. Beckford-Vera
- , Robert R. Flavell
- & Timothy J. Henrich
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Article
| Open AccessDifferential V2-directed antibody responses in non-human primates infected with SHIVs or immunized with diverse HIV vaccines
Here the authors show that an HIV vaccine in non-human primates that focuses antibodies on the V1V2 region of gp120 is superior to infection or immunization with whole envelope vaccines for inducing V1V2 antibodies with anti-viral functions that correlate with protection.
- Svenja Weiss
- , Vincenza Itri
- & Susan Zolla-Pazner
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| Open AccessInduction of tier-2 neutralizing antibodies in mice with a DNA-encoded HIV envelope native like trimer
HIV envelope is a target for vaccine development, but induction of broadly neutralizing antibodies has been difficult. Here, the authors show that electroporation with a synthetic DNA vaccine construct allows in vivo production of HIV envelope native like trimers to induce autologous tier-2 neutralizing antibodies targeting a C3/V5 epitope in mice.
- Ziyang Xu
- , Susanne Walker
- & Daniel W. Kulp
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Article
| Open AccessPhagocytosis by an HIV antibody is associated with reduced viremia irrespective of enhanced complement lysis
While antibodies neutralize HIV via Fab recognition of viral surface antigens, antibody Fc domains mediate effector functions, including antibody-dependent cellular phagocytosis (ADCP) and cytotoxicity (ADCC), and complement (C') activity. Here, Spencer et al. modify bNAb 10E8v4 to enhance C'-mediated potency in SHIV challenged rhesus macaques to probe its function in protection, showing that in the absence of neutralization, enhancing C' activities in vitro adds no value toward reducing viremia in either blood or tissue.
- David A. Spencer
- , Benjamin S. Goldberg
- & Ann J. Hessell
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Article
| Open AccessBroadly neutralizing anti-HIV-1 antibodies tether viral particles at the surface of infected cells
Broadly neutralizing antibodies (bNAbs) neutralize HIV-1 and exert Fc-dependent activities against infected cells. Here, Dufloo et al. show that bNAbs also block HIV-1 release by trapping viral particles at the surface of infected cells.
- Jérémy Dufloo
- , Cyril Planchais
- & Timothée Bruel
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| Open AccessLow CCR5 expression protects HIV-specific CD4+ T cells of elite controllers from viral entry
Here, Claireaux et al. show that people who naturally control HIV infection express lower levels of the viral co-receptor CCR5 in specific CD4+ T cells, and that this results from mutations or receptor internalization by CD4+ T cell-produced chemokines.
- Mathieu Claireaux
- , Rémy Robinot
- & Lisa A. Chakrabarti
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Article
| Open AccessLatency reversal plus natural killer cells diminish HIV reservoir in vivo
Here, Kim et al. describe a new kick and kill strategy utilizing a single administration of a protein kinase C modulator and latency reversing agent in combination with injections of allogeneic peripheral blood natural killer cells diminishes the HIV reservoir in HIV-infected humanized mice.
- Jocelyn T. Kim
- , Tian-Hao Zhang
- & Jerome A. Zack
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Article
| Open AccessTASOR epigenetic repressor cooperates with a CNOT1 RNA degradation pathway to repress HIV
The human silencing hub (HUSH) complex, which includes TASOR, deposits repressive marks on HIV proviruses, resulting in gene repression. Here, Matkovic et al. show that TASOR interacts with RNA Polymerase II, predominantly under its elongating state, and RNA degradation proteins to repress HIV provirus expression.
- Roy Matkovic
- , Marina Morel
- & Florence Margottin-Goguet
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Article
| Open AccessDistinct conformations of the HIV-1 V3 loop crown are targetable for broad neutralization
The V3-crown of the HIV-1 envelope protein largely elicits non-neutralizing antibodies. Here, the authors show that the V3-crown can be targeted by broadly neutralizing designed ankyrin repeat proteins recognizing two conformations one of which resembles CCR5- bound V3.
