Two rare variants that affect the same amino acid in CFTR have distinct responses to ivacaftor.

Some residues in the cystic fibrosis transmembrane conductance regulator (CFTR) channel are the site of more than one CFTR variant that cause cystic fibrosis. Here, we investigated the function of S1159F and S1159P, two variants associated with different clinical phenotypes, which affect the same pore-lining residue in transmembrane segment 12 that are both strongly potentiated by ivacaftor when expressed in CFBE41o- bronchial epithelial cells. To study the single-channel behaviour of CFTR, we applied the patch-clamp technique to Chinese hamster ovary cells heterologously expressing CFTR variants incubated at 27°C to enhance channel residence at the plasma membrane. S1159F- and S1159P-CFTR formed Cl- channels activated by cAMP-dependent phosphorylation and gated by ATP that exhibited thermostability at 37°C. Both variants modestly reduced the single-channel conductance of CFTR. By severely attenuating channel gating, S1159F- and S1159P-CFTR reduced the open probability (Po ) of wild-type CFTR by ≥75% at ATP (1 mM); S1159F-CFTR caused the greater decrease in Po consistent with its more severe clinical phenotype. Ivacaftor (10-100 nM) doubled the Po of both CFTR variants without restoring Po values to wild-type levels, but concomitantly, ivacaftor decreased current flow through open channels. For S1159F-CFTR, the reduction of current flow was marked at high (supersaturated) ivacaftor concentrations (0.5-1 µM) and voltage-independent, identifying an additional detrimental action of elevated ivacaftor concentrations. In conclusion, S1159F and S1159P are gating variants, which also affect CFTR processing and conduction, but not stability, necessitating the use of combinations of CFTR modulators to optimally restore their channel activity. KEY POINTS: Dysfunction of the ion channel cystic fibrosis transmembrane conductance regulator (CFTR) causes the genetic disease cystic fibrosis (CF). This study investigated two rare pathogenic CFTR variants, S1159F and S1159P, which affect the same amino acid in CFTR, to understand the molecular basis of disease and response to the CFTR-targeted therapy ivacaftor. Both rare variants diminished CFTR function by modestly reducing current flow through the channel and severely inhibiting ATP-dependent channel gating with S1159F exerting the stronger adverse effect, which correlates with its association with more severe disease. Ivacaftor potentiated channel gating by both rare variants without restoring their activity to wild-type levels, but concurrently reduced current flow through open channels, particularly those of S1159F-CFTR. Our data demonstrate that S1159F and S1159P cause CFTR dysfunction by multiple mechanisms that require combinations of CFTR-targeted therapies to fully restore channel function.

In vitro platform to model the function of ionocytes in the human airway epithelium.

BACKGROUND: Pulmonary ionocytes have been identified in the airway epithelium as a small population of ion transporting cells expressing high levels of CFTR (cystic fibrosis transmembrane conductance regulator), the gene mutated in cystic fibrosis. By providing an infinite source of airway epithelial cells (AECs), the use of human induced pluripotent stem cells (hiPSCs) could overcome some challenges of studying ionocytes. However, the production of AEC epithelia containing ionocytes from hiPSCs has proven difficult. Here, we present a platform to produce hiPSC-derived AECs (hiPSC-AECs) including ionocytes and investigate their role in the airway epithelium. METHODS: hiPSCs were differentiated into lung progenitors, which were expanded as 3D organoids and matured by air-liquid interface culture as polarised hiPSC-AEC epithelia. Using CRISPR/Cas9 technology, we generated a hiPSCs knockout (KO) for FOXI1, a transcription factor that is essential for ionocyte specification. Differences between FOXI1 KO hiPSC-AECs and their wild-type (WT) isogenic controls were investigated by assessing gene and protein expression, epithelial composition, cilia coverage and motility, pH and transepithelial barrier properties. RESULTS: Mature hiPSC-AEC epithelia contained basal cells, secretory cells, ciliated cells with motile cilia, pulmonary neuroendocrine cells (PNECs) and ionocytes. There was no difference between FOXI1 WT and KO hiPSCs in terms of their capacity to differentiate into airway progenitors. However, FOXI1 KO led to mature hiPSC-AEC epithelia without ionocytes with reduced capacity to produce ciliated cells. CONCLUSION: Our results suggest that ionocytes could have role beyond transepithelial ion transport by regulating epithelial properties and homeostasis in the airway epithelium.

Neurologic Complications in Adult Cancer Survivorship.

