The Mesocortical System Encodes the Strength of Subsequent Force Generation.

Our minds impact motor outputs. Such mind-motor interactions are critical for understanding motor control mechanisms and optimizing motor performance. In particular, incentive motivation strongly enhances motor performance. Dopaminergic neurons located in the ventral midbrain (VM) are believed to be the center of incentive motivation. Direct projections from the VM to the primary motor cortex constitute a mesocortical pathway. However, the functional role of this pathway in humans remains unclear. Recently, we demonstrated the functional role of the mesocortical pathway in human motor control in the context of incentive motivation by using functional magnetic resonance imaging (fMRI). Incentive motivation remarkably improved not only reaction times but also the peak grip force in subsequent grip responses. Although the reaction time has been used as a proxy for incentive motivation mediated by dopaminergic midbrain activity, the premovement activity of the mesocortical pathway is involved in controlling the force strength rather than the initiation of subsequent force generation. In this commentary, we review our recent findings and discuss remaining questions regarding the functional role of the mesocortical pathway in mind-motor interactions.

Dipeptidylpeptidase-4-targeted activatable fluorescent probes visualize senescent cells.

Senescent cells promote cancer development and progression through chronic inflammation caused by a senescence-associated secretory phenotype (SASP). Although various senotherapeutic strategies targeting senescent cells have been developed for the prevention and treatment of cancers, technology for the in vivo detection and evaluation of senescent cell accumulation has not yet been established. Here, we identified activatable fluorescent probes targeting dipeptidylpeptidase-4 (DPP4) as an effective probe for detecting senescent cells through an enzymatic activity-based screening of fluorescent probes. We also determined that these probes were highly, selectively, and rapidly activated in senescent cells during live cell imaging. Furthermore, we successfully visualized senescent cells in the organs of mice using DPP4-targeted probes. These results are expected to lead to the development of a diagnostic technology for noninvasively detecting senescent cells in vivo and could play a role in the application of DPP4 prodrugs for senotherapy.

Age and parous-experience dependent changes in emotional contagion for positive infant sounds.

Introduction: Emotional contagion is achieved by inferring and emotionally resonating with other persons' feelings. It is unclear whether age-related changes in emotional contagion for infant sounds are modulated by the experience of childbirth or childcare. This study aims to evaluate changes in inference and emotional resonance for positive and negative infant sounds (laughter and crying) among women, based on age and parous experience. Methods: A total of 241 women (60 young nulliparous, 60 young parous, 60 old nulliparous, and 61 old parous) completed a web-based questionnaire. After listening to three types of infant sounds (laughter, cooing, and crying), participants responded with their valence for hearing infant sounds and estimated infant valence on an 11-point Likert scale. Results: The analysis for emotional resonance revealed that the correlation coefficient between self and estimated infant valences was greater in young parous and old nulliparous women than in young nulliparous women, in laughter and cooing sounds. However, correlation coefficients for crying did not differ among any of the four groups. Conclusion: The degree of emotional resonance for infant valence increased depending on age and parous-experience for positive infant sounds.

Novel nerve-sparing robot-assisted radical prostatectomy with endopelvic fascia preservation and long-term outcomes for a single surgeon.

Although novel techniques for avoiding incontinence during robot-assisted radical prostatectomy have been developed, long-term oncological outcomes are unknown. The objective of this study was to determine the long-term oncological outcomes and functional outcomes of novel nerve-sparing robot-assisted radical prostatectomy with endopelvic fascia preservation for a single surgeon. Data from 100 patients who underwent structure-preserving prostatectomies performed by a single surgeon were retrospectively analyzed. The median console time was 123 min. Bilateral nerve-sparing was performed in 43% of patients underwent, and 57% underwent unilateral nerve-sparing surgery. Most patients (96%) reached complete pad-zero urinary continence by one year after surgery. Satisfactory erectile function was achieved in 97% of patients who underwent bilateral nerve-sparing surgery, and 80% of patients who underwent unilateral nerve-sparing surgery. The surgical margin was positive for 25% of patients, and the biochemical recurrence-free rate at 5 years was 77%. The cancer-specific survival rate was 100% during the median follow-up period of 4.5 years. Clavien-Dindo grade III complications occurred in 1% of cases. The outcomes for novel nerve-sparing robot-assisted radical prostatectomy with endopelvic fascia preservation were similar to previously reported oncological outcomes, with satisfactory functional outcomes. This operative method may be useful for patients who are eligible for nerve-sparing surgery.