- Nikolas Friedrich
- , Emanuel Stiegeler
- & Alexandra Trkola
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Article
| Open AccessHIV reprograms host m6Am RNA methylome by viral Vpr protein-mediated degradation of PCIF1
m6Am is a modification of the 5′ end of mRNAs catalyzed by PCIF1. Here, Zhang et al. show that HIV infection induces a decrease in m6Am of cellular mRNAs through Vpr-mediated PCIF1 ubiquitination and degradation, resulting in increased HIV replication through regulation of host transcription factors.
- Qiong Zhang
- , Yuqi Kang
- & Tariq M. Rana
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Article
| Open AccessTransformation of tenofovir into stable ProTide nanocrystals with long-acting pharmacokinetic profiles
Antiretroviral therapy (ART) for the treatment of HIV-1 requires life-long daily adherence to supress viral replication, and nucleoside reverse transcriptase inhibitors that are commonly used in ART have not been converted into long-acting agents. Here, the authors report two lipophilic tenofovir (TVF) ProTide nanoformulations, NM1TFV and NM2TFV, which sustain drug levels above therapeutic concentrations for two months after a single intramuscular dose in rats.
- Denise A. Cobb
- , Nathan Smith
- & Benson Edagwa
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Article
| Open AccessOral immune dysfunction is associated with the expansion of FOXP3+PD-1+Amphiregulin+ T cells during HIV infection
Anti-retroviral treatment does not fully resolve mucosal dysfunction and systemic inflammation in HIV infected individuals. Authors show here that an unusual population of regulatory T cells, distinguished by Amphiregulin expression and the incapability to suppress CD4 T cells might contribute to disrupted oral immune protection in HIV patients.
- N. Bhaskaran
- , E. Schneider
- & P. Pandiyan
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Article
| Open AccessNon-invasive plasma glycomic and metabolic biomarkers of post-treatment control of HIV
Current HIV cure-focused clinical trials rely on analytic treatment interruption (ATI) to evaluate post-treatment control (PTC). Here, combining untargetted metabolomics and glycomics in two HIV clinical cohorts, in vitro assays, and machine learning, the authors identify and validate metabolic and glycomic biomarkers linked to inflammatory pathways and HIV latency reactivation associated with PTC, suggesting non-invasive biomarkers as an alternative to predict HIV remission.
- Leila B. Giron
- , Clovis S. Palmer
- & Mohamed Abdel-Mohsen
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Article
| Open AccessIn-depth single-cell analysis of translation-competent HIV-1 reservoirs identifies cellular sources of plasma viremia
To provide in depth characterization of HIV reservoir cells, the authors here develop a single-cell approach to simultaneously sequence TCR, integration sites and proviral genomes, called STIP-Seq, and show that the translation-competent reservoir mainly consists of proviruses with short deletions at the 5’-end of the genome.
- Basiel Cole
- , Laurens Lambrechts
- & Linos Vandekerckhove
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Article
| Open AccessAntibody-based CCR5 blockade protects Macaques from mucosal SHIV transmission
CCR5 is a co-receptor for many transmitted HIV strains. Here, the authors show that biweekly injection of the CCR5-specific antibody Leronlimab protects rhesus macaques against infection following repeated intrarectal challenges of a CCR5-tropic SHIV.
- Xiao L. Chang
- , Gabriela M. Webb
- & Jonah B. Sacha
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Article
| Open AccessIL-21 and IFNα therapy rescues terminally differentiated NK cells and limits SIV reservoir in ART-treated macaques
Infection of African green monkeys with SIV is associated with reduced pathogenicity. Here the authors explore the requirement of differentiated NK cell populations in a pathogenic Rhesus macaque model of SIV infection and show administration of IL-21 and IFNα rescues terminally differentiated NK cells, similarly to what found in African green monkeys, and limits the SIV reservoir in antiretroviral therapy treated macaques.