Over the past decade, the improvement in cancer diagnostics and therapeutics has extended the overall survival of patients diagnosed with cancer including brain cancer. However, despite these unprecedented medical successes, patients continue to experience numerous neurologic complications after treatment that interfere with their independence, functionality, and overall quality of life. These include, among others, cognitive impairment, endocrinopathies, peripheral and cranial neuropathies, and vasculopathy. This article describes the long-term neurologic complications cancer survivors commonly experience to increase awareness of these complications and discuss treatments when available. Further research is necessary to understanding of mechanisms of neurologic injury and advance diagnosis and treatment. Effective patient education, monitoring, and managing neurologic issues after cancer treatment may improve independence, functionality, and quality of life during survivorship.

Perioperative Neurocognitive Function in Glioma Surgery.

PURPOSE OF REVIEW: This review provides a concise overview of the recent literature regarding preoperative and postoperative neurocognitive functioning (NCF) in patients with glioma. Brief discussion also covers contemporary intraoperative brain mapping work, with a focus on potential influence of mapping upon NCF outcomes following awake surgery. RECENT FINDINGS: Most patients with glioma exhibit preoperative NCF impairment, with severity varying by germ line and tumoral genetics, tumor grade, and lesion location, among other characteristics. Literature regarding postoperative NCF changes is mixed, though numerous studies indicate a majority of patients exhibit immediate and short-term worsening. This is often followed by recovery over several months; however, a substantial portion of patients harbor persisting declines. Decline appears related to surgically-induced structural and functional brain alterations, both local and distal to the tumor and resection cavity. Importantly, NCF decline may be mitigated to some extent by intraoperative brain mapping, including mapping of both language-mediated and nonverbal functions. Research regarding perioperative NCF in patients with glioma has flourished over recent years. While this has increased our understanding of contributors to NCF and risk of decline associated with surgical intervention, more work is needed to better preserve NCF throughout the disease course.

Can two wrongs make a right? F508del-CFTR ion channel rescue by second-site mutations in its transmembrane domains.

Deletion of phenylalanine 508 (F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel is the most common cause of cystic fibrosis. The F508 residue is located on nucleotide-binding domain 1 (NBD1) in contact with the cytosolic extensions of the transmembrane helices, in particular intracellular loop 4 (ICL4). To investigate how absence of F508 at this interface impacts the CFTR protein, we carried out a mutagenesis scan of ICL4 by introducing second-site mutations at 11 positions in cis with F508del. Using an image-based fluorescence assay, we measured how each mutation affected membrane proximity and ion-channel function. The scan strongly validated the effectiveness of R1070W at rescuing F508del defects. Molecular dynamics simulations highlighted two features characterizing the ICL4/NBD1 interface of F508del/R1070W-CFTR: flexibility, with frequent transient formation of interdomain hydrogen bonds, and loosely stacked aromatic sidechains (F1068, R1070W, and F1074, mimicking F1068, F508, and F1074 in WT CFTR). F508del-CFTR displayed a distorted aromatic stack, with F1068 displaced toward the space vacated by F508, while in F508del/R1070F-CFTR, which largely retained F508del defects, R1070F could not form hydrogen bonds and the interface was less flexible. Other ICL4 second-site mutations which partially rescued F508del-CFTR included F1068M and F1074M. Methionine side chains allow hydrophobic interactions without the steric rigidity of aromatic rings, possibly conferring flexibility to accommodate the absence of F508 and retain a dynamic interface. These studies highlight how both hydrophobic interactions and conformational flexibility might be important at the ICL4/NBD1 interface, suggesting possible structural underpinnings of F508del-induced dysfunction.

A topological switch in CFTR modulates channel activity and sensitivity to unfolding.

The cystic fibrosis transmembrane conductance regulator (CFTR) anion channel is essential to maintain fluid homeostasis in key organs. Functional impairment of CFTR due to mutations in the cftr gene leads to cystic fibrosis. Here, we show that the first nucleotide-binding domain (NBD1) of CFTR can spontaneously adopt an alternate conformation that departs from the canonical NBD fold previously observed. Crystallography reveals that this conformation involves a topological reorganization of NBD1. Single-molecule fluorescence resonance energy transfer microscopy shows that the equilibrium between the conformations is regulated by adenosine triphosphate binding. However, under destabilizing conditions, such as the disease-causing mutation F508del, this conformational flexibility enables unfolding of the ß-subdomain. Our data indicate that, in wild-type CFTR, this conformational transition of NBD1 regulates channel function, but, in the presence of the F508del mutation, it allows domain misfolding and subsequent protein degradation. Our work provides a framework to design conformation-specific therapeutics to prevent noxious transitions.

