Systematic discovery of TLR signaling components delineates viral-sensing circuits.

Deciphering the signaling networks that underlie normal and disease processes remains a major challenge. Here, we report the discovery of signaling components involved in the Toll-like receptor (TLR) response of immune dendritic cells (DCs), including a previously unkown pathway shared across mammalian antiviral responses. By combining transcriptional profiling, genetic and small-molecule perturbations, and phosphoproteomics, we uncover 35 signaling regulators, including 16 known regulators, involved in TLR signaling. In particular, we find that Polo-like kinases (Plk) 2 and 4 are essential components of antiviral pathways in vitro and in vivo and activate a signaling branch involving a dozen proteins, among which is Tnfaip2, a gene associated with autoimmune diseases but whose role was unknown. Our study illustrates the power of combining systematic measurements and perturbations to elucidate complex signaling circuits and discover potential therapeutic targets.

Two-year clinical outcomes and complication rates in anatomic and reverse shoulder arthroplasty implanted with Exactech GPS intraoperative navigation.

INTRODUCTION: We compared the 2-year clinical outcomes of both anatomic and reverse total shoulder arthroplasty (ATSA and RTSA) using intraoperative navigation compared to traditional positioning techniques. We also examined the effect of glenoid implant retroversion on clinical outcomes. HYPOTHESIS: In both ATSA and RTSA, computer navigation would be associated with equal or better outcomes with fewer complications. Final glenoid version and degree of correction would not show outcome differences. MATERIAL AND METHODS: A total of 216 ATSAs and 533 RTSAs were performed using preoperative planning and intraoperative navigation with a minimum of 2-year follow-up. Matched cohorts (2:1) for age, gender, and follow-up for cases without intraoperative navigation were compared using all standard shoulder arthroplasty clinical outcome metrics. Two subanalyses were performed on navigated cases comparing glenoids positioned greater or less than 10° of retroversion and glenoids corrected more or less than 15°. RESULTS: For ASTA, no statistical differences were found between the navigated and non-navigated cohorts for postoperative complications, glenoid implant loosening, or revision rate. No significant differences were seen in any of the ATSA outcome metrics besides higher internal and external rotation in the navigated cohort. For RTSA, the navigated cohort showed an ARR of 1.7% (95% CI 0%, 3.4%) for postoperative complications and 0.7% (95% CI 0.1%, 1.2%) for dislocations. No difference was found in the revision rate, glenoid implant loosening, acromial stress fracture rates, or scapular notching. Navigated RTSA patients demonstrated significant improvements over non-navigated patients in internal rotation, external rotation, maximum lifting weight, the Simple Shoulder Test (SST), Constant, and Shoulder Arthroplasty Smart (SAS) scores. For the navigated subcohorts, ATSA cases with a higher degree of final retroversion showed significant improvement in pain, Constant, American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES), SST, University of California-Los Angeles shoulder score (UCLA), and Shoulder Pain and Disability Index (SPADI) scores. No significant differences were found in the RTSA subcohort. Higher degrees of version correction showed improvement in external rotation, SST, and Constant scores for ATSA and forward elevation, internal rotation, pain, SST, Constant, ASES, UCLA, SPADI, and SAS scores for RTSA. CONCLUSION: The use of intraoperative navigation shoulder arthroplasty is safe, produces at least equally good outcomes at 2 years as standard instrumentation does without any increased risk of complications. The effect of final implant position above or below 10° of glenoid retroversion and correction more or less than 15° does not negatively impact outcomes.

Identification of Novel Protein Expression Changes Following Cisplatin Treatment and Application to Combination Therapy.

Determining the effect of chemotherapeutic treatment on changes in protein expression can provide important targets for overcoming resistance. Due to challenges in simultaneously measuring large numbers of proteins, a paucity of data exists on global changes. To overcome these challenges, we utilized microwestern arrays that allowed us to measure the abundance and modification state of hundreds of cell signaling and transcription factor proteins in cells following drug exposure. HapMap lymphoblastoid cell lines (LCLs) were exposed to cisplatin, a chemotherapeutic agent commonly used to treat testicular, head and neck, non-small cell lung, and gynecological cancers. We evaluated the expression of 259 proteins following 2, 6, and 12 h of cisplatin treatment in two LCLs with discordant sensitivity to cisplatin. Of these 259 proteins, 66 displayed significantly different protein expression changes (p < 0.05). Fifteen of these proteins were evaluated in a second pair of LCLs with discordant sensitivities to cisplatin; six demonstrated significant differences in expression. We then evaluated a subset of 63 proteins in a second set of LCLs with discordant sensitivity, and 40% of those that were significant in the first pair were also significant in the second part with concordant directionality (p < 0.05). We functionally validated one of the top proteins identified, PDK1, and demonstrated a synergistic relationship between cisplatin and a PDK1 inhibitor in multiple lung cancer lines. This study highlights the potential for identifying novel targets through an understanding of cellular changes in protein expression and modification following drug treatments.

