Biology subjects

Allen, E. J.

Publications and source records attributed to Allen, E. J..

14 recordsLinked to original sources

bioRxiv2026

A Tissue Virus Microenvironment with Activated Stress Responses Underlies Durable SIV Persistence

HIV persistence during suppressive antiretroviral therapy (ART) remains a central barrier to cure, with the majority of reservoirs residing in gut-associated lymphoid tissues (GALT). Here, we define a spatially organized viral microenvironment (VME) that sustains reservoir durability and governs early viral rebound by comparing animals initiating ART early after infection (transient reservoirs) versus late (persistent reservoirs). Using immunoPET/CT-guided sampling of SIV-infected rhesus macaques combined with spatial transcriptomics, we interrogated tissue sites of viral production during the eclipse phase following analytical treatment interruption (ATI). Our results revealed that viral rebound from persistent reservoirs arises from discrete, transcriptionally active foci enriched in the mucosa lining the gut lumen. Eclipse phase persistent reservoirs were characterized by increased proviral burden and a distinct tissue state marked by activation of stress-response, metabolic, mitochondrial, and cell cycle programs coupled to repression of cytoplasmic translation and increased cellular senescence. These features co-occurred with immunosuppressive cellular architectures resembling tertiary lymphoid structures enriched for Treg cells, innate lymphoid cells, and mast cells, regulated by Treg-centered cell-cell interaction networks. In contrast, transient reservoirs displayed enhanced translational and metabolic activity and were embedded within immune-active environments enriched for CD8 T cells, Th17, Tfh, and activated CD4 T cells. Machine learning identified stress adaptation, hypoxia, metabolic rewiring, and cytoskeletal remodeling pathways as dominant predictors of viral density within persistent VMEs, with strong convergence on programs observed in tumor microenvironments (TME). Orthogonal validation confirmed activation of the integrated stress response (ISR) at sites of viral production in concurrence with results of immunofluorescent microscopy revealing SIV gag expression in two populations primarily in the mucosa, differentiated by the phosphorylation of eIF2. Together, these findings establish the VME as a critical determinant of reservoir persistence, integrating immune regulation, tissue remodeling, and translational control to enable viral survival. This framework suggests that effective HIV cure strategies will require coordinated disruption of VME-supportive functions in addition to targeting infected cells.

microbiology↗

bioRxiv2025

Hierarchical Processing of Natural Scenes in the Human Pulvinar

The hierarchical organization of the ventral visual cortex has been the focus of theories and computational models characterizing high-level visual processing and object recognition, often overlooking potential contributions of subcortical structures. The pulvinar, through its extensive reciprocal connections with ventral visual cortex, is well-positioned to play a prominent role in high-level visual recognition processes. Here, we investigated whether the pulvinar plays such a role using a high-resolution 7T fMRI dataset of responses to tens of thousands of natural scenes. Encoding models testing the representation of different stimulus features revealed a pulvinar region selective for bodies and faces presented within the contralateral visual hemifield. Model-free analyses demonstrated that this region is predominantly co-active with body- and face-selective cortical areas during natural scene viewing. This functional specificity was embedded within a broader gradient of cortical correlations across the pulvinar mirroring the hierarchical organization of ventral visual cortex. These findings challenge cortico-centric models of object vision and implicate a role of the pulvinar in high-level vision. More broadly, these results demonstrate that principles of cortical organization, including functional clustering and hierarchical organization, also manifest in subcortex, and highlight the value of using naturalistic stimuli to probe visual function.

neuroscience↗

bioRxiv2025

Cortical substrates of perceptual confusion between pitch and timbre

Pitch and timbre, two fundamental perceptual attributes of sound, are critical for both speech and music. Although governed by different acoustic parameters, pitch and brightness (one of the primary dimensions of timbre) can be perceptually confused. Here we identify potential neural substrates of this well-known illusion by independently manipulating pitch and brightness while measuring fMRI responses. First, we show that the preferred pitch of individual voxels within auditory cortex decreases systematically as stimulus brightness increases, and vice versa, consistent with predictions from perceptual confusion. Second, we demonstrate that pitch and brightness share a common tuning gradient across auditory cortex, implying a shared trajectory of cortical activation for changes in each dimension. The pattern of results at both local and global cortical levels are consistent with the principle of efficient coding, with the brain exploiting correlations between pitch and brightness in natural sounds via a shared neural code.