MoCA Intraindividual Cognitive Variability in Older Adults With Type 1 Diabetes.

Older adults with type 1 diabetes (T1D) may have an elevated risk of developing Alzheimer disease and related dementia. Higher intraindividual cognitive variability (IICV) has been proposed as a novel risk factor of Alzheimer disease and related dementia. Here, we examined the association between cross-domain IICV measured using the Montreal Cognitive Assessment (MoCA) and cognitive impairment measured using traditional neuropsychological tests in older individuals with T1D. Participants with T1D (N=201) completed both the MoCA and a battery of traditional neuropsychological tests. Participants with cognitive impairment, determined using traditional tests, had significantly higher IICV scores and significantly lower total MoCA scores ( P <0.001). However, the effect of the total score was greater than that of the IICV score on the likelihood of cognitive impairment (total odds ratio=3.50, IICV odds ratio=2.03, P <0.001). The MoCA total score performed better than the MoCA IICV score in identifying T1D individuals classified with cognitive impairment.

Executive functions mediate the association between alcohol use and declarative memory symptoms in daily life.

Alcohol use is associated with memory problems in young adults with HIV, but the cognitive mechanisms of that association are not known. Sixty adults (aged 19-24 years) living with HIV were administered the Alcohol, Smoking, and Substance Involvement Screening Test to assess alcohol use, Behavior Rating Inventory of Executive Function for self-reported executive functions, and the Prospective and Retrospective Memory Questionnaire (PRMQ) for dailiy memory functioning. Controlling for mood, self-reported executive functions fully mediated the relationship between alcohol use and memory (indirect effect b=.568, 95%CI [.209,.888]). Findings suggest that self-reported executive dysregulation of memory processes (e.g., Strategic encoding and retrieval) may drive the effects of alcohol use on daily memory symptoms.

Correlating genotype with phenotype using CFTR-mediated whole-cell Cl- currents in human nasal epithelial cells.

Dysfunction of the epithelial anion channel cystic fibrosis transmembrane conductance regulator (CFTR) causes a wide spectrum of disease, including cystic fibrosis (CF) and CFTR-related diseases (CFTR-RDs). Here, we investigate genotype-phenotype-CFTR function relationships using human nasal epithelial (hNE) cells from a small cohort of non-CF subjects and individuals with CF and CFTR-RDs and genotypes associated with either residual or minimal CFTR function using electrophysiological techniques. Collected hNE cells were either studied directly with the whole-cell patch-clamp technique or grown as primary cultures at an air-liquid interface after conditional reprogramming. The properties of cAMP-activated whole-cell Cl- currents in freshly isolated hNE cells identified them as CFTR-mediated. Their magnitude varied between hNE cells from individuals within the same genotype and decreased in the rank order: non-CF > CFTR residual function > CFTR minimal function. CFTR-mediated whole-cell Cl- currents in hNE cells isolated from fully differentiated primary cultures were identical to those in freshly isolated hNE cells in both magnitude and behaviour, demonstrating that conditional reprogramming culture is without effect on CFTR expression and function. For the cohort of subjects studied, CFTR-mediated whole-cell Cl- currents in hNE cells correlated well with CFTR-mediated transepithelial Cl- currents measured in vitro with the Ussing chamber technique, but not with those determined in vivo with the nasal potential difference assay. Nevertheless, they did correlate with the sweat Cl- concentration of study subjects. Thus, this study highlights the complexity of genotype-phenotype-CFTR function relationships, but emphasises the value of conditionally reprogrammed hNE cells in CFTR research and therapeutic testing. KEY POINTS: The genetic disease cystic fibrosis is caused by pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR), an ion channel, which controls anion flow across epithelia lining ducts and tubes in the body. This study investigated CFTR function in nasal epithelial cells from people with cystic fibrosis and CFTR variants with a range of disease severity. CFTR function varied widely in nasal epithelial cells depending on the identity of CFTR variants, but was unaffected by conditional reprogramming culture, a cell culture technique used to grow large numbers of patient-derived cells. Assessment of CFTR function in vitro in nasal epithelial cells and epithelia, and in vivo in the nasal epithelium and sweat gland highlights the complexity of genotype-phenotype-CFTR function relationships.

Local resolution characteristics of atmospheric turbulence.

