Biology subjects

Garrett, N.

Publications and source records attributed to Garrett, N..

12 recordsLinked to original sources

bioRxiv2026

Low seroprevalence of neutralizing antibodies to gorilla adenovirus 32 (GRAd32) in southern African populations supports evaluation of this vector platform for HIV vaccine development

Adenoviruses (Ads) are widely used as vaccine vectors. However, pre-existing immunity to commonly used serotypes, like Ad5, can reduce vaccine immunogenicity, with neutralizing antibody titers >200 previously shown to impact vaccine efficacy. Gorilla adenovirus (GRAd) vectors have been developed to evade pre-existing anti-vector responses, but their seroprevalence in southern Africa is poorly defined. Here, we assessed seroprevalence to GRAd32, Ad26 and Ad5 before (baseline) and after COVID-19 vaccination, in cohorts from South Africa and Zimbabwe. Sera from South African participants enrolled in the Sisonke sub-study (n=100, prior to Ad26.COV2.S vaccination) and the follow-up "Booster after Sisonke" (BaSiS) study (n=226) were tested for neutralizing antibodies to Ad5, Ad26, and GRAd32. These samples included paired pre/post boost samples for 27 donors. We also tested sera from the Zimbabwean Mutala cohort (n=131, of which 44 were unvaccinated, and 87 vaccinated with inactivated vaccines). Participants living with HIV (PLWH) comprised 30-50% of each cohort. In the pre-vaccination samples from the Sisonke cohort, geometric mean titers (GMT) for anti-GRAd32, Ad26, and Ad5 antibodies were 78, 142, and 459, with neutralization titers >200 observed in 14%, 32%, and 68% of participants, respectively. Similarly, in the unvaccinated participants in the Mutala cohort, GMTs for GRAd32, Ad26, and Ad5 were 117, 245, and 536, with neutralizing titers >200 in 22%, 42%, and 69% of participants. We observed no significant difference in Ad antibody titers between PLWH and those living without HIV. We next assessed the impact of COVID-19 vaccination on titers. Vaccination with inactivated COVID-19 vaccines (Sinopharm/Sinovac) did not significantly affect Ad5, Ad26 or GRAd32 titers in an unpaired analysis. In contrast, [~]9 months after Ad26.COV2.S vaccination, anti-Ad26 titers for longitudinally sampled participants (n=27) increased 10-fold from a GMT of 141 to 1,426. By comparison, GRAd32 responses were not significantly altered by Ad26.COV2.S vaccination, while anti-Ad5 responses showed a modest <2-fold increase. Our data support previous findings that, whereas anti-Ad5 neutralizing antibody responses are commonly detected globally, GRAd32 responses are less frequent. Importantly, GRAd32 neutralizing responses remained unchanged after Ad26.COV2.S vaccination. HIV status had no significant effect on antibody titers. These results support the use of the GRAd32 vector in upcoming HIV vaccine trials, including in regions where Ad26-based COVID-19 vaccines were widely deployed.

immunology↗

bioRxiv2026

Confirmation Bias Exists in the Face of False Information

Confirmation bias impacts judgments and decisions across a range of domains including finance, policy and science. Here we examine whether explicitly labelling information as true or false disrupts a core underlying computational mechanism that can generate this pervasive bias - asymmetric learning. Human participants (Study 1: N=47; Study 2: N=57) completed a 2 alternative forced choice (2AFC) task previously used to test for the presence of confirmation bias. Participants made choices between pairs of options that could win or lose money and received either factual or counterfactual feedback after each choice. We introduced a key novel feature into the task - providing explicit cues that signalled to participants whether feedback they had seen was true (verified) or false (debunked). Learning in response to feedback was attenuated under false compared to true labels but was present under both. Fitting participants choices to computational models enabled us to examine how sensitivity to the feedback varied as a function of both the label (true/false) and confirmation (confirmatory/disconfirmatory). This revealed a distinct pattern of learning rates typical of confirmation bias (enhanced learning from positive prediction errors for chosen options and from negative prediction errors for unchosen options) in response to both true and false labels. The findings highlight how confirmation bias plays an important role in the effectiveness of interventions designed to verify true and/or debunk false claims. Verification is less likely to succeed when information disconfirms prior beliefs. Conversely, debunking false claims is unlikely to succeed when the information confirms ones prior beliefs.