- Justin Harper
- , Nicolas Huot
- & Mirko Paiardini
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Article
| Open AccessUsing mobile phone data to reveal risk flow networks underlying the HIV epidemic in Namibia
Human mobility influences the spatial distribution of infectious diseases such as HIV. Here, the authors use call data records from mobile phones to model HIV networks in Namibia and estimate that ~40% of the risk of HIV acquisition is driven by mobility.
- Eugenio Valdano
- , Justin T. Okano
- & Sally Blower
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Article
| Open AccessHuman anogenital monocyte-derived dendritic cells and langerin+cDC2 are major HIV target cells
Epithelial tissue mononuclear phagocytes (MNP) can transmit HIV to CD4 T cells, but less is known about sub-epithelial cells. Here, the authors describe MNPs in human anogenital and colorectal tissues and find that CD14+CD1c+ monocyte-derived dendritic cells and langerin-expressing conventional dendritic cells 2 preferentially take up and transmit HIV.
- Jake W. Rhodes
- , Rachel A. Botting
- & Andrew N. Harman
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Article
| Open AccessData linkage to evaluate the long-term risk of HIV infection in individuals seeking post-exposure prophylaxis
Individuals seeking post-exposure prophylaxis (PEP) for HIV may represent an important risk group for future HIV infection. Here the authors find HIV infections at long-term follow-up in 22 of 348 men who have sex with men, and 0 of 623 other PEP seekers.
- Frédérique Hovaguimian
- , Huldrych F. Günthard
- & S. Yerly
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Article
| Open AccessFecal microbiota transplantation in HIV: A pilot placebo-controlled study
It is unknown whether capsulized fecal microbiota transplantation (FMT) can modify the microbiota of people with HIV. Here, the authors report the results of a pilot double-blind study, where 30 HIV-infected subjects on ART were randomized to either weekly oral FMT capsules or placebo for 8 weeks, and show that transplanted microbiota successfully engrafts and is able to attenuate HIV-associated dysbiosis.
- Sergio Serrano-Villar
- , Alba Talavera-Rodríguez
- & Santiago Moreno
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| Open AccessHIV-1 diversity considerations in the application of the Intact Proviral DNA Assay (IPDA)
The intact proviral DNA assay quantifies the genomically intact HIV reservoir, but assay failure due to HIV-1 polymorphism has been observed. Here, the authors report a 28% failure rate in a cohort of people with HIV-1, and note within-host HIV-1 diversity as a further challenge to IPDA accuracy.
- Natalie N. Kinloch
- , Yanqin Ren
- & R. Brad Jones
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Article
| Open AccessCRISPR based editing of SIV proviral DNA in ART treated non-human primates
Removal of integrated HIV DNA remains a roadblock for HIV cure. Here, Mancuso et al. show that intravenous administration of an adeno-associated virus-based CRISPR/Cas9 gene editing construct to SIV-infected macaques results in excision of integrated proviral DNA from infected blood cells and tissues known to be viral reservoirs.
- Pietro Mancuso
- , Chen Chen
- & Kamel Khalili
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Article
| Open AccessVaccine elicitation of HIV broadly neutralizing antibodies from engineered B cells
A vaccine to generate durable HIV broadly neutralizing antibodies (bnAb) from engineered B cells holds promise as an HIV functional cure. Here, the authors show that CRISPR/Cas-modified B cells expressing bnAbs as functional antigen receptors can be immunized to generate long-lived, germinal centre matured bnAb memory and plasma cells in mice.
- Deli Huang
- , Jenny Tuyet Tran
- & James E. Voss
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| Open AccessHeritability of the HIV-1 reservoir size and decay under long-term suppressive ART
The HIV reservoir is a major hurdle for a cure of HIV, but the factors determining its size and dynamics remain unclear. Here the authors show in a large cohort of 610 HIV-1 infected individuals, who are on suppressive ART for a median of 5.4 years, that viral genetic factors contribute substantially to the HIV-1 reservoir size.