D. L. Fried's concept of a "Lucky Image" for turbulent image streams can be seen as creating different degrees of localized resolution in images. These localized regions of resolution can be derived from Fried's equation for the probability of obtaining a Lucky Image. The existence of local resolution variations when imaging through turbulence also implies local variations in the point-spread-functions (PSFs) caused by turbulence. We characterize these local variations by using simple measures on PSFs collected in the presence of atmospheric turbulence. We also compile these variations into an empirical probability density function (PDF) that describes the different resolutions in local regions of turbulent imagery and can be used to characterize specific conditions of turbulence, e.g., the coherence diameter.

"Do I Have a Memory Problem? I Can't Recall": An Evaluation of Measurement Invariance in Subjective Reporting of Memory Symptoms among Persons with and without Objective HIV-Associated Memory Impairment.

OBJECTIVE: Memory symptoms and objective impairment are common in HIV disease and are associated with disability. A paradoxical issue is that objective episodic memory failures can interfere with accurate recall of memory symptoms. The present study assessed whether responses on a self-report scale of memory symptoms demonstrate measurement invariance in persons with and without objective HIV-associated memory impairment. METHOD: In total, 505 persons with HIV completed the Prospective and Retrospective Memory Questionnaire (PRMQ). Objective memory impairment (n = 141) was determined using a 1-SD cutoff on clinical tests of episodic memory. PRMQ measurement invariance was assessed by confirmatory factor analyses examining a one-factor model with increasing cross-group equality constraints imposed on factor loadings and item thresholds (i.e., configural, weak, and strong invariance). RESULTS: Configural model fit indicated that identical items measured a one-factor model for both groups. Comparison to the weak model indicated that factor loadings were equivalent across groups. However, there was evidence of partial strong invariance, with two PRMQ item thresholds differing across memory impairment groups. Post hoc analyses using a 1.5-SD memory impairment cutoff (n = 77) revealed both partial weak and partial strong invariance, such that PRMQ item loadings differed across memory groups for three items. CONCLUSIONS: The PRMQ demonstrated a robust factor structure among persons with and without objective HIV-associated memory impairment. However, on select PRMQ items, individuals with memory impairment reported observed scores that were relatively higher than their latent score, while items were more strongly associated with the memory factor in a group with greater memory impairment.

CFTR Modulators: From Mechanism to Targeted Therapeutics.

People with cystic fibrosis (CF) suffer from a multi-organ disorder caused by loss-of-function variants in the gene encoding the epithelial anion channel cystic fibrosis transmembrane conductance regulator (CFTR). Tremendous progress has been made in both basic and clinical sciences over the past three decades since the identification of the CFTR gene. Over 90% of people with CF now have access to therapies targeting dysfunctional CFTR. This success was made possible by numerous studies in the field that incrementally paved the way for the development of small molecules known as CFTR modulators. The advent of CFTR modulators transformed this life-threatening illness into a treatable disease by directly binding to the CFTR protein and correcting defects induced by pathogenic variants. In this chapter, we trace the trajectory of structural and functional studies that brought CF therapies from bench to bedside, with an emphasis on mechanistic understanding of CFTR modulators.

Carbon monoxide-releasing molecules inhibit the cystic fibrosis transmembrane conductance regulator Cl- channel.

The gasotransmitter carbon monoxide (CO) regulates fluid and electrolyte movements across epithelial tissues. However, its action on anion channels is incompletely understood. Here, we investigate the direct action of CO on the cystic fibrosis transmembrane conductance regulator (CFTR) by applying CO-releasing molecules (CO-RMs) to the intracellular side of excised inside-out membrane patches from cells heterologously expressing wild-type human CFTR. Addition of increasing concentrations of tricarbonyldichlororuthenium(II) dimer (CORM-2) (1-300 µM) inhibited CFTR channel activity, whereas the control RuCl3 (100 µM) was without effect. CORM-2 predominantly inhibited CFTR by decreasing the frequency of channel openings and, hence, open probability (Po). But, it also reduced current flow through open channels with very fast kinetics, particularly at elevated concentrations. By contrast, the chemically distinct CO-releasing molecule CORM-3 inhibited CFTR by decreasing Po without altering current flow through open channels. Neither depolarizing the membrane voltage nor raising the ATP concentration on the intracellular side of the membrane affected CFTR inhibition by CORM-2. Interestingly, CFTR inhibition by CORM-2, but not by CFTRinh-172, was prevented by prior enhancement of channel activity by the clinically approved CFTR potentiator ivacaftor. Similarly, when added after CORM-2, ivacaftor completely relieved CFTR inhibition. In conclusion, CORM-2 has complex effects on wild-type human CFTR consistent with allosteric inhibition and open-channel blockade. Inhibition of CFTR by CO-releasing molecules suggests that CO regulates CFTR activity and that the gasotransmitter has tissue-specific effects on epithelial ion transport. The action of ivacaftor on CFTR Cl- channels inhibited by CO potentially expands the drug's clinical utility.

