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2.
Sci Rep ; 11(1): 11695, 2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083648

RESUMO

Investigations of the human neuromuscular junction (NMJ) have predominately utilised experimental animals, model organisms, or monolayer cell cultures that fail to represent the physiological complexity of the synapse. Consequently, there remains a paucity of data regarding the development of the human NMJ and a lack of systems that enable investigation of the motor unit. This work addresses this need, providing the methodologies to bioengineer 3D models of the human motor unit. Spheroid culture of iPSC derived motor neuron progenitors augmented the transcription of OLIG2, ISLET1 and SMI32 motor neuron mRNAs ~ 400, ~ 150 and ~ 200-fold respectively compared to monolayer equivalents. Axon projections of adhered spheroids exceeded 1000 µm in monolayer, with transcription of SMI32 and VACHT mRNAs further enhanced by addition to 3D extracellular matrices in a type I collagen concentration dependent manner. Bioengineered skeletal muscles produced functional tetanic and twitch profiles, demonstrated increased acetylcholine receptor (AChR) clustering and transcription of MUSK and LRP4 mRNAs, indicating enhanced organisation of the post-synaptic membrane. The number of motor neuron spheroids, or motor pool, required to functionally innervate 3D muscle tissues was then determined, generating functional human NMJs that evidence pre- and post-synaptic membrane and motor nerve axon co-localisation. Spontaneous firing was significantly elevated in 3D motor units, confirmed to be driven by the motor nerve via antagonistic inhibition of the AChR. Functional analysis outlined decreased time to peak twitch and half relaxation times, indicating enhanced physiology of excitation contraction coupling in innervated motor units. Our findings provide the methods to maximise the maturity of both iPSC motor neurons and primary human skeletal muscle, utilising cell type specific extracellular matrices and developmental timelines to bioengineer the human motor unit for the study of neuromuscular junction physiology.

3.
Colorectal Dis ; 2021 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-34021689

RESUMO

AIM: Postoperative ileus (POI) is a major problem after colorectal surgery. Acetylcholinesterase inhibitors (ACEI) like pyridostigmine increase gastro-intestinal (GI) motility through a cholinergic anti-inflammatory pathway (CAIP). The purpose of this phase II pilot study is to determine the safety of oral pyridostigmine after elective colorectal surgery. METHODS: This is a stage 2b safety study (IDEAL framework). All adult patients undergoing elective colorectal resections or formation or reversal of stoma at the Royal Adelaide Hospital between September 2020 and January 2021 were eligible. The primary outcomes were 30-day postoperative complications, reported adverse events and GI-2: a validated composite outcome measure of recovery of GI function after surgery defined as the interval from surgery until first passage of stool and tolerance of a solid intake for 24 hrs (in whole days) in the absence of vomiting. RESULTS: Fifteen patients were included in the study. The median age was 58 (50-82) years, and seven (47%) were men. Most participants had an ASA grade ≥ II (53%), and the median BMI was 27 (24-35). There were 13 postoperative complications (seven were Clavien-Dindo (CD) 1, five CD 2, and one CD 3). None appeared directly related to pyridostigmine administration, and none of the patients had any overt symptoms of excessive parasympathetic activity. Median GI-2 was two days (1-4). CONCLUSION: Oral pyridostigmine appears to be safe to use after elective colorectal surgery in a select group of patients. However, considering this is a pilot study with a small sample size, larger controlled studies are needed to confirm this finding and establish efficacy for POI prevention.

