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CoPoP liposomes displaying stabilized clade C HIV-1 Env elicit tier 2 multiclade neutralization in rabbits
HIV vaccine candidates often have limited capacity to induce broadly neutralizing antibodies (nAbs). In this study, the authors show that stabilized Clade C HIV-1 Env protein trimers decorated on CoPoP liposomes induce nAbs against 18 of 20 multiclade tier 2 HIV-1 strains in immunized rabbits.
- Annemart Koornneef
- , Kanika Vanshylla
- & Frank Wegmann
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Article
| Open Access
Immunoglobulin G N-glycan markers of accelerated biological aging during chronic HIV infection
In this study, Giron et al. find that people living with chronic HIV experience accelerated aging-associated alterations in antibody glycans. These alterations, attributed to senescence enzymes, predict comorbidities and reduce the antiviral function of antibodies.
- Leila B. Giron
- , Qin Liu
- & Mohamed Abdel-Mohsen
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Autophagy-enhancing ATG16L1 polymorphism is associated with improved clinical outcome and T-cell immunity in chronic HIV-1 infection
T cell dysregulation is a hallmark of chronic HIV-1 infection that is partially restored by antiretroviral therapy. Here the authors show that ATG16L1 rs6861 polymorphism is associated clinically with prolonged control of disease pathogenesis, and functionally with enhanced autophagy and T-cell immunity in chronically HIV-1 infected individuals.
- Renée R. C. E. Schreurs
- , Athanasios Koulis
- & Carla M. S. Ribeiro
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Clearance of persistent SARS-CoV-2 associates with increased neutralizing antibodies in advanced HIV disease post-ART initiation
There is limited data on immune factors contributing to SARS-CoV-2 viral clearance in people living with HIV. Here, the authors show that re-emergence of the neutralizing antibody response may be key to clearing persistent SARS-CoV-2 infection in ART-mediated recovery from immunosuppression in advanced HIV disease.
- Farina Karim
- , Catherine Riou
- & Alex Sigal
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Centrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4+ T cells
People living with HIV-1 are at an increased risk of developing various cancers. Here, the authors suggest that HIV-1-encoded Vpr can promote oncogenesis by forming a ternary complex with VprBP and Plk4 and inducing Plk4-dependent centriole overduplication and aneuploidy.
- Jung-Eun Park
- , Tae-Sung Kim
- & Kyung S. Lee
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TGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirs in vivo
Treatment with the clinical stage TGF-β inhibitor galunisertib promotes latency reversal of HIV/SIV. Here, using a treatment regimen similar to the one tested in clinical trials, the authors show how galunisertib affects immune cell function, increases SIV reactivation, and reduces the viral reservoir in macaques.
- Jinhee Kim
- , Deepanwita Bose
- & Elena Martinelli
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| Open Access
Income determines the impact of cash transfers on HIV/AIDS: cohort study of 22.7 million Brazilians
Brazil has operated a conditional cash transfer program to support families living in precarious conditions since 2004. Here, the authors use linked administrative and health data to investigate the impacts of the program on HIV/AIDS-related outcomes, demonstrating strong positive associations.
- Andréa F. Silva
- , Inês Dourado
- & Davide Rasella
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HIV-associated gut microbial alterations are dependent on host and geographic context
Here, the authors compare the fecal microbial community of individuals in the U.S., Uganda, and Botswana, and identify significant bacterial taxa alterations with both treated and untreated HIV infection although with a high degree of uniqueness in each cohort, and also significant differences between populations that report men who have sex with men (MSM) behavior and non-MSM populations.
- Muntsa Rocafort
- , David B. Gootenberg
- & Douglas S. Kwon
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Early antiretroviral therapy favors post-treatment SIV control associated with the expansion of enhanced memory CD8+ T-cells
HIV remission has been seen in people living with HIV after the cessation of antiretroviral therapy and is termed post treatment control. Here Passaes and colleagues present an SIV model that shows early initiation of antiretroviral therapy after SIV infection is linked to improved post treatment control upon cessation of antiviral therapy and associates with the expansion of an enhanced memory pool of CD8 + T cells‘.