Antigen-specific memory NK cell responses against HIV and influenza use the NKG2/HLA-E axis.

Multiple studies have broadened the roles of natural killer (NK) cells functioning as purely innate lymphocytes by demonstrating that they are capable of putative antigen-specific immunological memory against multiple infectious agents including HIV-1 and influenza. However, the mechanisms underlying antigen specificity remain unknown. Here, we demonstrate that antigen-specific human NK cell memory develops upon exposure to both HIV and influenza, unified by a conserved and epitope-specific targetable mechanism largely dependent on the activating CD94/NKG2C receptor and its ligand HLA-E. We validated the permanent acquisition of antigen specificity by individual memory NK cells by single-cell cloning. We identified elevated expression of KLRG1, α4ß7, and NKG2C as biomarkers of antigen-specific NK cell memory through complex immunophenotyping. Last, we uncovered individual HLA-E-restricted peptides that may constitute the dominant NK cell response in HIV-1- and influenza-infected persons in vivo. Our findings clarify the mechanisms contributing to antigen-specific memory NK cell responses and suggest that they could be potentially targeted therapeutically for vaccines or other therapeutic interventions.

Premovement activity in the mesocortical system links peak force but not initiation of force generation under incentive motivation.

Motivation facilitates motor performance; however, the neural substrates of the psychological effects on motor performance remain unclear. We conducted a functional magnetic resonance imaging experiment while human subjects performed a ready-set-go task with monetary incentives. Although subjects were only motivated to respond quickly, increasing the incentives improved not only reaction time but also peak grip force. However, the trial-by-trial correlation between reaction time and peak grip force was weak. Extensive areas in the mesocortical system, including the ventral midbrain (VM) and cortical motor-related areas, exhibited motivation-dependent activity in the premovement "Ready" period when the anticipated monetary reward was displayed. This premovement activity in the mesocortical system correlated only with subsequent peak grip force, whereas the activity in motor-related areas alone was associated with subsequent reaction time and peak grip force. These findings suggest that the mesocortical system linking the VM and motor-related regions plays a role in controlling the peak of force generation indirectly associated with incentives but not the initiation of force generation.

Multiplex interrogation of the NK cell signalome reveals global downregulation of CD16 signaling during lentivirus infection through an IL-18/ADAM17-dependent mechanism.

Despite their importance, natural killer (NK) cell responses are frequently dysfunctional during human immunodeficiency virus-1 (HIV-1) and simian immunodeficiency virus (SIV) infections, even irrespective of antiretroviral therapies, with poorly understood underlying mechanisms. NK cell surface receptor modulation in lentivirus infection has been extensively studied, but a deeper interrogation of complex cell signaling is mostly absent, largely due to the absence of any comprehensive NK cell signaling assay. To fill this knowledge gap, we developed a novel multiplex signaling analysis to broadly assess NK cell signaling. Using this assay, we elucidated that NK cells exhibit global signaling reduction from CD16 both in people living with HIV-1 (PLWH) and SIV-infected rhesus macaques. Intriguingly, antiretroviral treatment did not fully restore diminished CD16 signaling in NK cells from PLWH. As a putative mechanism, we demonstrated that NK cells increased surface ADAM17 expression via elevated plasma IL-18 levels during HIV-1 infection, which in turn reduced surface CD16 downregulation. We also illustrated that CD16 expression and signaling can be restored by ADAM17 perturbation. In summary, our multiplex NK cell signaling analysis delineated unique NK cell signaling perturbations specific to lentiviral infections, resulting in their dysfunction. Our analysis also provides mechanisms that will inform the restoration of dysregulated NK cell functions, offering potential insights for the development of new NK cell-based immunotherapeutics for HIV-1 disease.