4.
Behav Brain Res ; 409: 113337, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-33933522

RESUMO

Stereotyped behavior is rhythmic, repetitive movement that is essentially invariant in form. Stereotypy is common in several clinical disorders, such as autism spectrum disorders (ASD), where it is considered maladaptive. However, it also occurs early in typical development (TD) where it is hypothesized to serve as the foundation on which complex, adaptive motor behavior develops. This transition from stereotyped to complex movement in TD is thought to be supported by sensorimotor integration. Stereotypy in clinical disorders may persist due to deficits in sensorimotor integration. The present study assessed whether differences in sensorimotor processing may limit the expression of complex motor behavior in individuals with ASD and contribute to the clinical stereotypy observed in this population. Adult participants with ASD and TD performed a computer-based stimulus-tracking task in the presence and absence of visual feedback. Electroencephalography was recorded during the task. Groups were compared on motor performance (root mean square error), motor complexity (sample entropy), and neural complexity (multiscale sample entropy of the electroencephalography signal) in the presence and absence of visual feedback. No group differences were found for motor performance or motor complexity. The ASD group demonstrated greater neural complexity and greater differences between feedback conditions than TD individuals, specifically in signals relevant to sensorimotor processing. Motor performance and motor complexity correlated with clinical stereotypy in the ASD group. These findings support the hypothesis that individuals with ASD have differences in sensorimotor processing when executing complex motor behavior and that stereotypy is associated with low motor complexity.

5.
Bull Math Biol ; 83(6): 65, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33932176

RESUMO

The mountain pine beetle (MPB) is among the most destructive eruptive forest pests in North America. A recent increase in the frequency and severity of outbreaks, combined with an eastward range expansion towards untouched boreal pine forests, has spurred a great interest by government, industry and academia into the population ecology of this tree-killing bark beetle. Modern approaches to studying the spread of the MPB often involve the analysis of large-scale, high-resolution datasets on landscape-level damage to pine forests. This creates a need for new modelling tools to handle the unique challenges associated with large sample sizes and spatial effects. In two companion papers (Koch et al. in Environ Ecol Stat. https://doi.org/10.1007/s10651-020-00456-2 , 2020a; J R Soc Interface 17(170):20200434, 2020b), we explain how the computational challenges of dispersal and spatial autocorrelation can be addressed using separable kernels. In this paper, we use these ideas to capture nonstationary patterns in the dispersal flights of MPB. This facilitates a landscape-level inference of subtle properties of MPB attack behaviour based on aerial surveys of killed pine. Using this model, we estimate the size of the cryptic endemic MPB population, which formerly has been measurable only by means of costly and time-intensive ground surveys.

6.
Nature ; 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33971664

RESUMO

Betacoronaviruses caused the outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome, as well as the current pandemic of SARS coronavirus 2 (SARS-CoV-2)1-4. Vaccines that elicit protective immunity against SARS-CoV-2 and betacoronaviruses that circulate in animals have the potential to prevent future pandemics. Here we show that the immunization of macaques with nanoparticles conjugated with the receptor-binding domain of SARS-CoV-2, and adjuvanted with 3M-052 and alum, elicits cross-neutralizing antibody responses against bat coronaviruses, SARS-CoV and SARS-CoV-2 (including the B.1.1.7, P.1 and B.1.351 variants). Vaccination of macaques with these nanoparticles resulted in a 50% inhibitory reciprocal serum dilution (ID50) neutralization titre of 47,216 (geometric mean) for SARS-CoV-2, as well as in protection against SARS-CoV-2 in the upper and lower respiratory tracts. Nucleoside-modified mRNAs that encode a stabilized transmembrane spike or monomeric receptor-binding domain also induced cross-neutralizing antibody responses against SARS-CoV and bat coronaviruses, albeit at lower titres than achieved with the nanoparticles. These results demonstrate that current mRNA-based vaccines may provide some protection from future outbreaks of zoonotic betacoronaviruses, and provide a multimeric protein platform for the further development of vaccines against multiple (or all) betacoronaviruses.

7.
NPJ Vaccines ; 6(1): 50, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33837212

RESUMO

The development of an effective AIDS vaccine remains a challenge. Nucleoside-modified mRNAs formulated in lipid nanoparticles (mRNA-LNP) have proved to be a potent mode of immunization against infectious diseases in preclinical studies, and are being tested for SARS-CoV-2 in humans. A critical question is how mRNA-LNP vaccine immunogenicity compares to that of traditional adjuvanted protein vaccines in primates. Here, we show that mRNA-LNP immunization compared to protein immunization elicits either the same or superior magnitude and breadth of HIV-1 Env-specific polyfunctional antibodies. Immunization with mRNA-LNP encoding Zika premembrane and envelope or HIV-1 Env gp160 induces durable neutralizing antibodies for at least 41 weeks. Doses of mRNA-LNP as low as 5 µg are immunogenic in macaques. Thus, mRNA-LNP can be used to rapidly generate single or multi-component vaccines, such as sequential vaccines needed to protect against HIV-1 infection. Such vaccines would be as or more immunogenic than adjuvanted recombinant protein vaccines in primates.