neuroscience↗

bioRxiv2025

Factors Influencing Emerald Ash Borer Ecological Interactions

Emerald ash borer beetles (Agrilus planipennis) in North America are a destructive invasive species that increase tree mortality continent-wide, resulting in major ecological and economic impacts. Trees that are infested experience mortality rates which can exceed 99%, disrupting ecological communities and threatening the $218 billion forestry industry in North America. Given the ecological and economic impact of these pests, we seek to identify biological interactions and gain a better understanding of what ecological factors might influence these relationships. We use DNA metabarcoding from multiple markers to analyze the fungal, parasitic, plant, and microbial interactions of these beetles, and assess the relative importance of life stage (e.g., larvae, pupae, and adults), collection location, habitat, and date on the detection of ecological interactions. We detected 30 different taxonomic orders including 29 order-level interactions in larva1-stage individuals (3 animal, 17 bacteria, and 9 fungi), 64 in larva2-stage individuals (8 animal, 24 bacteria, and 32 fungi), 10 in larva3-stage individuals (2 animal, 3 bacteria, and 5 fungi), 74 in the pupae (5 animal, 31 bacteria, and 38 fungi), and 82 in the adult beetles (4 animal, 48 bacteria, 29 fungi, and 1 parasitic alveolate). These detections include several likely agents of biocontrol including the known commercially available Beauveria fungus, and several potential parasites including Wolbachia and ichneumonid wasps. A random forest model suggests the detection of interactions is best predicted by collection date and life stage, with interactions more likely to be detected in pupal samples which may be the ideal target for future analysis, where cost and time constraints prevent the more thorough analysis of all life stages.

ecology↗

bioRxiv2025

HIV-1 Rebound Virus Consists of a Small Number of Lineages That Entered the Reservoir Close to ART Initiation

HIV-1 persists as a latent reservoir during suppressive antiretroviral therapy (ART). Viral rebound occurs upon ART interruption, posing a challenge to cure efforts. Characterizing viral populations fuelling rebound is imperative to curing HIV-1. We used longitudinal samples collected pretherapy from women in the CAPRISA 002 cohort to create an evolutionary time- line to determine the pretherapy timepoint when the rebound virus originally entered the long- lived reservoir. Participants (N=10) were untreated for an average of 5 years then on ART for an average of 2 years before viral rebound (defined as >1000 RNA copies/ml). env sequences were used to characterize the longitudinal pre-ART evolving viral RNA population, the proviral DNA reservoir during ART, and viral RNA in the plasma during rebound. For each participant, between 1 and 3 major viral lineages were identified in the plasma during rebound. A total of 20 rebound virus lineages were examined for the 10 participants, and 19 were found to have entered the reservoir around the time of therapy initiation. The one lineage estimated to enter the reservoir more than a year before therapy was observed in a participant who was untreated for more than 8 years, yet retained moderate CD4 T cell counts. Analysis of the viral DNA reservoir, from which the rebound viruses emanated, revealed that while 95% of rebounding lineages dated to the year before ART initiation, only 61% of unique proviruses dated to that time period. Strikingly, for three participants with DNA reservoirs dominated by viruses from earlier in untreated infection, only 33% of unique proviruses dated to the year before ART initiation, yet 83% of rebounding lineages dated to that time. Our results show that rebound virus almost exclusively comes from the portion of the latent reservoir that formed around the time of therapy initiation, even when the reservoir is composed of diverse sequences from across the pre-ART time period. Author SummaryHIV-1 is maintained in a long-lived reservoir during suppressive therapy. Virus rebounds if therapy is discontinued. We found that in most cases rebound virus comes from a pool of viral sequences that entered the long-lived reservoir around the time of therapy initiation. While the viral DNA reservoir is on average also skewed toward sequences replicating around the time of therapy initiation, the rebound virus almost exclusively comes from this portion of the latent reservoir, even when the reservoir contained proviruses from much earlier in untreated infection. Thus, we hypothesize that there are features of the viruses forming the latent reservoir around the time of therapy initiation, or features of the host at that time, that select these viruses as initiators of rebound during therapy discontinuation.

microbiology↗

bioRxiv2024

The role of Nef in the long-term persistence of the replication-competent HIV reservoir in South African women