Enhanced prediction of Src homology 2 (SH2) domain binding potentials using a fluorescence polarization-derived c-Met, c-Kit, ErbB, and androgen receptor interactome.

Many human diseases are associated with aberrant regulation of phosphoprotein signaling networks. Src homology 2 (SH2) domains represent the major class of protein domains in metazoans that interact with proteins phosphorylated on the amino acid residue tyrosine. Although current SH2 domain prediction algorithms perform well at predicting the sequences of phosphorylated peptides that are likely to result in the highest possible interaction affinity in the context of random peptide library screens, these algorithms do poorly at predicting the interaction potential of SH2 domains with physiologically derived protein sequences. We employed a high throughput interaction assay system to empirically determine the affinity between 93 human SH2 domains and phosphopeptides abstracted from several receptor tyrosine kinases and signaling proteins. The resulting interaction experiments revealed over 1000 novel peptide-protein interactions and provided a glimpse into the common and specific interaction potentials of c-Met, c-Kit, GAB1, and the human androgen receptor. We used these data to build a permutation-based logistic regression classifier that performed considerably better than existing algorithms for predicting the interaction potential of several SH2 domains.

Reverse total shoulder arthroplasty with structural bone grafting of large glenoid defects.

BACKGROUND: Large glenoid defects pose difficulties in shoulder arthroplasty. Structural grafts consisting of a humeral head autograft, iliac crest, and allograft have been described. Few series describe grafts used with reverse total shoulder arthroplasty (RTSA). METHODS: We retrospectively reviewed patients who had undergone primary or revision RTSA. We identified 44 patients (20 men and 24 women; mean age, 69 years) as having a bulk structural graft to the glenoid behind the baseplate. The grafts consisted of a humeral head autograft in 29, iliac crest autograft in 1, or femoral head allograft in 14. Range of motion data, American Shoulder and Elbow Surgeons score, simple shoulder test, shoulder pain and disability index, and Constant scores were obtained from preoperative and the latest follow-up visits. Radiographs were reviewed from the initial postoperative visit and the latest follow-up. The grafting cohort was compared with an age- and sex-matched cohort of RTSA patients without glenoid grafting. RESULTS: Improvements were seen in the functional outcome scores at the latest follow-up. No significant differences were found in the preoperative or postoperative data between allografts and autografts. Postoperative scores for the bone graft cohort were significantly lower than those in the cohort without grafting. Complete or partial incorporation was shown radiographically in 81% of grafts. Six baseplates were considered loose. Complications included 2 infections, 1 dislocation, 1 humeral loosening, and 2 instances of clinical aseptic baseplate loosening. Six patients showed mild scapular notching. CONCLUSIONS: The use of bulk structural grafts is a promising treatment option. Allografts may yield equally acceptable results compared with autografts.

Innate immune and chemically triggered oxidative stress modifies translational fidelity.

Translational fidelity, essential for protein and cell function, requires accurate transfer RNA (tRNA) aminoacylation. Purified aminoacyl-tRNA synthetases exhibit a fidelity of one error per 10,000 to 100,000 couplings. The accuracy of tRNA aminoacylation in vivo is uncertain, however, and might be considerably lower. Here we show that in mammalian cells, approximately 1% of methionine (Met) residues used in protein synthesis are aminoacylated to non-methionyl-tRNAs. Remarkably, Met-misacylation increases up to tenfold upon exposing cells to live or non-infectious viruses, toll-like receptor ligands or chemically induced oxidative stress. Met is misacylated to specific non-methionyl-tRNA families, and these Met-misacylated tRNAs are used in translation. Met-misacylation is blocked by an inhibitor of cellular oxidases, implicating reactive oxygen species (ROS) as the misacylation trigger. Among six amino acids tested, tRNA misacylation occurs exclusively with Met. As Met residues are known to protect proteins against ROS-mediated damage, we propose that Met-misacylation functions adaptively to increase Met incorporation into proteins to protect cells against oxidative stress. In demonstrating an unexpected conditional aspect of decoding mRNA, our findings illustrate the importance of considering alternative iterations of the genetic code.