8.
JCI Insight ; 6(10)2021 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-33908897

RESUMO

Effective SARS-CoV-2 vaccines are urgently needed. Although most vaccine strategies have focused on systemic immunization, here we compared the protective efficacy of 2 adjuvanted subunit vaccines with spike protein S1: an intramuscularly primed/boosted vaccine and an intramuscularly primed/intranasally boosted mucosal vaccine in rhesus macaques. The intramuscular-alum-only vaccine induced robust binding and neutralizing antibody and persistent cellular immunity systemically and mucosally, whereas intranasal boosting with nanoparticles, including IL-15 and TLR agonists, elicited weaker T cell and Ab responses but higher dimeric IgA and IFN-α. Nevertheless, following SARS-CoV-2 challenge, neither group showed detectable subgenomic RNA in upper or lower respiratory tracts versus naive controls, indicating full protection against viral replication. Although mucosal and systemic protective mechanisms may differ, results demonstrate both vaccines can protect against respiratory SARS-CoV-2 exposure. In summary, we have demonstrated that the mucosal vaccine was safe after multiple doses and cleared the input virus more efficiently in the nasal cavity and thus may act as a potent complementary reinforcing boost for conventional systemic vaccines to provide overall better protection.


Assuntos
/uso terapêutico , Macaca mulatta/imunologia , /imunologia , Imunidade Adaptativa , Animais , Anticorpos Neutralizantes/imunologia , /patologia , Humanos , Imunidade Celular , Imunidade Humoral , Vacinas de Subunidades/uso terapêutico
9.
J Virol ; 2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658341

RESUMO

Previously, we showed that substitution of HIV-1 Env residue 375-Ser by bulky aromatic residues enhances binding to rhesus CD4 and enables primary HIV-1 Envs to support efficient replication as simian-human immunodeficiency virus (SHIV) chimeras in rhesus macaques (RMs). Here, we test this design strategy more broadly by constructing SHIVs containing ten primary Envs corresponding to HIV-1 subtypes A, B, C, AE and AG. All ten SHIVs bearing wildtype Env375 residues replicated efficiently in human CD4+ T cells, but only one replicated efficiently in primary rhesus cells. This was a subtype AE SHIV that naturally contained His at Env375. Replacement of wildtype Env375 residues by Trp, Tyr, Phe or His in the other nine SHIVs led to efficient replication in rhesus CD4+ T cells in vitro and in vivo Nine SHIVs containing optimized Env375 alleles were grown large-scale in primary rhesus CD4+ T cells to serve as challenge stocks in preclinical prevention trials. These virus stocks were genetically homogeneous, native-like in Env antigenicity and tier-2 neutralization sensitivity, and transmissible by rectal, vaginal, penile, oral or intravenous routes. To facilitate future SHIV constructions, we engineered a simplified second-generation design scheme and validated it in RMs. Overall, our findings demonstrate that SHIVs bearing primary Envs with bulky aromatic substitutions at Env375 consistently replicate in RMs, recapitulating many features of HIV-1 infection in humans. Such SHIVs are efficiently transmitted by mucosal routes common to HIV-1 infection and can be used to test vaccine efficacy in preclinical monkey trials.ImportanceSHIV infection of Indian rhesus macaques is an important animal model for studying HIV-1 transmission, prevention, immunopathogenesis and cure. Such research is timely, given recent progress with active and passive immunization and novel approaches to HIV-1 cure. Given the multifaceted roles of HIV-1 Env in cell tropism and virus entry, and as a target for neutralizing and non-neutralizing antibodies, Envs selected for SHIV construction are of paramount importance. Until recently, it has been impossible to strategically design SHIVs bearing clinically relevant Envs that replicate consistently in monkeys. This changed with the discovery that bulky aromatic substitutions at residue Env375 confer enhanced affinity to rhesus CD4. Here, we show that 10 new SHIVs bearing primary HIV-1 Envs with residue 375 substitutions replicated efficiently in RMs and could be transmitted efficiently across rectal, vaginal, penile and oral mucosa. These findings suggest an expanded role for SHIVs as a model of HIV-1 infection.