HIV-1 Nef mediates immune evasion and viral pathogenesis in part through downregulation of cell surface cluster of differentiation 4 (CD4) and major histocompatibility complex class I (MHC-I) on infected cells. While Nef function of circulating viral populations found early in infection has been associated with reservoir size in early-treated cohorts, there is limited research on how its activity impacts reservoir size in people initiating treatment during chronic infection. In addition, there is little research on its role in persistence of viral variants during long-term antiretroviral therapy (ART). Phylogenetically distinct nef genes (n=82) with varying estimated times of reservoir entry were selected from viral outgrowth variants stimulated from the reservoir of South African women living with HIV who initiated ART during chronic infection (n=16). These nef genes were synthesized and used in a pseudovirus infection assay that measures CD4 and MHC-I downregulation via flow cytometry. Downregulation measures were compared to the size of the replication-competent viral reservoir (RC-VR), estimated by quantitative viral outgrowth assay (QVOA) at 5 years after treatment initiation, as well as proviral survival time. Maximum Nef-mediated MHC-I downregulation was significantly associated with RC-VR size (p=0.034), but this association was not observed for CD4 downregulation. Conversely, we did not find a consistent association between intraparticipant MHC-I or CD4 downregulation and the variant timing of entry into the reservoir. These data support a role for Nef-mediated MHC-I downregulation in determining RC-VR size, but more work is needed to determine Nefs role in the survival of individual viral variants over time. Author summaryUnderstanding the HIV reservoir, including viral determinants of reservoir formation and maintenance, is key for the rational design of cure interventions. In addition, for cure interventions to be equitable, it needs to be broadly applicable. While African women bear the greatest burden of HIV globally, most cure research has been performed in men living in the global North. Our study aims to elucidate attributes of the virus that contribute to reservoir dynamics in South African women on ART. We investigated the ability of the HIV accessory protein Nef to reduce the cell surface levels of two cellular proteins, CD4 and MHC-I, and compared this downregulation capacity with the size of the HIV reservoir and survival of cells infected with a given viral isolate. We found a positive association between an individuals measured reservoir size and MHC-I downregulation, but not CD4 downregulation. There was little evidence for a survival benefit for stronger Nef MHC-I reduction, but more research is needed on this subject. These data support earlier work and suggest that Nefs interaction with MHC-I may be a target to restrict the latent reservoir and inform alternate cure strategies.

pathology↗

bioRxiv2024

Rare twin cysteine residues in the HIV-1 envelope variable region 1 link to neutralization escape and breadth development

The identification of HIV-1 Envelope glycoprotein (Env) traits associated with development of neutralization cross-reactivity in natural infection is critical for vaccine design. Here we describe the presence of additional Cysteine (Cys) residues in V1 that are enriched among people with elite neutralization breadth. Using >65,000 V1 sequences from the CATNAP database, the AMP trials and three large longitudinal HIV infection cohorts, the SHCS, ZPHI and CAPRISA studies, we show that Env variants with extra V1 Cys are present at low levels throughout infection and fluctuate in frequency over time within participants. We demonstrate an independent association of extra V1 Cys with elite plasma neutralization, and a strong preference for two versus one extra Cys, suggesting certain Envs introduce an additional disulfide bond for stabilization. We observed high levels of neutralization resistance among Envs from 34 bNAb donors, of which 17.6% had elongated V1 regions with extra Cys. We show that extra V1 Cys moderately increase neutralization resistance in an Env from a V2- Apex bNAb-inducer. Modulation of the accessibility of bNAb epitopes on this Env by extra V1 Cys enhanced epitope shielding of several regions, but increased V2 exposure. This suggests that escape from autologous neutralizing activity drove insertion of the extra V1 Cys, creating a modified antigen that may have favored V2 bNAb induction in this donor. Overall, we identify a rare motif of twin Cys in V1 that confers increased neutralization resistance and Env stabilization, is associated with bNAb induction, and may hold potential for incorporation into future HIV bNAb immunogens.