- Caroline Passaes
- , Delphine Desjardins
- & Asier Sáez-Cirión
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Article
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Potent latency reversal by Tat RNA-containing nanoparticle enables multi-omic analysis of the HIV-1 reservoir
Reactivating latent HIV reservoirs could be beneficial towards a functional cure. Here, the authors show that Tat-LNP effectively reactivates HIV while preserving the cell transcriptome. Upon reactivation, p24+ cells exhibit distinct genes and pathways potentially contributing to their persistence.
- Marion Pardons
- , Basiel Cole
- & Linos Vandekerckhove
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Article
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High monoclonal neutralization titers reduced breakthrough HIV-1 viral loads in the Antibody Mediated Prevention trials
Antibody Mediated Prevention (AMP) trials showed that the broadly neutralizing antibody VRC01 could prevent some HIV-1 acquisitions. Here the authors use VRC01 levels and the sensitivity of each acquired HIV virus to predict viral loads in the AMP studies and show that VRC01 influenced viral loads, though potency was lower in vivo than expected.
- Daniel B. Reeves
- , Bryan T. Mayer
- & Srilatha Edupuganti
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Article
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Adults on pre-exposure prophylaxis (tenofovir-emtricitabine) have faster clearance of anti-HIV monoclonal antibody VRC01
Small molecule drugs can affect clearance of monoclonal antibodies, but this hasn’t been assessed for oral HIV-1 pre-exposure prophylaxis. Here, the authors find that faster serum clearance of an experimental IgG1 monoclonal antibody, VRC01, is associated with use of tenofovir-emtricitabine, possibly explained by increased epithelial intestinal permeability.
- Yunda Huang
- , Lily Zhang
- & Maria P. Lemos
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| Open Access
Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site
Antibodies targeting the HIV-1 fusion peptide rarely achieve more than 60% neutralization breadth. Here, the authors develop an anti-FP antibody enhancing its potency to 80% and structurally resolve the expanded FP-binding site that allows the antibody to target diverse viral variants.
- Bailey B. Banach
- , Sergei Pletnev
- & Brandon J. DeKosky
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Inadequate structural constraint on Fab approach rather than paratope elicitation limits HIV-1 MPER vaccine utility
It is still unclear why HIV-1 vaccines targeting MPER induce antibodies that fail to bind HIV. Here, the authors show that antibodies targeting membrane-proximal linear epitopes of virion spike proteins must generate relevant antibody paratopes and approach angles to ligate their quarry in a topologically restricted site.
- Kemin Tan
- , Junjian Chen
- & Mikyung Kim
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Probabilities of developing HIV-1 bNAb sequence features in uninfected and chronically infected individuals
Successful induction of broadly neutralizing antibodies is a main challenge in HIV vaccine development. The authors provide a framework to determine probabilities of antibody sequence development and show that uninfected and chronically infected individuals have the same chances to develop HIV-1 neutralizing antibodies.
- Christoph Kreer
- , Cosimo Lupo
- & Florian Klein
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Article
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A combined adjuvant approach primes robust germinal center responses and humoral immunity in non-human primates
Protein antigens, such as HIV envelope protein, require adjuvants for high immunogenicity. Here the authors show that a combined adjuvant approach with slow antigen delivery and potent ISCOMs adjuvant primes robust germinal center activity and humoral immunity in non-human primates. pSer-modified antigen shifts immunodominance to allow subdominant epitope-targeting of rare B cells.
- Ivy Phung
- , Kristen A. Rodrigues
- & Shane Crotty
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CD8+ T cells control SIV infection using both cytolytic effects and non-cytolytic suppression of virus production
Control of HIV and SIV infection is largely thought to be achieved through direct lysis of target cells. Here, using mathematical modelling of viral load data from rhesus macaques, the authors propose that virus control is best explained by the combination of cytolytic and non-cytolytic effects.