Mapping glucose-mediated gut-to-brain signalling pathways in humans.

OBJECTIVES: Previous fMRI studies have demonstrated that glucose decreases the hypothalamic BOLD response in humans. However, the mechanisms underlying the CNS response to glucose have not been defined. We recently demonstrated that the slowing of gastric emptying by glucose is dependent on activation of the gut peptide cholecystokinin (CCK1) receptor. Using physiological functional magnetic resonance imaging this study aimed to determine the whole brain response to glucose, and whether CCK plays a central role. EXPERIMENTAL DESIGN: Changes in blood oxygenation level-dependent (BOLD) signal were monitored using fMRI in 12 healthy subjects following intragastric infusion (250ml) of: 1M glucose+predosing with dexloxiglumide (CCK1 receptor antagonist), 1M glucose+placebo, or 0.9% saline (control)+placebo, in a single-blind, randomised fashion. Gallbladder volume, blood glucose, insulin, and GLP-1 and CCK concentrations were determined. Hunger, fullness and nausea scores were also recorded. PRINCIPAL OBSERVATIONS: Intragastric glucose elevated plasma glucose, insulin, and GLP-1, and reduced gall bladder volume (an in vivo assay for CCK secretion). Glucose decreased BOLD signal, relative to saline, in the brainstem and hypothalamus as well as the cerebellum, right occipital cortex, putamen and thalamus. The timing of the BOLD signal decrease was negatively correlated with the rise in blood glucose and insulin levels. The glucose+dex arm highlighted a CCK1-receptor dependent increase in BOLD signal only in the motor cortex. CONCLUSIONS: Glucose induces site-specific differences in BOLD response in the human brain; the brainstem and hypothalamus show a CCK1 receptor-independent reduction which is likely to be mediated by a circulatory effect of glucose and insulin, whereas the motor cortex shows an early dexloxiglumide-reversible increase in signal, suggesting a CCK1 receptor-dependent neural pathway.

Systems analysis of EGF receptor signaling dynamics with microwestern arrays.

We describe microwestern arrays, which enable quantitative, sensitive and high-throughput assessment of protein abundance and modifications after electrophoretic separation of microarrayed cell lysates. This method allowed us to measure 91 phosphosites on 67 proteins at six time points after stimulation with five epidermal growth factor (EGF) concentrations in A431 human carcinoma cells. We inferred the connectivities among 15 phosphorylation sites in 10 receptor tyrosine kinases (RTKs) and two sites from Src kinase using Bayesian network modeling and two mutual information-based methods; the three inference methods yielded substantial agreement on the network topology. These results imply multiple distinct RTK coactivation mechanisms and support the notion that small amounts of experimental data collected from phenotypically diverse network states may enable network inference.

Functional neuroimaging demonstrates that ghrelin inhibits the central nervous system response to ingested lipid.

OBJECTIVE: Gut-derived humoural factors activate central nervous system (CNS) mechanisms controlling energy intake and expenditure, and autonomic outflow. Ghrelin is secreted from the stomach and stimulates food intake and gastric emptying, but the relevant mechanisms are poorly understood. Nutrient-activated CNS systems can be studied in humans by physiological/pharmacological MRI (phMRI). This method has been used to examine the CNS responses to exogenous ghrelin. DESIGN: phMRI was used to study the CNS responses in healthy people to a ghrelin bolus (0.3 nmol/kg, intravenous) in the post-prandial state, and an intravenous infusion of ghrelin (1.25 pmol/kg/min) alone and after intragastric lipid (dodecanoate, C12) in people who have fasted. RESULTS: A ghrelin bolus decreased the blood oxygenation level dependent (BOLD) signal detected by phMRI in feeding-activated areas of the CNS in the post-prandial state. Infusion of ghrelin reversed the effect of C12 in delaying gastric emptying but had no effect on hunger. Intragastric C12 caused strong bilateral activation of a matrix of CNS areas, including the brain stem, hypothalamus and limbic areas which was attenuated by exogenous ghrelin. Ghrelin infusion alone had a small but significant stimulatory effect on CNS BOLD signals. CONCLUSION: Ghrelin inhibits activation of the hypothalamus and brain stem induced by ingested nutrients, suggesting a role in suppression of gut-derived satiety signals in humans.