Development and validation of novel nomogram to identify the candidates for extended pelvic lymph node dissection for prostate cancer patients in the robotic era.

OBJECTIVES: To determine candidates for extended pelvic lymph node dissection using a novel nomogram to assess the risk of lymph node invasion in Japanese prostate cancer patients in the robotic era. METHODS: A total of 538 patients who underwent robot-assisted radical prostatectomy with extended pelvic lymph node dissection in three hospitals were retrospectively analyzed. Medical records were reviewed uniformly and the following data collected: prostate-specific antigen, age, clinical T stage, primary and secondary Gleason score at prostate biopsy, and percentage of positive core numbers. Finally, data from 434 patients were used for developing the nomogram and data from 104 patients were used for external validation. RESULTS: Lymph node invasion was detected in 47 (11%) and 16 (15%) patients in the development and validation set, respectively. Based on multivariate analysis, prostate-specific antigen, clinical T stage ≥3, primary Gleason score, grade group 5, and percentage of positive cores were selected as variables to incorporate into the nomogram. The area under the curve values were 0.781 for the internal and 0.908 for the external validation, respectively. CONCLUSIONS: The present nomogram can help urologists identify candidates for extended pelvic lymph node dissection concomitant with robot-assisted radical prostatectomy among patients with prostate cancer.

Feasibility of single-port laparoscopic partial adrenalectomy with selective adrenal venous sampling and high-resolution ultrasound for unilateral aldosterone-producing adenomas.

BACKGROUND: The surgical and endocrinological outcomes of single-port laparoscopic partial adrenalectomy for patients with aldosterone-producing adenomas are unknown. Precise diagnosis of intra-adrenal aldosterone activity and a precise surgical procedure may improve outcomes. In this study, we aimed to determine the surgical and endocrinological outcomes of single-port laparoscopic partial adrenalectomy with preoperative segmental selective adrenal venous sampling and intraoperative high-resolution laparoscopic ultrasound in patients with unilateral aldosterone-producing adenomas. We identified 53 patients with partial adrenalectomy and 29 patients with laparoscopic total adrenalectomy. Single-port surgery was performed for 37 and 19 patients, respectively. METHODS: A single-center, retrospective cohort study. All patients with unilateral aldosterone-producing adenomas diagnosed by selective adrenal venous sampling and treated surgically between January 2012 and February 2015 were included. Follow-up with biochemical and clinical assessments was set at 1 year after surgery for short-term outcomes and was performed every 3 months after surgery. RESULTS: We identified 53 patients with partial adrenalectomy and 29 patients with laparoscopic total adrenalectomy. Single-port surgery was performed for 37 and 19 patients, respectively. Single-port surgery was associated with shorter operative and laparoscopic times (odds ratio, 0.14; 95% confidence interval, 0.039-0.49; P = .002 and odds ratio, 0.13; 95% confidence interval, 0.032-0.57; P = .006, respectively). All single-port and multi-port partial adrenalectomy cases showed complete short-term (median 1 year) biochemical success, and 92.9% (26 of 28 patients) who underwent single-port partial adrenalectomy and 100% (13 of 13 patients) who underwent multi-port partial adrenalectomy showed complete long-term (median 5.5 years) biochemical success. No complications were observed with single-port adrenalectomy. CONCLUSION: Single-port partial adrenalectomy is feasible after selective adrenal venous sampling for unilateral aldosterone-producing adenomas, with shorter operative and laparoscopic times and a high rate of complete biochemical success.

Natural Killer Cells Regulate Acute SIV Replication, Dissemination, and Inflammation, but Do Not Impact Independent Transmission Events.