- Benjamin B. Policicchio
- , Erwing Fabian Cardozo-Ojeda
- & Ruy M. Ribeiro
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HIV-1 treatment timing shapes the human intestinal memory B-cell repertoire to commensal bacteria
HIV-1 infection is known to impact the gut mucosa, effecting the microbiota and immune system, but early antiretroviral therapy is linked to partial reversal of this phenomena. Here the authors explore the impact of early commencement of antiretroviral therapy and show this can limit the abnormal responses of intestinal B cells associated with HIV-1 infection.
- Cyril Planchais
- , Luis M. Molinos-Albert
- & Hugo Mouquet
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Mucosal application of the broadly neutralizing antibody 10-1074 protects macaques from cell-associated SHIV vaginal exposure
HIV-1 can be transmitted by infected cells in body fluids and an efficient prophylaxis should prevent this. Here the authors show that the HIV-1 antibody 10-1074, when applied as topical vaginal gel, inhibits cell-associated transmission in non-human primates.
- Karunasinee Suphaphiphat
- , Delphine Desjardins
- & Mariangela Cavarelli
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Estimating the contribution of CD4 T cell subset proliferation and differentiation to HIV persistence
The authors used mathematical modeling of human data to study how HIV persists despite suppressive antiretroviral therapy. They found that when latently infected CD4+ T cells proliferate or differentiate, they can create HIV DNA and passage it into other subsets. More mature CD4 cell subsets then clear HIV DNA faster.
- Daniel B. Reeves
- , Charline Bacchus-Souffan
- & Peter W. Hunt
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| Open Access
Associations of modern initial antiretroviral therapy regimens with all-cause mortality in people living with HIV in resource-limited settings: a retrospective multicenter cohort study in China
First-line integrase strand transfer inhibitors are commonly used for people with HIV. Here, Wu et al. report results from a multicenter cohort study in China observing significant differences in all-cause mortality among patients between various treatment groups.
- Xinsheng Wu
- , Guohui Wu
- & Huachun Zou
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| Open Access
Structural basis of HIV-1 Vif-mediated E3 ligase targeting of host APOBEC3H
HIV-1 Vif antagonizes multiple human APOBEC3 cytidine deaminases for immune evasion. Here, the authors determine the structure of human APOBEC3H bound to HIV-1 Vif and E3 ubiquitin ligase, providing a mechanistic basis for the virus-host arms race.
- Fumiaki Ito
- , Ana L. Alvarez-Cabrera
- & Xiaojiang S. Chen
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Engaging an HIV vaccine target through the acquisition of low B cell affinity
Broadly neutralizing antibodies (bnAbs) for HIV have been difficult to elicit with one issue being the low B cell affinity required. Here the authors use a transgenic mouse bearing human-like antibody repertoires to show that low affinity B cells persist which enables vaccine expansion of antibodies against the CD4 binding site, a conserved HIV bnAb target.
- Larance Ronsard
- , Ashraf S. Yousif
- & Daniel Lingwood
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Intradermal but not intramuscular modified vaccinia Ankara immunizations protect against intravaginal tier2 simian-human immunodeficiency virus challenges in female macaques
The route of vaccine administration is known to effect the induction of immune response and the quality of such immunity. Here the authors show that intradermal but not intramuscular vaccination using live-attenuated vaccinia-based SHIV vaccine confers protection in the SHIV model in female macaques and characterise the induced immune response.
- Venkata S. Bollimpelli
- , Pradeep B. J Reddy
- & Rama R. Amara
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HIV-1 promotes ubiquitination of the amyloidogenic C-terminal fragment of APP to support viral replication
Amyloid precursor protein has been identified as an inhibitor of HIV-1 replication. Here, Gu et al further characterise the details and impact of this interaction on HIV replication in myeloid cells that contribute to neurological disease.
- Feng Gu
- , Marie Boisjoli
- & Mojgan H. Naghavi
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Impact of misclassified defective proviruses on HIV reservoir measurements
Quantifying intact proviruses is key to understanding decreases in HIV reservoirs but results can differ depending on the method. To balance sensitivity and specificity of two assays, the authors use mathematical models and measurements of intact and defective proviruses to assess how misclassification can impact estimates of natural and therapeutic reservoir reduction.