A quantitative protein interaction network for the ErbB receptors using protein microarrays.

Although epidermal growth factor receptor (EGFR; also called ErbB1) and its relatives initiate one of the most well-studied signalling networks, there is not yet a genome-wide view of even the earliest step in this pathway: recruitment of proteins to the activated receptors. Here we use protein microarrays comprising virtually every Src homology 2 (SH2) and phosphotyrosine binding (PTB) domain encoded in the human genome to measure the equilibrium dissociation constant of each domain for 61 peptides representing physiological sites of tyrosine phosphorylation on the four ErbB receptors. This involved 77,592 independent biochemical measurements and provided a quantitative protein interaction network that reveals many new interactions, including ones that fall outside of our current view of domain selectivity. By slicing through the network at different affinity thresholds, we found surprising differences between the receptors. Most notably, EGFR and ErbB2 become markedly more promiscuous as the threshold is lowered, whereas ErbB3 does not. Because EGFR and ErbB2 are overexpressed in many human cancers, our results suggest that the extent to which promiscuity changes with protein concentration may contribute to the oncogenic potential of receptor tyrosine kinases, and perhaps other signalling proteins as well.

SH2 domains recognize contextual peptide sequence information to determine selectivity.

Selective ligand recognition by modular protein interaction domains is a primary determinant of specificity in signaling pathways. Src homology 2 (SH2) domains fulfill this capacity immediately downstream of tyrosine kinases, acting to recruit their host polypeptides to ligand proteins harboring phosphorylated tyrosine residues. The degree to which SH2 domains are selective and the mechanisms underlying selectivity are fundamental to understanding phosphotyrosine signaling networks. An examination of interactions between 50 SH2 domains and a set of 192 phosphotyrosine peptides corresponding to physiological motifs within FGF, insulin, and IGF-1 receptor pathways indicates that individual SH2 domains have distinct recognition properties and exhibit a remarkable degree of selectivity beyond that predicted by previously described binding motifs. The underlying basis for such selectivity is the ability of SH2 domains to recognize both permissive amino acid residues that enhance binding and non-permissive amino acid residues that oppose binding in the vicinity of the essential phosphotyrosine. Neighboring positions affect one another so local sequence context matters to SH2 domains. This complex linguistics allows SH2 domains to distinguish subtle differences in peptide ligands. This newly appreciated contextual dependence substantially increases the accessible information content embedded in the peptide ligands that can be effectively integrated to determine binding. This concept may serve more broadly as a paradigm for subtle recognition of physiological ligands by protein interaction domains.

Post-flooding disaster crop diversity recovery: a case study of Cowpea in Mozambique.

To restore food security to a traditional African cropping system following a sudden loss of seed, genetic diversity must be re-established. This study examines the extent to which Cowpea diversity was reinstated two years after a flood disaster in Gaza Province, Mozambique. The contribution that seed from various sources made to the recovery was assessed using semi-structured interviews and morphological and molecular data. Data suggest that diversity had recovered to some extent yet there was evidence of a narrowing of the genetic base, with fewer rare alleles and differences in the distribution of allele frequencies. Although the main channels for accessing seed after the flood were seed relief and markets, these sources contributed to minimal and different diversity. It appears that diversity was regained primarily through social networking in the form of loans or gifts of seed from friends and relatives. The results of the study are discussed in relation to seed relief approaches.

Inhibition of HIV Replication by Apolipoprotein A-I Binding Protein Targeting the Lipid Rafts.