- Chenjie Wan
- , Nadine Bachmann
- & Sabine Yerly
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Article
| Open AccessSingle-cell TCR sequencing reveals phenotypically diverse clonally expanded cells harboring inducible HIV proviruses during ART
The cause of clonal expansions in the HIV reservoir remains unclear. Here, Gantner et al. perform single-cell TCR sequencing on longitudinal samples from eight individuals on antiretroviral therapy and find that antigens inducing clonal expansions of memory cells are major contributors to the HIV reservoir.
- Pierre Gantner
- , Amélie Pagliuzza
- & Nicolas Chomont
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| Open AccessClearance of HIV infection by selective elimination of host cells capable of producing HIV
The latent human immunodeficiency virus (HIV) reservoir in patients poses a problem for HIV cure. Here, Li et al. show that a combination of compounds inducing viral reactivation and cell death, inhibiting autophagy and blocking new infections can eliminate HIV infection in 50% of humanized HIV infected mice and in blood samples from infected patients.
- Min Li
- , Wei Liu
- & Jin Wang
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Article
| Open AccessGlycopeptide epitope facilitates HIV-1 envelope specific humoral immune responses by eliciting T cell help
T cells recognize peptide antigens presented in the context of MHC but can additionally recognize non-conventional ligands. Here the authors show T cells specific for a HIV-1 associated glycopeptide antigen presented by MHC class II help envelope (Env) trimer induced humoral immune responses.
- Lina Sun
- , Amy V. Paschall
- & Fikri Y. Avci
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Article
| Open AccessHIV-associated gut dysbiosis is independent of sexual practice and correlates with noncommunicable diseases
The role of sexual practice in HIV-associated gut microbiota remains poorly understood. Here, in a cohort of chronically treated HIV-infected people, the authors show microbiome signatures to be independent of sex and sexual practice and that the extent of dysbiosis correlates with nadir CD4, inflammatory markers, and comorbidities.
- I. Vujkovic-Cvijin
- , O. Sortino
- & I. Sereti
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Article
| Open AccessSex-specific innate immune selection of HIV-1 in utero is associated with increased female susceptibility to infection
Sex differences in the immune response to vaccines and infections have been well described in children and adults. Here the authors describe, in a cohort of 177 HIV-infected infants, innate immune sex differences in fetal life that increase female susceptibility to intrauterine HIV infection and increase the chances of subsequent HIV remission in infected males.
- Emily Adland
- , Jane Millar
- & Philip Goulder
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| Open AccessMigration, hotspots, and dispersal of HIV infection in Rakai, Uganda
HIV prevalence varies throughout Africa, but the contribution of migration remains unclear. Using population-based data from ~22,000 persons, Grabowski et al. show that HIV-positive migrants selectively migrate to high prevalence areas and that out-migrants from these areas geographically disperse.
- Mary Kate Grabowski
- , Justin Lessler
- & Ronald H. Gray
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Article
| Open AccessImmune checkpoint modulation enhances HIV-1 antibody induction
Elucidation of broadly neutralizing antibodies (bnAb) is a goal in HIV vaccine development. Here, Bradley et al. show that administration of CTLA-4 blocking antibody with vaccine antigens increases HIV-1 envelope antibody responses in macaques and a bnAb precursor mouse model.
- Todd Bradley
- , Masayuki Kuraoka
- & Barton F. Haynes
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Article
| Open AccessThe role of sex work laws and stigmas in increasing HIV risks among sex workers
HIV incidence among sex workers remains high in many settings. Here, the authors utilize individual-level data across ten countries in sub-Saharan Africa and suggest that increasingly punitive and non-protective laws are associated with HIV, and that stigmas and sex work laws may operate jointly in increasing HIV risk.
- Carrie E. Lyons
- , Sheree R. Schwartz
- & Stefan Baral
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Article
| Open AccessDisruption of the HIV-1 Envelope allosteric network blocks CD4-induced rearrangements
Here, using cryo-EM and smFRET, Henderson et al. show how tryptophan 571 in the HIV-1 Env acts as a conformational switch during receptor-mediated viral entry and design HIV-1 Env proteins that cannot undergo conformational changes. This has important implications for HIV-1 vaccine design.