- Daniel B. Reeves
- , Christian Gaebler
- & Michel C. Nussenzweig
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Structural insights into RNA bridging between HIV-1 Vif and antiviral factor APOBEC3G
HIV-1 hijacks a host ubiquitin ligase complex using viral infectivity factor Vif to degrade antiviral factor A3G. Here, Kouno et al. report the cryoEM structure of the A3G-Vif complex and A3G ubiquitination in vitro using solubility-enhanced variants.
- Takahide Kouno
- , Satoshi Shibata
- & Matthias Wolf
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The HIV-1 capsid core is an opportunistic nuclear import receptor
Nuclear import of the HIV-1 capsid (CA) is mediated through direct interactions with components of the nuclear pore complexes. Here, the authors identify Nup35 and POM121 as HIV-1 CA interacting factors regulating nuclear entry and further demonstrate regulation of the process by soluble factors Cyclophilin A and CPSF6.
- Guangai Xue
- , Hyun Jae Yu
- & Vineet N. KewalRamani
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Article
| Open Access
Molecular basis of differential HLA class I-restricted T cell recognition of a highly networked HIV peptide
Cytotoxic lymphocytes (CTL) are important in the control of HIV and some HLA alleles are associated with protection or susceptibility to disease. Here the authors characterise an epitope where variants bind to HLA-B57 or HLA-B53 and they characterise the structural and functional TCR recognition differences.
- Xiaolong Li
- , Nishant Kumar Singh
- & Jia-huai Wang
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Transmission modeling to infer tuberculosis incidence prevalence and mortality in settings with generalized HIV epidemics
Accurately estimating the burden of tuberculosis is challenging due to incomplete registration systems and the relationship with HIV. Here, the authors develop a Bayesian modelling strategy accounting for these factors that estimates age- and country-specific annual risks of infection and the proportion resulting from recent infection.
- Peter J. Dodd
- , Debebe Shaweno
- & Helen Ayles
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| Open Access
Direct intranodal tonsil vaccination with modified vaccinia Ankara vaccine protects macaques from highly pathogenic SIVmac251
Mucosal surfaces are a primary route of HIV entry, yet the compartmentalisation between mucosal and peripheral immune systems remain a challenge for HIV vaccine candidates. Authors utilise a combination of intranodal tonsil MALT and systemic vaccination in the rhesus macaque model to explore immune responses and protection from highly pathogenic simian homologue of HIV.
- Jeffy G. Mattathil
- , Asisa Volz
- & Joseph J. Mattapallil
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Phenotypic characterization of single CD4+ T cells harboring genetically intact and inducible HIV genomes
Some HIV-infected cells persist during antiretroviral therapies (ART) but their phenotype is less clear. Dufour et al. show that HIV-infected cells that persist in people receiving ART are phenotypically diverse and that CD4+ T cells expressing the integrin VLA-4 are highly enriched in replication-competent HIV.
- Caroline Dufour
- , Corentin Richard
- & Nicolas Chomont
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Prolonged experimental CD4+ T-cell depletion does not cause disease progression in SIV-infected African green monkeys
HIV infection results in the depletion of CD4+ T cells overtime and the loss of coordinated cellular immunity, but how this corresponds to the SIV infected African Green Monkey (AGM) model of non-progressive disease is not known. Here the authors assess the impact of experimental CD4+ T cell depletion in AGM and show that lack of disease progression and resistance to AIDS in this model are independent of CD4+ T cell loss.
- Quentin Le Hingrat
- , Paola Sette
- & Ivona Pandrea
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Ultra-long-acting in-situ forming implants with cabotegravir protect female macaques against rectal SHIV infection
In this study, the authors developed an ultra-long-acting injectable, biodegradable, and removable in-situ forming implant delivering cabotegravir (CAB ISFI). CAB ISFI was well tolerated and protected against multiple rectal SHIV challenges in female macaques.