Parathyroid hormone increases CFTR expression and function in Caco-2 intestinal epithelial cells.

Parathyroid hormone (PTH) enhances cystic fibrosis transmembrane conductance regulator (CFTR)-mediated anion secretion by the human intestinal epithelial cell line Caco-2. With the patch-clamp and Ussing chamber techniques, we investigated how PTH stimulates CFTR activity in Caco-2 cells. Cell-attached recordings revealed that PTH stimulated the opening of CFTR-like channels, while impedance analysis demonstrated that PTH increased apical membrane capacitance, a measure of membrane surface area. Using ion substitution experiments, the PTH-stimulated increase in short-circuit current (Isc), a measure of transepithelial ion transport, was demonstrated to be Cl-- and HCO3--dependent. However, the PTH-stimulated increase in Isc was unaffected by the carbonic anhydrase inhibitor acetazolamide, but partially blocked by the intermediate-conductance Ca2+-activated K+ channel (IKCa) inhibitor clotrimazole. TRAM-34, a related IKCa inhibitor, failed to directly inhibit CFTR Cl- channels in cell-free membrane patches, excluding its action on CFTR. In conclusion, PTH enhances CFTR-mediated anion secretion by Caco-2 monolayers by increasing the expression and function of CFTR in the apical membrane and IKCa activity in the basolateral membrane.

Alteration of protein function by a silent polymorphism linked to tRNA abundance.

Synonymous single nucleotide polymorphisms (sSNPs) are considered neutral for protein function, as by definition they exchange only codons, not amino acids. We identified an sSNP that modifies the local translation speed of the cystic fibrosis transmembrane conductance regulator (CFTR), leading to detrimental changes to protein stability and function. This sSNP introduces a codon pairing to a low-abundance tRNA that is particularly rare in human bronchial epithelia, but not in other human tissues, suggesting tissue-specific effects of this sSNP. Up-regulation of the tRNA cognate to the mutated codon counteracts the effects of the sSNP and rescues protein conformation and function. Our results highlight the wide-ranging impact of sSNPs, which invert the programmed local speed of mRNA translation and provide direct evidence for the central role of cellular tRNA levels in mediating the actions of sSNPs in a tissue-specific manner.

Preferred Formation of Heteromeric Channels between Coexpressed SK1 and IKCa Channel Subunits Provides a Unique Pharmacological Profile of Ca2+-Activated Potassium Channels.

Three small conductance calcium-activated potassium channel (SK) subunits have been cloned and found to preferentially form heteromeric channels when expressed in a heterologous expression system. The original cloning of the gene encoding the intermediate conductance calcium-activated potassium channel (IKCa) was termed SK4 because of the high homology between channel subtypes. Recent immunovisualization suggests that IKCa is expressed in the same subcellular compartments of some neurons as SK channel subunits. Stochastic optical reconstruction microscopy super-resolution microscopy revealed that coexpressed IKCa and SK1 channel subunits were closely associated, a finding substantiated by measurement of fluorescence resonance energy transfer between coexpressed fluorophore-tagged subunits. Expression of homomeric SK1 channels produced current that displayed typical sensitivity to SK channel inhibitors, while expressed IKCa channel current was inhibited by known IKCa channel blockers. Expression of both SK1 and IKCa subunits gave a current that displayed no sensitivity to SK channel inhibitors and a decreased sensitivity to IKCa current inhibitors. Single channel recording indicated that coexpression of SK1 and IKCa subunits produced channels with properties intermediate between those observed for homomeric channels. These data indicate that SK1 and IKCa channel subunits preferentially combine to form heteromeric channels that display pharmacological and biophysical properties distinct from those seen with homomeric channels.

Differential thermostability and response to cystic fibrosis transmembrane conductance regulator potentiators of human and mouse F508del-CFTR.