- Rory Henderson
- , Maolin Lu
- & S. Munir Alam
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Article
| Open AccessNatural selection favoring more transmissible HIV detected in United States molecular transmission network
Here, the authors use a molecular epidemiological approach to investigate the frequency and intensity of clustering of HIV with different set-point viral loads and find that frequently transmitted strains in genetic transmission clusters have significantly higher viral loads than nonclustered viruses.
- Joel O. Wertheim
- , Alexandra M. Oster
- & Walid Heneine
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Article
| Open AccessExtracellular vesicles from symbiotic vaginal lactobacilli inhibit HIV-1 infection of human tissues
Lactobacillus associates with vaginal protection from HIV-1 infection. Here, the authors show that lactobacilli extracellular vesicles contain bacterial proteins and metabolites that inhibit HIV-1 infection in T cells and in human cervico-vaginal and tonsillar tissues ex vivo via altering viral Env proteins.
- Rogers A. Ñahui Palomino
- , Christophe Vanpouille
- & Leonid Margolis
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Article
| Open AccessDeclines in HIV incidence among men and women in a South African population-based cohort
Here, the authors investigate the outcome of prevention services scale-up on HIV incidence in a South African large population-based HIV surveillance cohort with over a decade of follow-up and associate a 43% reduction in incidence to earlier male medical circumcision and increased levels of antiretroviral therapy coverage.
- Alain Vandormael
- , Adam Akullian
- & Frank Tanser
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Article
| Open AccessAn MPER antibody neutralizes HIV-1 using germline features shared among donors
Here, the authors identify a broadly neutralizing antibody from an HIV-infected person that recognizes the membrane-proximal external region (MPER) of HIV envelope glycoprotein (Env) and has a short CDRH3 and low polyreactivity. Structural analysis shows how the antibody binds the MPER and Env on the viral membrane.
- Lei Zhang
- , Adriana Irimia
- & Michael B. Zwick
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Article
| Open AccessHPV infection and the genital cytokine milieu in women at high risk of HIV acquisition
Cervicovaginal inflammation and human papillomavirus (HPV) are separately associated with increased risk of HIV acquisition. Here the authors longitudinally profile 48 cervicovaginal cytokines and HPV status in a large observational HIV high-risk cohort, and show the same cytokines associate with HPV infection and HIV risk.
- Lenine J. P. Liebenberg
- , Lyle R. McKinnon
- & Quarraisha Abdool Karim
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Article
| Open AccessResident memory T cells are a cellular reservoir for HIV in the cervical mucosa
Using cervical explant models and cervical tissue from ART-suppressed HIV+ women, the authors here show that resident memory T cells (TRM) in the cervical mucosa are preferentially infected and harbor more viral DNA, RNA and protein than non-TRM, suggesting that TRM may serve as viral reservoir in the cervical mucosa.
- Jon Cantero-Pérez
- , Judith Grau-Expósito
- & Meritxell Genescà
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Article
| Open AccessRepeated semen exposure decreases cervicovaginal SIVmac251 infection in rhesus macaques
High frequency semen exposure has been associated with activation of anti-HIV mechanisms in HIV negative sex workers. Here, Abdulhaqq et al. show that repeated vaginal exposure to semen reduces vaginal infection by SIV in non-human primates, and is associated with lower CCR5 expression in CD4 T-cells and a local type-I interferon response.
- Shaheed A. Abdulhaqq
- , Melween Martinez
- & Luis J. Montaner
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Article
| Open AccessMapping the drivers of within-host pathogen evolution using massive data sets
Various host factors may impact within-host pathogen evolution. Here, the authors develop a Bayesian approach for identifying host-pathogen interactions using large data sets of pathogen diversity, and apply it to investigate HLA-induced selection in the HIV-1 genome.