Natural killer (NK) cells are potent effector cells of the innate immune system possessing both cytotoxic and immunoregulatory capabilities, which contribute to their crucial role in controlling human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections. However, despite significant evidence for NK cell modulation of HIV disease, their specific contribution to transmission and control of acute infection remains less clear. To elucidate the contribution of NK cells during acute SIV infection, we performed an acute necropsy study, where rhesus macaques (RM) were subjected to preinfection depletion of systemic NK cells using established methods of IL-15 neutralization, followed by subsequent challenge with barcoded SIVmac239X. Our study showed that depletion was highly effective, resulting in near total ablation of all NK cell subsets in blood, liver, oral, and rectal mucosae, and lymph nodes (LN) that persisted through the duration of the study. Meanwhile, frequencies and phenotypes of T cells remained virtually unchanged, indicating that our method of NK cell depletion had minimal off-target effects. Importantly, NK cell-depleted RM demonstrated an early and sustained 1 to 2 log increase in viremia over controls, but sequence analysis suggested no difference in the number of independent transmission events. Acute bulk, central memory (CM), and CCR5+ CD4+ T cell depletion was similar between experimental and control groups, while CD8+ T cell activation was higher in NK cell-depleted RM as measured by Ki67 and PD-1 expression. Using 27-plex Luminex analyses, we also found modestly increased inflammatory cytokines in NK cell-depleted RM compared to control animals. In the effort to determine the impact of NK cells on HIV/SIV transmission and acute viremia, future studies will be necessary to better harness these cells for future viral therapies. Collectively, these data suggest NK cells are important modulators of lentivirus dissemination and disease but may not have the capacity to independently eliminate individual transmission events. IMPORTANCE Natural killer (NK) cells as major effector cells of the innate immune system can contribute significantly to human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) control. However, a specific role for NK cells in blocking lentivirus transmission remains incompletely clear. In this study, we depleted NK cells prior to challenge with a barcoded SIV. Importantly, our studied showed systemic NK cell depletion was associated with a significant increase in acute viremia, but did not impact the number of independent transmission events. Collectively, these data suggest NK cells are critical modulators of early lentivirus replication but may not regulate individual transmission events at mucosal portals of entry.

RNaseH2A downregulation drives inflammatory gene expression via genomic DNA fragmentation in senescent and cancer cells.

Cellular senescence caused by oncogenic stimuli is associated with the development of various age-related pathologies through the senescence-associated secretory phenotype (SASP). SASP is mediated by the activation of cytoplasmic nucleic acid sensors. However, the molecular mechanism underlying the accumulation of nucleotide ligands in senescent cells is unclear. In this study, we revealed that the expression of RNaseH2A, which removes ribonucleoside monophosphates (rNMPs) from the genome, is regulated by E2F transcription factors, and it decreases during cellular senescence. Residual rNMPs cause genomic DNA fragmentation and aberrant activation of cytoplasmic nucleic acid sensors, thereby provoking subsequent SASP factor gene expression in senescent cells. In addition, RNaseH2A expression was significantly decreased in aged mouse tissues and cells from individuals with Werner syndrome. Furthermore, RNaseH2A degradation using the auxin-inducible degron system induced the accumulation of nucleotide ligands and induction of certain tumourigenic SASP-like factors, promoting the metastatic properties of colorectal cancer cells. Our results indicate that RNaseH2A downregulation provokes SASP through nucleotide ligand accumulation, which likely contributes to the pathological features of senescent, progeroid, and cancer cells.

Pathological complete response of plasmacytoid variant bladder cancer to pembrolizumab following genomic analysis.