Cross-species comparative studies have highlighted differences between human and mouse cystic fibrosis transmembrane conductance regulator (CFTR), the epithelial Cl- channel defective in cystic fibrosis (CF). Here, we compare the impact of the most common CF mutation F508del on the function of human and mouse CFTR heterologously expressed in mammalian cells and their response to CFTR modulators using the iodide efflux and patch-clamp techniques. Once delivered to the plasma membrane, human F508del-CFTR exhibited a severe gating defect characterized by infrequent channel openings and was thermally unstable, deactivating within minutes at 37°C. By contrast, the F508del mutation was without effect on the gating pattern of mouse CFTR, and channel activity demonstrated thermostability at 37°C. Strikingly, at all concentrations tested, the clinically approved CFTR potentiator ivacaftor was without effect on the mouse F508del-CFTR Cl- channel. Moreover, eight CFTR potentiators, including ivacaftor, failed to generate CFTR-mediated iodide efflux from CHO cells expressing mouse F508del-CFTR. However, they all produced CFTR-mediated iodide efflux with human F508del-CFTR-expressing CHO cells, while fifteen CFTR correctors rescued the plasma membrane expression of both human and mouse F508del-CFTR. Interestingly, the CFTR potentiator genistein enhanced CFTR-mediated iodide efflux from CHO cells expressing either human or mouse F508del-CFTR, whereas it only potentiated human F508del-CFTR Cl- channels in cell-free membrane patches, suggesting that its action on mouse F508del-CFTR is indirect. Thus, the F508del mutation has distinct effects on human and mouse CFTR Cl- channels.

Extrapyramidal motor signs in older adults with HIV disease: frequency, 1-year course, and associations with activities of daily living and quality of life.

Age and HIV disease have additive effects on neural systems that support motor functioning. The current study examined the combined impact of aging and HIV on extrapyramidal motor functions, which were hypothesized to influence on activities of daily living (ADLs) and quality of life (QoL). Participants included 336 adults classified by HIV serostatus and age. A research nurse administered the Unified Parkinson's Disease Rating Scale (UPDRS) and participants completed the modified Lawton & Brody ADL and the Short Form Survey Instrument (SF-36) questionnaires as part of a larger neuropsychological research battery. A convenience subset of 172 participants completed a 14-month follow-up evaluation. At baseline, only older age was associated with mild extrapyramidal signs; however, at 14-month follow-up, independent adverse effects of both HIV status and age group were observed on a 3-level UPDRS change variable. Among older HIV+ adults, the presence of mild UPDRS motor signs was independently associated with basic and instrumental ADL dependence, as well as lower physical (ps < .05), but not mental QoL. In the modern treatment era, older HIV+ adults show higher frequency of mild extrapyramidal signs as compared to younger individuals (but not older HIV- persons) and are at higher risk of incident extrapyramidal signs relative to HIV- persons (but not younger HIV+ persons). When present in older HIV+ adults, extrapyramidal signs are of mild severity but nevertheless increase the risk of daily functioning problems and lower health-related physical QoL.

Frequency and Correlates of Subjective Cognitive Impairment in HIV Disease.

The increasing prevalence of older adults living with HIV has raised growing concerns about a possible rise in the incidence of neurocognitive disorders due to HIV and other age-related factors. In typical aging, subjective cognitive impairment (SCI) among individuals with normal neurocognitive functioning may be an early manifestation of an incipient neurocognitive disorder. The current study examined the frequency and correlates of SCI in 188 HIV-infected adults without performance-based neurocognitive deficits or a current psychiatric disorder and 133 HIV seronegative comparison participants. All participants completed the Prospective and Retrospective Memory Questionnaire and Profile of Mood States Confusion/Bewilderment scale. Consistent with the diagnostic criteria proposed by Jessen et al. (Alzheimers Dement 10(6):844-852, 2014), participants were classified with SCI if their scores on either of the self-reported measures was greater than 1.5 SD above the normative mean. A logistic regression controlling for current mood complaints and lifetime history of substance use disorders revealed that HIV infection increased the odds of SCI (odds ratio= 4.5 [1.6, 15.4], p = 0.004). Among HIV+ individuals, SCI was associated with lower performance-based learning and delayed memory scores (Cohen's d range 0.41-0.42.) and poorer global everyday functioning (odds ratio= 8.5 [2.6, 15.9]), but not HIV disease severity (ps > 0.10). In a sample of individuals without neurocognitive impairment or elevated mood symptoms, HIV disease was associated with a nearly fivefold increased odds of SCI compared to seronegative individuals, which may indicate an increased risk for developing major neurocognitive disorders as these HIV+ individuals age.