- Duncan S. Palmer
- , Isaac Turner
- & Gil McVean
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Article
| Open AccessSequential LASER ART and CRISPR Treatments Eliminate HIV-1 in a Subset of Infected Humanized Mice
Here, the authors show that sequential treatment with long-acting slow-effective release ART and AAV9- based delivery of CRISPR-Cas9 results in undetectable levels of virus and integrated DNA in a subset of humanized HIV-1 infected mice. This proof-of-concept study suggests that HIV-1 elimination is possible.
- Prasanta K. Dash
- , Rafal Kaminski
- & Howard E. Gendelman
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Article
| Open AccessDifficult-to-neutralize global HIV-1 isolates are neutralized by antibodies targeting open envelope conformations
Here, the authors report that specific monoclonal antibodies isolated from vaccinated rhesus macaques can neutralize a subset of Tier 2 difficult-to-neutralize HIV-1 that express Env in an open conformation, suggesting that V3 loop-specific targeting can bias the estimation of vaccine-induced bnAbs.
- Qifeng Han
- , Julia A. Jones
- & Kevin O. Saunders
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Article
| Open AccessIdentification of HIV transmitting CD11c+ human epidermal dendritic cells
Composition and function of immune populations at barrier surfaces is crucial for response to infection. Here, the authors identify a population of dendritic cells in human epidermis, abundant in anogenital epithelia and distinct from Langerhans cells by surface phenotype and by high capacity for HIV infection and transmission.
- Kirstie M. Bertram
- , Rachel A. Botting
- & Andrew N. Harman
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Article
| Open AccessStructure and immunogenicity of a stabilized HIV-1 envelope trimer based on a group-M consensus sequence
Stabilized, native-like trimers of the HIV envelope protein, such as SOSIP trimers, are potential antigens for an HIV vaccine. Here, the authors generate a SOSIP trimer based on the consensus sequence of group M isolates, determine its structure and exposure of common epitopes, and show immunogenicity in rabbits and non-human primates.
- Kwinten Sliepen
- , Byung Woo Han
- & Rogier W. Sanders
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Article
| Open AccessSchistosoma mansoni treatment reduces HIV entry into cervical CD4+ T cells and induces IFN-I pathways
Schistosoma mansoniinfection has been linked with an increased risk of HIV acquisition in women. Here, the authors show that standard S. mansoniinfection treatment causes a reduction of HIV entry into cervical and blood CD4+ T cells, which is sustained for up to two months and is associated with de-repression of IFN-I signaling.
- Sergey Yegorov
- , Vineet Joag
- & Rupert Kaul
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Article
| Open AccessCTL-mediated immunotherapy can suppress SHIV rebound in ART-free macaques
Viral rebound following discontinuation of antiretroviral therapy (ART) is a major obstacle for HIV cure. Here, the authors show that adoptive cellular therapy using autologous Env-specific T cells augmented by therapeutic vaccination can control viral rebound after ART interruption in a SHIV macaque model.
- Jin Fan
- , Hua Liang
- & Yiming Shao
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Article
| Open AccessKappa chain maturation helps drive rapid development of an infant HIV-1 broadly neutralizing antibody lineage
Development of broadly neutralizing antibodies (bnAb) against HIV-1 in infected adults is a multi-step process unachievable by current vaccine approaches. Here the authors reconstruct the ontogeny of an infant bnAb, which develops in fewer steps, and identify its unique features that may shorten the path to HIV vaccines.
- Cassandra A. Simonich
- , Laura Doepker
- & Julie Overbaugh
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Article
| Open AccessExperimental and computational analyses reveal that environmental restrictions shape HIV-1 spread in 3D cultures
Here, using an integrative experimental and computational approach, Imle et al. show how cell motility and density affect HIV cell-associated transmission in a three-dimensional tissue-like culture system of CD4+ T cells and collagen, and how different collagen matrices restrict infection by cell-free virions.
- Andrea Imle
- , Peter Kumberger
- & Oliver T. Fackler