10.
J Cell Physiol ; 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33738797

RESUMO

Fatty acids (FA) exert physiological and pathophysiological effects leading to changes in skeletal muscle metabolism and function, however, in vitro models to investigate these changes are limited. These experiments sought to establish the effects of physiological and pathophysiological concentrations of exogenous FA upon the function of tissue engineered skeletal muscle (TESkM). Cultured initially for 14 days, C2C12 TESkM was exposed to FA-free bovine serum albumin alone or conjugated to a FA mixture (oleic, palmitic, linoleic, and α-linoleic acids [OPLA] [ratio 45:30:24:1%]) at different concentrations (200 or 800 µM) for an additional 4 days. Subsequently, TESkM morphology, functional capacity, gene expression and insulin signaling were analyzed. There was a dose response increase in the number and size of lipid droplets within the TESkM (p < .05). Exposure to exogenous FA increased the messenger RNA expression of genes involved in lipid storage (perilipin 2 [p < .05]) and metabolism (pyruvate dehydrogenase lipoamide kinase isozyme 4 [p < .01]) in a dose dependent manner. TESkM force production was reduced (tetanic and single twitch) (p < .05) and increases in transcription of type I slow twitch fiber isoform, myosin heavy chain 7, were observed when cultured with 200 µM OPLA compared to control (p < .01). Four days of OPLA exposure results in lipid accumulation in TESkM which in turn results in changes in muscle function and metabolism; thus, providing insight ito the functional and mechanistic changes of TESkM in response to exogenous FA.

11.
Nat Commun ; 12(1): 1474, 2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33674572

RESUMO

The establishment of a long-lived viral reservoir is the key obstacle for achieving an HIV-1 cure. However, the anatomic, virologic, and immunologic features of the viral reservoir in tissues during antiretroviral therapy (ART) remain poorly understood. Here we present a comprehensive necroscopic analysis of the SIV/SHIV viral reservoir in multiple lymphoid and non-lymphoid tissues from SIV/SHIV-infected rhesus macaques suppressed with ART for one year. Viral DNA is observed broadly in multiple tissues and is comparable in animals that had initiated ART at week 1 or week 52 of infection. In contrast, viral RNA is restricted primarily to lymph nodes. Ongoing viral RNA transcription is not the result of unsuppressed viral replication, as single-genome amplification and subsequent phylogenetic analysis do not show evidence of viral evolution. Gag-specific CD8+ T cell responses are predominantly observed in secondary lymphoid organs in animals chronically infected prior to ART and these responses are dominated by CD69+ populations. Overall, we observe that the viral reservoir in rhesus macaques is widely distributed across multiple tissue sites and that lymphoid tissues act as a site of persistent viral RNA transcription under conditions of long-term ART suppression.


Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/virologia , Linfonodos/virologia , RNA Viral/genética , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/imunologia , Animais , Linfócitos T CD8-Positivos , DNA Viral , Modelos Animais de Doenças , Feminino , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Linfonodos/imunologia , Tecido Linfoide/virologia , Macaca mulatta , Filogenia , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Vírus da Imunodeficiência Símia/genética , Carga Viral , Replicação Viral
12.
JCO Oncol Pract ; : OP2000701, 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33534616

RESUMO

Despite efforts to enhance enrollment and the merger of national cooperative groups, < 5% of patients with cancer will enroll into a clinical trial. Additionally, clinical trials are affected by a lack of diversity inclusive of minority patients, rural residents, or low-income individuals. COVID-19 further exacerbated known barriers of reduced physician-patient interaction, physician availability, trial activation and enrollment, financial resources, and capacity for conducting research. Based on the cumulative insight of academic and community clinical researchers, we have created a white paper identifying existing challenges in clinical trial conduct and have provided specific recommendations of sustainable modifications to improve efficiency in the activation and conduct of clinical trials with an overarching goal of providing improved access and care to our patients with cancer.