immunology↗

bioRxiv2022

Model based control can give rise to devaluation insensitive choice

Influential recent work aims to ground psychiatric dysfunction in the brains basic computational mechanisms. For instance, compulsive symptoms as in drug abuse have been argued to arise from imbalance between multiple systems for instrumental learning. Computational models suggest that such multiplicity arises because the brain adaptively simplifies laborious "model-based" deliberation by sometimes relying on a cheaper, more habitual "model-free" shortcut. Support for this account comes in part from failures to appropriately change behavior in light of new events. Notably, instrumental responding can, in some circumstances, persist despite reinforcer devaluation, perhaps reflecting control by model-free mechanisms that are driven by past reinforcement rather than knowledge of the (now devalued) outcome. However, another important line of theory - heretofore mostly studied in Pavlovian conditioning - posits a different mechanism that can also modulate behavioral change. It concerns how animals identify different rules or contingencies that may apply in different circumstances, by covertly clustering experiences into distinct groups identified with different "latent causes" or contexts. Such clustering has been used to explain the return of Pavlovian responding following extinction. Here we combine both lines of theory to investigate the consequences of latent cause inference on instrumental sensitivity to reinforcer devaluation. We show that because segregating events into different latent clusters prevents generalization between them, instrumental insensitivity to reinforcer devaluation can arise in this theory even using only model-based planning, and does not require or imply any habitual, model-free component. In simulations, these ersatz habits (like laboratory ones) emerge after overtraining, interact with contextual cues, and show preserved sensitivity to reinforcer devaluation on a separate consumption test, a standard control. While these results do not rule out a contribution of model-free learning per se, they point to a subtle and important role of state inference in instrumental learning and highlight the need for caution in using reinforcer devaluation procedures to rule in (or out) the contribution of different learning mechanisms. They also offer a new perspective on the neurocomputational substrates of drug abuse and the relevance of laboratory reinforcer devaluation procedures to this phenomenon.

neuroscience↗

bioRxiv2022

Decision heuristics in contexts exploiting intrinsic skill

Heuristics can inform human decision making in complex environments through a reduction of computational requirements (accuracy-resource trade-off) and a robustness to overparameterisation (less-is-more). However, tasks capturing the efficiency of heuristics typically ignore action proficiency in determining rewards. The requisite movement parameterisation in sensorimotor control questions whether heuristics preserve efficiency when actions are nontrivial. We developed a novel action selection-execution task requiring joint optimisation of action selection and spatio-temporal skillful execution. Optimal choices could be determined by a simple spatial heuristic, or by more complex planning. Computational models of action selection parsimoniously distinguished human participants who adopted the heuristic from those using a more complex planning strategy. Broader comparative analyses then revealed that participants using the heuristic showed combined decisional (selection) and skill (execution) advantages, consistent with a less-is-more framework. In addition, the skill advantage of the heuristic group was predominantly in the core spatial features that also shaped their decision policy, evidence that the dimensions of information guiding action selection might be yoked to salient features in skill learning. Author SummaryWe often must choose between actions and then execute them, e.g., a tennis player chooses between a forehand and backhand and then skilfully executes the shot. To select actions, the player might plan their action with either shot, and select whichever simulated outcome is more advantageous. However, a more efficient approach might instead be to use a "heuristic", i.e., a simpler rule, such as, forehand always on one side of the court, and backhand on the other. In this work, we look at whether styles of planning are related to physical skill performing actions, e.g., would a more skillful tennis player be more likely to use planning or a heuristic? We use a new task that requires people to choose and execute complex actions. Regarding choices, we use computational modeling to identify which people use some degree of planning, and which people use a simpler heuristic. Then, regarding action execution, we reveal that heuristic decision makers are in fact more skilled. However, they are not superiorly skilled in all aspects of performance, showing an advantage solely in the aspect of skill most closely linked to the information (spatial) they use for their heuristic. We therefore reveal the first ever evidence that a relation exists between the complexity of our action-related decisions and how broadly we learn associated motor behaviour.

neuroscience↗

bioRxiv2021

Neutralizing antibodies elicited by the Ad26.COV2.S COVID-19 vaccine show reduced activity against 501Y.V2 (B.1.351), despite protection against severe disease by this variant.

The emergence of SARS-CoV-2 variants, such as 501Y.V2, with immune evasion mutations in the spike has resulted in reduced efficacy of several COVID-19 vaccines. However, the efficacy of the Ad26.COV2.S vaccine, when tested in South Africa after the emergence of 501Y.V2, was not adversely impacted. We therefore assessed the binding and neutralization capacity of n=120 South African sera (from Day 29, post-vaccination) from the Janssen phase 3 study, Ensemble. Spike binding assays using both the Wuhan-1 D614G and 501Y.V2 Spikes showed high levels of cross-reactivity. In contrast, in a subset of 27 sera, we observed significantly reduced neutralization of 501Y.V2 compared to Wuhan-1 D614G, with 22/27 (82%) of sera showing no detectable neutralization of 501Y.V2 at Day 29. These data suggest that even low levels of neutralizing antibodies may contribute to protection from moderate/severe disease. In addition, Fc effector function and T cells may play an important role in protection by this vaccine against 501Y.V2.