Apolipoprotein A-I binding protein (AIBP) is a protein involved in regulation of lipid rafts and cholesterol efflux. AIBP has been suggested to function as a protective factor under several sets of pathological conditions associated with increased abundance of lipid rafts, such as atherosclerosis and acute lung injury. Here, we show that exogenously added AIBP reduced the abundance of lipid rafts and inhibited HIV replication in vitro as well as in HIV-infected humanized mice, whereas knockdown of endogenous AIBP increased HIV replication. Endogenous AIBP was much more abundant in activated T cells than in monocyte-derived macrophages (MDMs), and exogenous AIBP was much less effective in T cells than in MDMs. AIBP inhibited virus-cell fusion, specifically targeting cells with lipid rafts mobilized by cell activation or Nef-containing exosomes. MDM-HIV fusion was sensitive to AIBP only in the presence of Nef provided by the virus or exosomes. Peripheral blood mononuclear cells from donors with the HLA-B*35 genotype, associated with rapid progression of HIV disease, bound less AIBP than cells from donors with other HLA genotypes and were not protected by AIBP from rapid HIV-1 replication. These results provide the first evidence for the role of Nef exosomes in regulating HIV-cell fusion by modifying lipid rafts and suggest that AIBP is an innate factor that restricts HIV replication by targeting lipid rafts.IMPORTANCE Apolipoprotein A-I binding protein (AIBP) is a recently identified innate anti-inflammatory factor. Here, we show that AIBP inhibited HIV replication by targeting lipid rafts and reducing virus-cell fusion. Importantly, AIBP selectively reduced levels of rafts on cells stimulated by an inflammatory stimulus or treated with extracellular vesicles containing HIV-1 protein Nef without affecting rafts on nonactivated cells. Accordingly, fusion of monocyte-derived macrophages with HIV was sensitive to AIBP only in the presence of Nef. Silencing of endogenous AIBP significantly upregulated HIV-1 replication. Interestingly, HIV-1 replication in cells from donors with the HLA-B*35 genotype, associated with rapid progression of HIV disease, was not inhibited by AIBP. These results suggest that AIBP is an innate anti-HIV factor that targets virus-cell fusion.

T cells with high PD-1 expression are associated with lower HIV-specific immune responses despite long-term antiretroviral therapy.

OBJECTIVE: We evaluated frequencies of T cells with high PD-1 expression (PD-1) before and after long-term effective antiretroviral therapy (ART), and determined if frequencies on-ART correlated positively with measures of HIV persistence and negatively with HIV-specific responses. METHODS: We enrolled individuals who started ART during chronic infection and had durable suppression of viremia for at least 4 years (N = 99). We assessed PD-1 T-cell frequencies at timepoints pre-ART and on-ART using flow cytometry, and evaluated how frequencies on-ART are associated with measures of HIV persistence, HIV-specific immune responses, and immune activation levels. RESULTS: Pre-ART, PD-1 CD4 T cells correlated positively with viremia and negatively with CD4 T-cell count. At year 1 on-ART, %PD-1 CD4 T cells decreased but then remained stable at 4 and 6-15 years on-ART, whereas %PD-1 CD8 T cells on-ART remained similar to pre-ART. PD-1 CD4 T cells correlated positively with HIV DNA pre-ART and on-ART, and with CD4 T-cell activation on-ART. PD-1 CD4 T cells negatively correlated with HIV Gag-specific and Env-specific T-cell responses but not with CMV-specific or EBV-specific responses. PD-1 CD8 T cells trended towards a negative correlation with responses to Gag and Env, but not to CMV and EBV. CONCLUSION: PD-1 T cells persist in blood despite prolonged suppression on ART, correlate with HIV DNA levels, and are associated with lower HIV-specific T-cell responses but not CMV-specific or EBV-specific responses, suggesting that these cells are HIV-specific. The findings support evaluating PD-1 blockade strategies for their effect on HIV persistence and HIV-specific immunity.

Systems-level analysis of ErbB4 signaling in breast cancer: a laboratory to clinical perspective.

Although expression of the ErbB4 receptor tyrosine kinase in breast cancer is generally regarded as a marker for favorable patient prognosis, controversial exceptions have been reported. Alternative splicing of ErbB4 pre-mRNAs results in the expression of distinct receptor isoforms with differential susceptibility to enzymatic cleavage and different downstream signaling protein recruitment potential that could affect tumor progression in different ways. ErbB4 protein expression from nontransfected cells is generally low compared with ErbB1 in most cell lines, and much of our knowledge of the role of ErbB4 in breast cancer is derived from the ectopic overexpression of the receptor in non-breast-derived cell lines. One of the primary functions of ErbB4 in vivo is in the maturation of mammary glands during pregnancy and lactation induction. Pregnancy and extended lactation durations have been correlated with reduced risk of breast cancer, and the role of ErbB4 in tumor suppression may therefore be linked with its role in lactation. Most reports are consistent with a role for ErbB4 in reversing growth stimuli triggered by other ErbB family members during puberty. In this report, we provide a systems-level examination of several reports highlighting the seemingly opposing roles of ErbB4 in breast cancer and potential explanations for the discrepancies and draw the conclusion that future studies examining the function of ErbB4 in breast cancer should also take into account the pregnancy history, lactation status, and hormone supplementation or ablation history of the patient from whom the tumor or tumor cells are derived.