neuroscience↗

bioRxiv2024

Temporal asymmetry of neural representations predicts memory decisions

A stimulus can be familiar for multiple reasons. It might have been recently encountered, or is similar to recent experience, or is similar to typical experience. Understanding how the brain translates these sources of similarity into memory decisions is a fundamental, but challenging goal. Here, using fMRI, we computed neural similarity between a current stimulus and events from different temporal windows in the past and future (from seconds to days). We show that trial-by-trial memory decisions (is this stimulus old?) were predicted by the difference in similarity to past vs. future events (temporal asymmetry). This relationship was (i) evident in lateral parietal and occipitotemporal cortices, (ii) strongest when considering events from the recent past (minutes ago), and (iii) most pronounced when veridical (true) memories were weak. These findings suggest a new perspective in which the brain supports memory decisions by comparing what actually occurred to what is likely to occur.

neuroscience↗

bioRxiv2024

Nonlinear progression across the occult transition establishes cancer lethality

Cancer screening is based upon a linear model of neoplastic growth and malignant progression. Yet, historical observations suggest that malignant progression is uncoupled from growth which may explain the paradoxical increase in early-stage breast cancer detection without a dramatic reduction in metastatic burden. Here we lineage trace millions of genetically transformed field cells and thousands of screen detectable and symptomatic tumors using a cancer rainbow mouse model of HER2+ breast cancer. Transition rates from field cell to screen detectable tumor and then to symptomatic tumors were estimated from a dynamical model of tumor development. Field cells are orders of magnitude less likely to transition to a screen detectable tumor than the subsequent transition of a screen detectable tumor to a symptomatic tumor. Our model supports a critical occult transition in tumor development during which time a transformed cell becomes a bona fide neoplasm. Lineage tracing and test-by-transplantation reveals that nonlinear progression during or prior to the occult transition gives rise to nascent lethal cancers at screen detection. Simulations illustrate how occult transition rates are a critical determinant of tumor growth and malignancy in the lifetime of a host. Our data provides direct experimental evidence that cancers can deviate from the predictable linear progression model foundational to current screening paradigms

cancer biology↗

bioRxiv2022

Re-expression of CA1 and entorhinal activity patterns preserves temporal context memory at long timescales

Converging, cross-species evidence indicates that memory for time is supported by hippocampal area CA1 and entorhinal cortex. However, limited evidence characterizes how these regions preserve temporal memories over long timescales (e.g., months). At long timescales, memoranda may be encountered in multiple temporal contexts, potentially creating interference. Here, using 7T fMRI, we measured CA1 and entorhinal activity patterns as human participants viewed thousands of natural scene images distributed, and repeated, across many months. We show that memory for an images original temporal context was predicted by the degree to which CA1/entorhinal activity patterns from the first encounter with an image were re-expressed during re-encounters occurring minutes to months later. Critically, temporal memory signals were dissociable from predictors of recognition confidence, which were carried by distinct medial temporal lobe expressions. These findings suggest that CA1 and entorhinal cortex preserve temporal memories across long timescales by coding for and reinstating temporal context information.

neuroscience↗

bioRxiv2022

Color-biased regions in the ventral visual pathway are food-selective

The ventral visual pathway is well known to be involved in recognizing and categorizing objects (Kanwisher and Dilks, 2013). Three color-biased areas have also been found between face and place selective areas in the ventral visual pathway (Lafer-Sousa et al., 2016). To understand the function of these color-biased areas in a region known for object recognition, we analyzed the Natural Scenes Dataset (NSD; Allen et al., 2022), a large 7T fMRI dataset from 8 participants who viewed up to 30,000 trials of images of colored natural scenes. In a whole-brain analysis, we correlated the average color saturation of the images and the voxel responses, revealing color-biased areas that diverge into two streams in the ventral visual pathway, beginning in V4 and extending medially and laterally of the Fusiform Face Area in both hemispheres. We drew regions of interest (ROIs) for the two streams and found that the images for each ROI that evoked the largest responses had certain characteristics: They contained food, contained circular objects, had higher color saturation, contained warmer hues, and had more luminance entropy. A multiple linear regression showed that the presence of food in images was the strongest predictor of voxel responses in the medial and lateral color-biased regions for all eight participants, but that color saturation also contributed independently to voxel responses. Our results show that these areas are food-selective and color biased. We suggest that these streams might be involved in using color to recognize and judge the properties of food.

neuroscience↗

bioRxiv2022

Brain-optimized neural networks learn non-hierarchical models of representation in human visual cortex