immunology↗

bioRxiv2019

Sympathetic and parasympathetic involvement in time constrained sequential foraging

Appraising sequential offers relative to an unknown future opportunity and a time cost requires an optimization policy that draws on a learned estimate of an environments richness. Converging evidence points to a learning asymmetry, whereby estimates of this richness update with a bias toward integrating positive information. We replicate this bias in a sequential foraging (prey selection) task and probe associated activation within two branches of the autonomic system, sympathetic and parasympathetic branches, using trial-by-trial measures of simultaneously recorded cardiac autonomic physiology. In general, lower value offers were accepted during periods of autonomic drive, both in the sympathetic (shorter pre-ejection period PEP) and parasympathetic (higher HF HRV) branches. In addition, we reveal a unique adaptive role for the sympathetic branch in learning. It was specifically associated with adaptation to a deteriorating environment: it correlated with both the rate of negative information integration in belief estimates and downward changes in moment-to-moment environmental richness, and was predictive of optimal performance on the task. The findings are consistent with a parallel processing framework whereby autonomic function serves both learning and executive demands of prey selection.\n\nSignificance statementThe value of choices (accepting a job) depends on context (richness of the current job market). Learning contexts, therefore, is crucial for optimal decision-making. Humans demonstrate a bias when learning contexts; we learn faster about improvements vs deteriorations. New techniques allow us to cleanly measure fast acting stress responses that might fluctuate with trial-by-trial learning. Using these new methods, we observe here that increased stress - specifically sympathetic (heart contractility) - might help overcome the learning bias (making us faster at learning contextual deterioration) and thereafter guide us toward better context appropriate decisions. For the first time we show that specific building blocks of good decision-making might benefit from short bursts of specific inputs of the stress system.

physiology↗

bioRxiv2019

Biased belief updating and suboptimal choice in foraging decisions

In many choice scenarios, including prey, employment, and mate search, options are not encountered simultaneously and so cannot be directly compared. Deciding which ones optimally to engage, and which to forego, requires developing accurate beliefs about the overall distribution of prospects. However, the role of learning in this process - and how biases due to learning may affect choice - are poorly understood. In three experiments, we adapted a classic prey selection task from foraging theory to examine how individuals kept track of an environments reward rate and adjusted their choices in response to its fluctuations. In accord with qualitative predictions from optimal foraging models, participants adjusted their selectivity to the richness of the environment: becoming less selective in poorer environments and increasing acceptance of less profitable options. These preference shifts were observed not just in response to global (between block) manipulations of the offer distributions, but also to local, trial-by-trial offer variation within a block, suggesting an incremental learning rule. Further offering evidence into the learning process, these preference changes were more pronounced when the environment improved compared to when it deteriorated. All these observations were best explained by a trial-by-trial learning model in which participants estimate the overall reward rate, but with upward vs. downward changes controlled by separate learning rates. A failure to adjust expectations sufficiently when an environment becomes worse leads to suboptimal choices: options that are valuable given the environmental conditions are rejected in the false expectation that better options will materialize. These findings offer a previously unappreciated parallel in the serial choice setting of observations of asymmetric updating and resulting biased (often overoptimistic) estimates in other domains.

neuroscience↗

bioRxiv2019

The Replication-Competent HIV-1 Latent Reservoir is Primarily Established Near the Time of Therapy Initiation

Although antiretroviral therapy (ART) is highly effective at suppressing HIV-1 replication, the virus persists as a latent reservoir in resting CD4+ T cells during therapy. Little is known about the dynamics of reservoir formation and this reservoir forms even when ART is initiated early after infection. The reservoir of individuals who initiate therapy in chronic infection is generally larger and genetically more diverse than that of individuals who initiate in acute infection, suggesting the reservoir is formed continuously throughout untreated infection. To determine when viruses enter the latent reservoir, we compared sequences of replication-competent viruses from resting CD4+ T cells from nine women on therapy to viral sequences circulating in blood collected longitudinally prior to therapy. We found that 78% of viruses from the latent reservoir were most genetically similar to viruses replicating just prior to therapy initiation. This proportion is far greater than expected if the reservoir forms continuously and is always long-lived. Thus, therapy alters the host environment in a way that allows the formation of a majority of the long-lived latent HIV-1 reservoir.\n\nOne Sentence SummaryMost of the long-lived, replication-competent HIV-1 reservoir is formed at the time of therapy initiation.

microbiology↗