Effect of Tuberosity Healing on Clinical Outcomes in Elderly Patients Treated With a Reverse Shoulder Arthroplasty for 3- and 4-Part Proximal Humerus Fractures.

OBJECTIVES: To evaluate tuberosity union rate and clinical outcome after 3- and 4-part proximal humerus fractures in the elderly. DESIGN: Retrospective, multicenter database cohort study. SETTING: Level I and Level II trauma centers. PATIENTS: Fifty-five patients older than 65 years had insertion of reverse shoulder arthroplasty (RTSA) for OTA/AO 11-B and 11-C proximal humerus fractures. INTERVENTION: Treatment with RTSA using a dedicated low profile onlay fracture stem using variable tuberosity fixation. MAIN OUTCOME MEASURES: Constant score, the American Shoulder and Elbow Surgeons score, Shoulder Pain and Disability Index score, University of California at Los Angeles score, Simple Shoulder Test score, visual analog pain score, shoulder function score, active range of motion, external rotation (ER)-specific tasks and position, rate of greater tuberosity healing, effect of tuberosity healing on overall clinical metrics, incidence of humeral lucency, and scapular notching. RESULTS: Eighty-three percent of the greater tuberosities that were repaired united. Greater tuberosity union resulted in greater active ER (P = 0.0415). There was a statistically significant difference in the ability to do ER-type activities between the 2 cohorts reflected in the ability to position one's hand behind their head with the elbow forward (P = 0.002) and comb their hair (P < 0.001). CONCLUSION: The use of a low profile onlay fracture stem in RTSA for acute 3- and 4-part proximal humerus fractures in the elderly can result in a high tuberosity union rate. Greater tuberosity healing significantly influences ER and ER-type activities that are not apparent by analysis of the overall metrics studied. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Microwestern Arrays for Systems-Level Analysis of SH2 Domain-Containing Proteins.

The Microwestern Array (MWA) method combines the scalability and miniaturization afforded by the Reverse Phase Lysate Array (RPLA) approach with the electrophoretic separation characteristic of the Western blot. This technology emulates the creation of an array of small Western blots on a single sheet of nitrocellulose allowing for the sensitive and quantitative measurement of hundreds of proteins from hundreds of cell lysates with minimal cost and maximal accuracy, precision, and reproducibility. The MWA is a versatile technology that can be easily configured for purposes such as antibody screening, cell signaling network inference, protein modification/phenotype regression analysis, and genomic/proteomic relationships. Accordingly, configurations for the MWA can be optimized for maximal numbers of proteins analyzed from small numbers of cell lysates, for small numbers of antibodies against large numbers of cell lysates, or for maximal resolution of protein size achieved by increased electrophoretic separation distance. For example, on a single gel, 6 samples can be printed 96 times if a few samples need to be assayed with a large number of antibodies. Alternatively, up to 100 samples can be assayed with four antibodies on a single gel. Intermediate configurations are also discussed.The efficiency of the MWA is orders of magnitude greater in reagents, labor, and time required per data point relative to the standard Western blotting method and orders of magnitude more sensitive than standard mass spectrometry methods. The MWA is therefore a very attractive approach for capturing global changes in protein abundances and modifications including tyrosine phosphorylation and SH2 domain binding sites.

IFITM1 targets HIV-1 latently infected cells for antibody-dependent cytolysis.

HIV-1 persistence in latent reservoirs during antiretroviral therapy (ART) is the main obstacle to virus eradication. To date, there is no marker that adequately identifies latently infected CD4+ T cells in vivo. Using a well-established ex vivo model, we generated latently infected CD4+ T cells and identified interferon-induced transmembrane protein 1 (IFITM1), a transmembrane antiviral factor, as being overexpressed in latently infected cells. By targeting IFITM1, we showed the efficient and specific killing of a latently infected cell line and CD4+ T cells from ART-suppressed patients through antibody-dependent cytolysis. We hypothesize that IFITM1 could mark natural reservoirs, identifying an immune target for killing of latently infected cells. These novel insights could be explored to develop clinical therapeutic approaches to effectively eradicate HIV-1.