Deep neural networks (DNNs) trained to perform visual tasks learn representations that align with the hierarchy of visual areas in the primate brain. This finding has been taken to imply that the primate visual system forms representations by passing them through a hierarchical sequence of brain areas, just as DNNs form representations by passing them through a hierarchical sequence of layers. To test the validity of this assumption, we optimized DNNs not to perform visual tasks but to directly predict brain activity in human visual areas V1-V4. Using a massive sampling of human brain activity, we constructed brain-optimized networks that predict brain activity even more accurately than task-optimized networks. We show that brain-optimized networks can learn representations that diverge from those formed in a strict hierarchy. Brain-optimized networks do not need to align representations in V1-V4 with layer depth; moreover, they are able to accurately model anterior brain areas (e.g., V4) without computing intermediary representations associated with posterior brain areas (e.g., V1). Our results challenge the view that human visual areas V1-V4 act--like the early layers of a DNN--as a serial pre-processing sequence for higher areas, and suggest they may subserve their own independent functions.

neuroscience↗

bioRxiv2021

Localization of infection in neonatal rhesus macaques after oral viral challenge

While vertical transmission of human immunodeficiency virus (HIV) can occur in utero and during delivery and through breastfeeding. We utilized Positron Emission Tomography (PET) imaging coupled with fluorescent microscopy of 64Cu-labeled photoactivatable-GFP-HIV (PA-GFP-BaL) to determine how HIV virions distribute and localize in neonatal rhesus macaques two and four hours after oral viral challenge. Our results show that by four hours after oral viral exposure, HIV virions localize to and penetrate the rectal mucosa. We also used a dual viral challenge with a non-replicative viral vector and a replication competent SHIV-1157ipd3N4 to examine viral transduction and dissemination at 96 hours. Our data show that while SHIV-1157ipd3N4 infection can be found in the oral cavity and upper gastrointestinal (GI) tract, the small and large intestine contained the largest number of infected cells. Moreover, we found that T cells were the biggest population of infected immune cells. Thus, thanks to these novel technologies, we are able to visualize and delineate of viral distribution and infection throughout the entire neonatal GI tract during acute viral infection. Author SummaryApproximately 1.8 million children are currently living with human immunodeficiency virus (HIV). While mother-to-child HIV transmission can occur in utero and during delivery, it most commonly occurs through breastfeeding, creating the need to understand how the virus moves throughout the body and infects the infant once breast milk is consumed. Here, we used multiple imaging techniques and PCR to determine how HIV distributes throughout the gastrointestinal tract after oral viral exposure and in which tissues and cell types become acutely infected. We found that HIV rapidly spreads throughout and penetrates the entire gastrointestinal tract as early as four hours after exposure. We also found that the intestine contained the largest number of infected cells at 96 hours and that most cells infected were T cells. Our study shows that these imaging technologies allow for the examination of viral distribution and infection in a rhesus macaque model.

cell biology↗

bioRxiv2021

Simultaneous in vivo Pharmacokinetics and Pharmacodynamics of TDF Intravaginal Ring during High-dose Vaginal SHIV Challenge in Pigtail Macaques

The demonstration of complete protection of macaques in a repeated low dose virus challenge by a tenofovir disoproxil fumarate (TDF) intravaginal ring (IVR) and the success of the dapivirine IVR in clinical trials highlighted the potential of IVRs as pre- exposure prophylaxis against HIV. Efficacy of TDF ring was not investigated in sexually active women. Our understanding of the mechanisms of protection is limited. To address this knowledge gap, we performed simultaneous pharmacokinetic and pharmacodynamic analysis of a TDF-IVR at the site of SIV challenge in pigtail macaques at the anatomical and cellular level. Specifically, we challenged TDF-IVR administered pigtail macaques with a single high dose of a non-replicative SIV-based vector containing a dual reporter system that helped us to identify the earliest targets of SIV infection within the mucosa. Two and three days after challenge, the macaques were euthanized and tenofovir (TFV) concentrations were measured in the female reproductive tract (FRT) by HPLC-MS/MS to correlate drug concentrations and SIV-vector transduction efficiency. TFV formed a gradient through the mucosal tissue, with the highest concentrations near the ring, in the upper vagina and endocervix. Despite this, several transduction events were identified with the most common sites being in the ovaries. Moreover, proviral DNA was detected in the cervix and vagina. Thus, our studies demonstrate an uneven distribution of TFV in the FRT of macaques after release from a TDF-IVR that leads to incomplete FRT protection from high viral dose challenge.

pharmacology and toxicology↗

bioRxiv2021

A massive 7T fMRI dataset to bridge cognitive and computational neuroscience

Extensive sampling of neural activity during rich cognitive phenomena is critical for robust understanding of brain function. We present the Natural Scenes Dataset (NSD), in which high-resolution fMRI responses to tens of thousands of richly annotated natural scenes are measured while participants perform a continuous recognition task. To optimize data quality, we develop and apply novel estimation and denoising techniques. Simple visual inspections of the NSD data reveal clear representational transformations along the ventral visual pathway. Further exemplifying the inferential power of the dataset, we use NSD to build and train deep neural network models that predict brain activity more accurately than state-of-the-art models from computer vision. NSD also includes substantial resting-state and diffusion data, enabling network neuroscience perspectives to constrain and enhance models of perception and memory. Given its unprecedented scale, quality, and breadth, NSD opens new avenues of inquiry in cognitive and computational neuroscience.