13.
J Environ Manage ; 283: 111923, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33477097

RESUMO

Aquatic invasive species (AIS) cause significant ecological and economic damages around the world. A major spread mechanism for AIS is traffic of boaters transporting their watercraft from invaded to uninvaded waterbodies. To inhibit the spread of AIS, Canadian provinces and American states often set up watercraft inspection stations at roadsides, where potentially infested boats are screened for AIS and, if necessary, decontaminated. However, since budgets for AIS control are limited, watercraft inspection stations can only be operated at specific locations and daytimes. Though theoretical studies provide managers with general guidelines for AIS management, more specific results are needed to determine when and where watercraft inspections would be most effective. This is the subject of this paper. We show how linear integer programming techniques can be used to optimize watercraft inspection policies under budget constraints. We introduce our approach as a general framework and apply it to the prevention of the spread of zebra and quagga mussels (Dreissena spp.) to the Canadian province of British Columbia. We consider multiple scenarios and show how variations in budget constraints, propagule sources, and model uncertainty affect the optimal policy. Based on these results, we identify simple, generally applicable principles for optimal AIS management.


Assuntos
Bivalves , Dreissena , Animais , Colúmbia Britânica , Espécies Introduzidas , Navios
14.
JCO Oncol Pract ; 17(1): 59-60, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33332169

Assuntos
Neoplasias , Humanos
15.
Evol Appl ; 13(10): 2521-2535, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33294006

RESUMO

Migration can reduce parasite burdens in migratory hosts, but it connects populations and can drive disease dynamics in domestic species. Farmed salmon are infested by sea louse parasites, often carried by migratory wild salmonids, resulting in a costly problem for industry and risk to wild populations when farms amplify louse numbers. Chemical treatment can control lice, but resistance has evolved in many salmon-farming regions. Resistance has, however, been slow to evolve in the north-east Pacific Ocean, where large wild-salmon populations harbour large sea louse populations. Using a mathematical model of host-macroparasite dynamics, we explored the roles of domestic, wild oceanic and connective migratory host populations in maintaining treatment susceptibility in associated sea lice. Our results show that a large wild salmon population, unexposed to direct infestation by lice from farms; high levels of on-farm treatment; and a healthy migratory host population are all critical to slowing or stopping the evolution of treatment resistance. Our results reproduce the "high-dose/refuge effect," from the agricultural literature, with the added requirement of a migratory host population to maintain treatment susceptibility. This work highlights the role that migratory hosts may play in shared wildlife/livestock disease, where evolution can occur in ecological time.

16.
Nature ; 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33276369

RESUMO

Recent studies have reported protective efficacy of both natural immunity1 and vaccine-induced immunity2-7 against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge in rhesus macaques. However, the importance of humoral and cellular immunity for protection against SARS-CoV-2 infection remains to be determined. Here we show that adoptive transfer of purified IgG from convalescent macaques protects naïve recipient rhesus macaques against SARS-CoV-2 challenge in a dose dependent fashion. Depletion of CD8+ T cells in convalescent animals partially abrogated the protective efficacy of natural immunity against SARS-CoV-2 re-challenge, suggesting the importance of cellular immunity in the context of waning or subprotective antibody titers. These data demonstrate that relatively low antibody titers are sufficient for protection against SARS-CoV-2 in rhesus macaques, and that cellular immune responses may also contribute to protection if antibody responses are suboptimal. We also show that higher antibody titers are required for therapy of SARS-CoV-2 infection in macaques. These findings have important implications for the development of SARS-CoV-2 vaccines and immune-based therapeutics.