Introduction: Plasmacytoid variant bladder cancer is a rare variant of urothelial carcinoma that accounts for 1% of bladder cancers. Plasmacytoid variant urothelial carcinoma is characterized by an aggressive phenotype and poor clinical outcomes. Case presentation: A 61-year-old woman presented with gross hematuria. Cystoscopy showed a 16-mm solid tumor. Transurethral resection of the bladder tumor was performed, and the pathological diagnosis was invasive plasmacytoid variant urothelial carcinoma. Although the pathological T stage was pT1, computed tomography showed right obturator lymph node swelling. Since previous reports indicate poor response to chemotherapy for this disease, clinical sequencing was performed. Based on the high tumor mutation burden revealed, pembrolizumab was administered for 4 cycles, and computed tomography showed a partial response. Robot-assisted radical cystectomy was performed, and a pathological complete response including the pelvic lymph node was observed. Conclusion: Pembrolizumab may be a treatment option for plasmacytoid variant urothelial carcinoma following genomic analysis.

Quantitative comparison of corticospinal tracts arising from different cortical areas in humans.

The corticospinal tract (CST), which plays a major role in the control of voluntary limb movements, arises from multiple motor- and somatosensory-related areas in monkeys. Although the cortical origin and quantitative differences in CSTs among the cortical areas are well-documented in monkeys, they are unclear in humans. We quantitatively investigated the CSTs from the cerebral cortex to the cervical cord in healthy volunteers using fiber tractography of diffusion-weighted magnetic resonance imaging. The corticospinal (CS) streamlines arose from nine cortical areas: primary motor area (mean ± SD = 49.71 ± 1.61%), dorsal (16.33 ± 1.37%) and ventral (11.02 ± 0.90%) premotor cortex, supplementary motor area (5.14 ± 0.36%), pre-supplementary motor area (2.46 ± 0.26%), primary somatosensory cortex (11.06 ± 0.91%), Brodmann area 5 (0.88 ± 0.09%), caudal cingulate zone (1.70 ± 0.30%), and posterior part of the rostral cingulate zone (1.70 ± 0.34%). In all cortical areas, the number of CS streamlines gradually decreased from the rostral to caudal spinal segments, but the proportion was maintained throughout the cervical cord. Over 75% of CS streamlines arose from the lateral surface of the frontal lobe, which may explain the voluntary control of dexterous and flexible limb movements in humans. (197/200 words).

Learning to Be Elite: Lessons From HIV-1 Controllers and Animal Models on Trained Innate Immunity and Virus Suppression.

Although antiretroviral therapy (ART) has drastically changed the lives of people living with human immunodeficiency virus-1 (HIV-1), long-term treatment has been associated with a vast array of comorbidities. Therefore, a cure for HIV-1 remains the best option to globally eradicate HIV-1/acquired immunodeficiency syndrome (AIDS). However, development of strategies to achieve complete eradication of HIV-1 has been extremely challenging. Thus, the control of HIV-1 replication by the host immune system, namely functional cure, has long been studied as an alternative approach for HIV-1 cure. HIV-1 elite controllers (ECs) are rare individuals who naturally maintain undetectable HIV-1 replication levels in the absence of ART and whose immune repertoire might be a desirable blueprint for a functional cure. While the role(s) played by distinct human leukocyte antigen (HLA) expression and CD8+ T cell responses expressing cognate ligands in controlling HIV-1 has been widely characterized in ECs, the innate immune phenotype has been decidedly understudied. Comparably, in animal models such as HIV-1-infected humanized mice and simian Immunodeficiency Virus (SIV)-infected non-human primates (NHP), viremic control is known to be associated with specific major histocompatibility complex (MHC) alleles and CD8+ T cell activity, but the innate immune response remains incompletely characterized. Notably, recent work demonstrating the existence of trained innate immunity may provide new complementary approaches to achieve an HIV-1 cure. Herein, we review the known characteristics of innate immune responses in ECs and available animal models, identify gaps of knowledge regarding responses by adaptive or trained innate immune cells, and speculate on potential strategies to induce EC-like responses in HIV-1 non-controllers.

Neural correlates with individual differences in temporal prediction during auditory-motor synchronization.