neuroscience↗

bioRxiv2020

PET/CT targeted tissue sampling reveals virus specific dIgA can alter the distribution and localization of HIV after rectal exposure

HIV vaccines have not been successful in clinical trials. Dimeric IgA (dIgA) is the most abundant antibody class in mucosal tissues, making dIgA a prime candidate for potential HIV vaccines. We coupled Positron Emission Tomography (PET) imaging and fluorescent microscopy of 64Cu-labeled, photoactivatable-GFP HIV (PA-GFP-BaL) and fluorescently labeled dIgA to determine how dIgA antibodies influence virus interaction with mucosal barriers and viral penetration in colorectal tissue. Our results show that HIV virions rapidly disseminate throughout the colon two hours after exposure. The presence of dIgA resulted in an increase in virions and penetration depth in the transverse colon. Moreover, virions were found in the mesenteric lymph nodes two hours after viral exposure, and the presence of dIgA led to an increase in virions in mesenteric lymph nodes. Taken together, these technologies enable in vivo and in situ visualization of antibody-virus interactions and detailed investigations of early events in HIV infection.

cell biology↗

bioRxiv2020

Dissociation of tonotopy and pitch in human auditory cortex

Frequency-to-place mapping, or tonotopy, is a fundamental organizing principle from the earliest stages of auditory processing in the cochlea to subcortical and cortical regions. Although cortical maps are referred to as tonotopic, previous studies employed sounds that covary in spectral content and higher-level perceptual features such as pitch, making it unclear whether these maps are inherited from cochlear organization and are indeed tonotopic, or instead reflect transformations based on higher-level features. We used high-resolution fMRI to measure BOLD responses in 10 participants as they listened to pure tones that varied in frequency or complex tones that independently varied in either spectral content or fundamental frequency (pitch). We show that auditory cortical gradients are in fact a mixture of maps organized both by spectral content and pitch. Consistent with hierarchical organization, primary regions were tuned predominantly to spectral content, whereas higher-level pitch tuning was observed bilaterally in surrounding non-primary regions.

neuroscience↗

bioRxiv2019

Longitudinal bioluminescent imaging of HIV-1 infection during antiretroviral therapy and treatment interruption in humanized mice

Non-invasive bioluminescent imaging (NIBLI) of HIV-1 infection dynamics allows for real-time monitoring of viral spread and the localization of infected cell populations in living animals. In this report, we describe full-length replication-competent GFP and Nanoluciferase (Nluc) expressing HIV-1 reporter viruses from two clinical transmitted / founder (T/F) stains: TRJO.c and Q23.BG505. By infecting humanized mice with these HIV-1 T/F reporter viruses, we were able to directly monitor longitudinal viral spread at whole-animal resolution via NIBLI at a sensitivity of as few as 30-50 infected cells. Bioluminescent signal strongly correlated with HIV-1 infection and responded proportionally to virus suppression in vivo in animals treated daily with a combination antiretroviral therapy (cART) regimen. Longitudinal NIBLI following cART withdrawal visualized tissue-sites that harbored virus during infection recrudescence. Notably, we observed rebounding infection in the same lymphoid tissues where infection was first observed prior to ART treatment. Our work demonstrates the utility of our system for studying in vivo viral infection dynamics and identifying infected tissue regions for subsequent analyses.\n\nAuthor SummaryNon-invasive bioluminescent imaging (NIBLI) in small animals allows for in vivo longitudinal imaging of infection spread and pathogenesis. We have taken advantage of the small luciferase reporter protein, Nanoluciferase (Nluc), to generate a replication-competent HIV-1 reporter virus to allow for NIBLI of viral infection in humanize mice. NIBLI via Nluc enabled us to directly visualize longitudinal spreading patterns before, during, and after interruption of daily doses of combined antiretroviral therapy (cART). We observed that rebounding infection often emerged in tissue regions originally associated with infected cells prior to cART treatment. Thus, Nluc-based NIBLI of HIV-1 infection can be used as an experimental tool to study early events involved in viral dissemination and spread from initial sites of infection to draining lymphoid tissues as well as locate infected tissues for subsequent cellular characterization of HIV-1 infected cells.

microbiology↗