17.
Cell Host Microbe ; 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33306985

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein acquired a D614G mutation early in the pandemic that confers greater infectivity and is now the globally dominant form. To determine whether D614G might also mediate neutralization escape that could compromise vaccine efficacy, sera from spike-immunized mice, nonhuman primates, and humans were evaluated for neutralization of pseudoviruses bearing either D614 or G614 spike. In all cases, the G614 pseudovirus was moderately more susceptible to neutralization. The G614 pseudovirus also was more susceptible to neutralization by receptor-binding domain (RBD) monoclonal antibodies and convalescent sera from people infected with either form of the virus. Negative stain electron microscopy revealed a higher percentage of the 1-RBD "up" conformation in the G614 spike, suggesting increased epitope exposure as a mechanism of enhanced vulnerability to neutralization. Based on these findings, the D614G mutation is not expected to be an obstacle for current vaccine development.

18.
J Tissue Eng ; 11: 2041731420967294, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33194170

RESUMO

Herein, the cytotoxicity of a novel zwitterionic sulfobetaine hydrogel system with a nano-clay crosslinker has been investigated. We demonstrate that careful selection of the composition of the system (monomer to Laponite content) allows the material to be formed into controlled shapes using an extrusion based additive manufacturing technique with the ability to tune the mechanical properties of the product. Moreover, the printed structures can support their own weight without requiring curing during printing which enables the use of a printing-then-curing approach. Cell culture experiments were conducted to evaluate the neural cytotoxicity of the developed hydrogel system. Cytotoxicity evaluations were conducted on three different conditions; a control condition, an indirect condition (where the culture medium used had been in contact with the hydrogel to investigate leaching) and a direct condition (cells growing directly on the hydrogel). The result showed no significant difference in cell viability between the different conditions and cells were also found to be growing on the hydrogel surface with extended neurites present.

19.
Laryngoscope Investig Otolaryngol ; 5(5): 919-927, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33134540

RESUMO

Objectives: The pervasiveness of hearing loss and the development of new potential therapeutic approaches have led to increased animal studies of the inner ear. However, translational relevance of such studies depends upon verification of protein localization data in human samples. Cadavers used for anatomical education provide a potential research resource, but are limiting due to difficulties in accessing sensory tissues from the dense temporal bones. This study seeks to reduce the often months-long process of decalcification and improve immunofluorescent staining of human cadaveric temporal bones for research use. Methods: Temporal bones were decalcified in either (a) hydrochloric acid-containing RDO solution for 2 days followed by 0.5 M ethylenediaminetetraacetic acid (EDTA) for 3 to 5 additional days, or (b) 0.5 M EDTA alone for 2 to 4 weeks. Image-iT FX signal enhancer (ISE) was used to improve immunofluorescent signal-to-noise ratios. Results: The data indicate that both methods speed decalcification and allow for immunolabeling of the extranuclear proteins neurofilament (heavy chain), myosin VIIa, oncomodulin and prestin. However, RDO decalcification was more likely to alter structural morphology of sensory tissues and hindered effective labeling of the nuclear proteins SRY-box transcription factor 2 and GATA binding protein 3. Conclusions: Although both approaches allow for rapid decalcification, EDTA appears superior to RDO for preserving cytoarchitecture and immunogenicity. Level of evidence: NA.

20.
Science ; 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33214287

RESUMO

Neutralizing antibodies elicited by HIV-1 coevolve with viral envelope proteins (Env) in distinctive patterns, in some cases acquiring substantial breadth. We report that primary HIV-1 envelope proteins-when expressed by simian-human immunodeficiency viruses in rhesus macaques-elicited patterns of Env-antibody coevolution strikingly similar to those in humans. This included conserved immunogenetic, structural and chemical solutions to epitope recognition and precise Env-am ino acid substitutions, insertions and deletions leading to virus persistence. The structure of one rhesus antibody, capable of neutralizing 49% of a 208-strain panel, revealed a V2-apex mode of recognition like that of human bNAbs PGT145/PCT64-35S. Another rhesus antibody bound the CD4-binding site by CD4 mimicry mirroring human bNAbs 8ANC131/CH235/VRC01. Virus-antibody coevolution in macaques can thus recapitulate developmental features of human bNAbs, thereby guiding HIV-1 immunogen design.

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