- Isabella C. Young
- , Ivana Massud
- & S. Rahima Benhabbour
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Article
| Open Access
HIV vaccine candidate efficacy in female macaques mediated by cAMP-dependent efferocytosis and V2-specific ADCC
HIV vaccine development can be aided by knowledge of correlates of protection. Here the authors identify engagement and reprogramming of tolerogenic CD14+ myeloid cells mediating a spatiotemporal balance of pro- and anti-inflammatory responses, as correlates of efficacy in female macaques vaccinated with the DNA/ALVAC/gp120/Alum platform.
- Massimiliano Bissa
- , Sohyoung Kim
- & Genoveffa Franchini
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Article
| Open Access
A click chemistry amplified nanopore assay for ultrasensitive quantification of HIV-1 p24 antigen in clinical samples
Accurate detection of antigen p24 for HIV−1 early diagnosis remains challenging. Here the authors present a click chemistry amplified nanopore (CAN) assay that allows p24 quantification at ultralow concentration range in clinical samples.
- Xiaojun Wei
- , Xiaoqin Wang
- & Chang Liu
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Article
| Open Access
Administration of broadly neutralizing anti-HIV-1 antibodies at ART initiation maintains long-term CD8+ T cell immunity
Broadly neutralising anti-HIV-1 antibody (bNAb) administration in nonhuman primates has been shown to stimulate adaptive T cell-specific immunity, with infection prevention observed. In this work, the authors longitudinally analyse HIV-1 specific cellular immunity in HIV-1- infected individuals starting ART with or without adjunctive bNAb treatment.
- Miriam Rosás-Umbert
- , Jesper D. Gunst
- & Ole S. Søgaard
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Article
| Open Access
The immune synapses reveal aberrant functions of CD8 T cells during chronic HIV infection
HIV infection over time is thought to result in premature aging and aberrant immune responses including the induction of immunological senescence. Here the authors show altered formation of immune synapses by naive CD8+ T cells and dysregulated synapse functioning at late differentiated stages in people living with HIV.
- Nadia Anikeeva
- , Maria Steblyanko
- & Yuri Sykulev
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Article
| Open Access
S100A8-mediated metabolic adaptation controls HIV-1 persistence in macrophages in vivo
HIV-1 eradication is hindered by viral persistence in different cell reservoirs, including circulatory CD4+ T-cells and tissue-resident macrophages. Here, by analyzing male genital mucosa from cART-suppressed HIV1-infected individuals, Real et al. show that M4 macrophages represent the major macrophage HIV-1 reservoir in this tissue. These macrophages have an inflammatory IL1R+S100A8+MMP7+M4-phenotype, and contain transcriptionally active HIV-1, which reactivate infectious virus production from viral latency in response to autocrine/paracrine S100A8-mediated glycolysis.
- Fernando Real
- , Aiwei Zhu
- & Morgane Bomsel
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Article
| Open Access
Prion-like low complexity regions enable avid virus-host interactions during HIV-1 infection
Host proteins CPSF6, NUP153, and SEC24C are vital for HIV-1 infection. They bind to the viral capsid protein and contribute to shuttling of virions through the cytoplasm (SEC24C), import into the nucleus (NUP153 and CPSF6) and subsequent trafficking to preferred integration sites (CPSF6). Here, Wei et al. combine structural, biochemical and virological assays to emphasize the importance of prion-like low complexity domains surrounding short phenylalanine-glycine regions in binding and increasing the avidity when interacting with viral capsid.
- Guochao Wei
- , Naseer Iqbal
- & Mamuka Kvaratskhelia
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Article
| Open Access
Mechanistic understanding of human SLFN11
Schlafen 11 serves as an antiviral restriction factor and a predictive biomarker in cancer. Here, the authors use cryoelectron microscopy and biochemical assays to understand tRNA endoribonuclease and DNA binding functions of human Schlafen 11.