Temporal prediction ability is vital for movement synchronization with external rhythmic stimuli (sensorimotor synchronization); however, little is known regarding individual variations in temporal prediction ability and its neural correlates. We determined the underlying neural correlates of temporal prediction and individual variations during auditory-motor synchronization. We hypothesized that the non-primary motor cortices, such as the premotor cortex and supplementary motor area, are the key brain regions that correlate individual variations in prediction ability. Functional magnetic resonance imaging (7T) was performed for 18 healthy volunteers who tapped to 3 types of auditory metronome beats: isochronous, tempo change, and random. The prediction ability was evaluated using prediction/tracking ratios that were computed based on cross-correlations between tap timing and pacing events. Participants with a higher prediction/tracking ratio (i.e. stronger predictive tendency) tapped to metronome beats more accurately and precisely. The prediction/tracking ratio was positively correlated with the activity in the bilateral dorsal premotor cortex (PMd), suggesting that the bilateral PMd explains the individual variation in prediction ability. These results indicate that the PMd is involved in generating a model for temporal prediction of auditory rhythm patterns and its activity would reflect model accuracy, which is critical for accurate and precise sensorimotor synchronization.

The dorsal premotor cortex encodes the step-by-step planning processes for goal-directed motor behavior in humans.

The dorsal premotor cortex (PMd) plays an essential role in visually guided goal-directed motor behavior. Although there are several planning processes for achieving goal-directed behavior, the separate neural processes are largely unknown. Here, we created a new visuo-goal task to investigate the step-by-step planning processes for visuomotor and visuo-goal behavior in humans. Using functional magnetic resonance imaging, we found activation in different portions of the bilateral PMd during each processing step. In particular, the activated area for rule-based visuomotor and visuo-goal mapping was located at the ventrorostral portion of the bilateral PMd, that for action plan specification was at the dorsocaudal portion of the left PMd, that for transformation was at the rostral portion of the left PMd, and that for action preparation was at the caudal portion of the bilateral PMd. Thus, the left PMd was involved throughout all of the processes, but the right PMd was involved only in rule-based visuomotor and visuo-goal mapping and action preparation. The locations related to each process were generally spatially separated from each other, but they overlapped partially. These findings revealed that there are functional subregions in the bilateral PMd in humans and these subregions form a functional gradient to achieve goal-directed behavior.

Cognitive control affects motor learning through local variations in GABA within the primary motor cortex.

The primary motor cortex (M1) is crucial for motor learning; however, its interaction with other brain areas during motor learning remains unclear. We hypothesized that the fronto-parietal execution network (FPN) provides learning-related information critical for the flexible cognitive control that is required for practice. We assessed network-level changes during sequential finger tapping learning under speed pressure by combining magnetic resonance spectroscopy and task and resting-state functional magnetic resonance imaging. There was a motor learning-related increase in preparatory activity in the fronto-parietal regions, including the right M1, overlapping the FPN and sensorimotor network (SMN). Learning-related increases in M1-seeded functional connectivity with the FPN, but not the SMN, were associated with decreased GABA/glutamate ratio in the M1, which were more prominent in the parietal than the frontal region. A decrease in the GABA/glutamate ratio in the right M1 was positively correlated with improvements in task performance (p = 0.042). Our findings indicate that motor learning driven by cognitive control is associated with local variations in the GABA/glutamate ratio in the M1 that reflects remote connectivity with the FPN, representing network-level motor sequence learning formations.

The integrative role of the M1 in motor sequence learning.

The primary motor cortex (M1) is crucial in motor learning. Whether the M1 encodes the motor engram for sequential finger tapping formed by an emphasis on speed is still inconclusive. The active states of engrams are hard to discriminate from the motor execution per se. As preparatory activity reflects the upcoming movement parameters, we hypothesized that the retrieval of motor engrams generated by different learning modes is reflected as a learning-related increase in the preparatory activity of the M1. To test this hypothesis, we evaluated the preparatory activity during the learning of sequential finger-tapping with the non-dominant left hand using a 7T functional MRI. Participants alternated between performing a tapping sequence as quickly as possible (maximum mode) or at a constant speed of 2 Hz paced by a sequence-specifying visual cue (constant mode). We found a training-related increase in preparatory activity in the network covering the bilateral anterior intraparietal sulcus and inferior parietal lobule extending to the right M1 during the maximum mode and the right M1 during the constant mode. These findings indicate that the M1, as the last effector of the motor output, integrates the motor engram distributed through the networks despite training mode differences.

Enhanced structural connectivity within the motor loop in professional boxers prior to a match.

Professional boxers train to reduce their body mass before a match to refine their body movements. To test the hypothesis that the well-defined movements of boxers are represented within the motor loop (cortico-striatal circuit), we first elucidated the brain structure and functional connectivity specific to boxers and then investigated plasticity in relation to boxing matches. We recruited 21 male boxers 1 month before a match (Time1) and compared them to 22 age-, sex-, and body mass index (BMI)-matched controls. Boxers were longitudinally followed up within 1 week prior to the match (Time2) and 1 month after the match (Time3). The BMIs of boxers significantly decreased at Time2 compared with those at Time1 and Time3. Compared to controls, boxers presented significantly higher gray matter volume in the left putamen, a critical region representing motor skill training. Boxers presented significantly higher functional connectivity than controls between the left primary motor cortex (M1) and left putamen, which is an essential region for establishing well-defined movements. Boxers also showed significantly higher structural connectivity in the same region within the motor loop from Time1 to Time2 than during other periods, which may represent the refined movements of their body induced by training for the match.

People with HIV-1 demonstrate type 1 interferon refractoriness associated with upregulated USP18.

HIV-1 infection persists in humans despite expression of antiviral type 1 interferons (IFN). Even exogenous administration of IFNα only marginally reduces HIV-1 abundance, raising the hypothesis that people living with HIV-1 (PLWH) are refractory to type 1 IFN. We demonstrated type 1 IFN refractoriness in CD4+ and CD8+ T cells isolated from HIV-1 infected persons by detecting diminished STAT1 phosphorylation (pSTAT1) and interferon-stimulated gene (ISG) induction upon type 1 IFN stimulation compared to healthy controls. Importantly, HIV-1 infected people who were virologically suppressed with antiretrovirals also showed type 1 IFN refractoriness. We found that USP18 levels were elevated in people with refractory pSTAT1 and ISG induction and confirmed this finding ex vivo in CD4+ T cells from another cohort of HIV-HCV coinfected persons who received exogenous pegylated interferon-α2b in a clinical trial. We used a cell culture model to recapitulate type 1 IFN refractoriness in uninfected CD4+ T cells that were conditioned with media from HIV-1 inoculated PBMCs, inhibiting de novo infection with antiretroviral agents. In this model, RNA interference against USP18 partly restored type 1 IFN responses in CD4+ T cells. We found evidence of type 1 IFN refractoriness in PLWH irrespective of virologic suppression that was associated with upregulated USP18, a process that might be therapeutically targeted to improve endogenous control of infection.ImportancePeople living with HIV-1 (PLWH) have elevated constitutive expression of type 1 interferons (IFN). However, it is unclear whether this impacts downstream innate immune responses. We identified refractory responses to type 1 IFN stimulation in T cells from PLWH, independent of antiretroviral treatment. Type 1 IFN refractoriness was linked to elevated USP18 levels in the same cells. Moreover, we found that USP18 levels predicted the anti-HIV-1 effect of type 1 IFN-based therapy on PLWH. In vitro, we demonstrated that refractory type 1 IFN responses were transferrable to HIV-1 uninfected target CD4+ T cells, and this phenomenon was mediated by type 1 IFN from HIV-1 infected cells. Type 1 IFN responses were partially restored by USP18 knockdown. Our findings illuminate a new mechanism by which HIV-1 contributes to innate immune dysfunction in PLWH, through the continuous production of type 1 IFN that induces a refractory state of responsiveness.