- Felix J. Metzner
- , Simon J. Wenzl
- & Katja Lammens
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Article
| Open Access
Limited impact of fingolimod treatment during the initial weeks of ART in SIV-infected rhesus macaques
Although antiretroviral therapy (ART) is able to successfully suppress plasma viremia in most people living with HIV, ART withdrawal typically results in viral replication and rebound. Authors investigate the effect, in terms of delay in viral replication, and immune cell dynamics in lymphoid tissue, of fingolimod (FTY720) administration at the time of ART initiation in SIV-infected rhesus macaques.
- Maria Pino
- , Amélie Pagliuzza
- & Mirko Paiardini
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Article
| Open Access
Immunogenicity to COVID-19 mRNA vaccine third dose in people living with HIV
HIV infection may affect the immune response to vaccination. Here the authors show that humoral response in persons living with HIV after the third dose of a SARS-CoV-2 vaccine is strong and higher than that achieved with the second dose, while cell-mediated immunity remains stable.
- Alessandra Vergori
- , Alessandro Cozzi Lepri
- & Eleonora Tartaglia
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Article
| Open Access
SARS CoV-2 mRNA vaccination exposes latent HIV to Nef-specific CD8+ T-cells
Here, the authors show in a cohort of people with HIV, COVID mRNA vaccination is followed by a transient boost in a particular profile of HIV-specific T-cell responses and a corresponding decrease in residual HIV RNA – suggesting productive immune engagement with infected cells.
- Eva M. Stevenson
- , Sandra Terry
- & R. Brad Jones
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Article
| Open Access
Early treatment regimens achieve sustained virologic remission in infant macaques infected with SIV at birth
Neonates and infants infected with HIV generally develop disease rapidly, with early antiretroviral therapy (ART) often failing to achieve a sustained state of ART-free virologic remission. Here, the authors study viral reservoirs in neonatal macaques with early initiation of ART and an integrase inhibitor.
- Xiaolei Wang
- , Eunice Vincent
- & Huanbin Xu
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Article
| Open Access
Identification of IOMA-class neutralizing antibodies targeting the CD4-binding site on the HIV-1 envelope glycoprotein
HIV-1 vaccine design aims to induce broadly neutralizing antibodies such as IOMA, the only described antibody in its class. Here, the authors present the isolation, characterisation and structure of three additional antibodies within the IOMA class
- Jelle van Schooten
- , Elinaz Farokhi
- & Marit J. van Gils
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Article
| Open Access
CD8 lymphocytes mitigate HIV-1 persistence in lymph node follicular helper T cells during hyperacute-treated infection
Despite antiretroviral therapy, HIV often persists in tissue sanctuary sites. In this work, authors investigate HIV persistence and T cell responses in lymph node biopsies obtained from individuals who initiated antiretroviral therapy in Fiebig stage I and beyond.
- Omolara O. Baiyegunhi
- , Jaclyn Mann
- & Zaza M. Ndhlovu
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Article
| Open Access
Therapeutic efficacy of combined active and passive immunization in ART-suppressed, SHIV-infected rhesus macaques
Antiretroviral therapy alone is insufficient in curing HIV-1 infection, due to latent viral reservoir persistency. Here, authors explore the post-virologic control of combining active and passive immunisation with vesatolimod, in a SHIV-infected rhesus macaque model.
- Victoria E. K. Walker-Sperling
- , Noe B. Mercado
- & Dan H. Barouch
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Article
| Open Access
Non-selective distribution of infectious disease prevention may outperform risk-based targeting
Pre-exposure prophylaxis (PrEP) is an effective HIV prevention measure but identifying those most at risk to target for treatment is challenging. Here, the authors demonstrate that non-selective PrEP distribution outperforms targeted strategies when use is not consistent, and/or prevalence of untreated HIV is high.
- Benjamin Steinegger
- , Iacopo Iacopini
- & Eugenio Valdano
Inflammation and cytomegalovirus viremia during pregnancy drive sex-differentiated differences in mortality and immune development in HIV-exposed infants