Complete correction of murine phenylketonuria by selection-enhanced hepatocyte transplantation.

BACKGROUND AND AIMS: Hepatocyte transplantation for genetic liver diseases has several potential advantages over gene therapy. However, the low efficiency of cell engraftment has limited its clinical implementation. This problem could be overcome by selectively expanding transplanted donor cells until they replace enough of the liver mass to achieve therapeutic benefit. We previously described a gene therapy method to selectively expand hepatocytes deficient in cytochrome p450 reductase (Cypor) using acetaminophen (APAP). Because Cypor is required for the transformation of APAP to a hepatotoxic metabolite, Cypor-deficient cells are protected from toxicity and are able to expand following APAP-induced liver injury. Here, we apply this selection system to correct a mouse model of phenylketonuria by cell transplantation. APPROACH AND RESULTS: Hepatocytes from a wild-type donor animal were edited in vitro to create Cypor deficiency and then transplanted into phenylketonuric animals. Following selection with APAP, blood phenylalanine concentrations were fully normalized and remained stable following APAP withdrawal. Cypor-deficient hepatocytes expanded from < 1% to ~14% in corrected animals, and they showed no abnormalities in blood chemistries, liver histology, or drug metabolism. CONCLUSIONS: We conclude that APAP-mediated selection of transplanted hepatocytes is a potential therapeutic for phenylketonuria with long-term efficacy and a favorable safety profile.

The SWI/SNF chromatin remodeling assemblies BAF and PBAF differentially regulate cell cycle exit and cellular invasion in vivo.

Chromatin remodelers such as the SWI/SNF complex coordinate metazoan development through broad regulation of chromatin accessibility and transcription, ensuring normal cell cycle control and cellular differentiation in a lineage-specific and temporally restricted manner. Mutations in genes encoding the structural subunits of chromatin, such as histone subunits, and chromatin regulating factors are associated with a variety of disease mechanisms including cancer metastasis, in which cancer co-opts cellular invasion programs functioning in healthy cells during development. Here we utilize Caenorhabditis elegans anchor cell (AC) invasion as an in vivo model to identify the suite of chromatin agents and chromatin regulating factors that promote cellular invasiveness. We demonstrate that the SWI/SNF ATP-dependent chromatin remodeling complex is a critical regulator of AC invasion, with pleiotropic effects on both G0 cell cycle arrest and activation of invasive machinery. Using targeted protein degradation and enhanced RNA interference (RNAi) vectors, we show that SWI/SNF contributes to AC invasion in a dose-dependent fashion, with lower levels of activity in the AC corresponding to aberrant cell cycle entry and increased loss of invasion. Our data specifically implicate the SWI/SNF BAF assembly in the regulation of the G0 cell cycle arrest in the AC, whereas the SWI/SNF PBAF assembly promotes AC invasion via cell cycle-independent mechanisms, including attachment to the basement membrane (BM) and activation of the pro-invasive fos-1/FOS gene. Together these findings demonstrate that the SWI/SNF complex is necessary for two essential components of AC invasion: arresting cell cycle progression and remodeling the BM. The work here provides valuable single-cell mechanistic insight into how the SWI/SNF assemblies differentially contribute to cellular invasion and how SWI/SNF subunit-specific disruptions may contribute to tumorigeneses and cancer metastasis.

Cell cycle perturbation uncouples mitotic progression and invasive behavior in a post-mitotic cell.

The acquisition of the post-mitotic state is crucial for the execution of many terminally differentiated cell behaviors during organismal development. However, the mechanisms that maintain the post-mitotic state in this context remain poorly understood. To gain insight into these mechanisms, we used the genetically and visually accessible model of C. elegans anchor cell (AC) invasion into the vulval epithelium. The AC is a terminally differentiated uterine cell that normally exits the cell cycle and enters a post-mitotic state before initiating contact between the uterus and vulva through a cell invasion event. Here, we set out to identify the set of negative cell cycle regulators that maintain the AC in this post-mitotic, invasive state. Our findings revealed a critical role for CKI-1 (p21CIP1/p27KIP1) in redundantly maintaining the post-mitotic state of the AC, as loss of CKI-1 in combination with other negative cell cycle regulators-including CKI-2 (p21CIP1/p27KIP1), LIN-35 (pRb/p107/p130), FZR-1 (Cdh1/Hct1), and LIN-23 (ß-TrCP)-resulted in proliferating ACs. Remarkably, time-lapse imaging revealed that these ACs retain their ability to invade. Upon examination of a node in the gene regulatory network controlling AC invasion, we determined that proliferating, invasive ACs do so by maintaining aspects of pro-invasive gene expression. We therefore report that the requirement for a post-mitotic state for invasive cell behavior can be bypassed following direct cell cycle perturbation.

State-of-the-art 2023 on gene therapy for phenylketonuria.

Phenylketonuria (PKU) or hyperphenylalaninemia is considered a paradigm for an inherited (metabolic) liver defect and is, based on murine models that replicate all human pathology, an exemplar model for experimental studies on liver gene therapy. Variants in the PAH gene that lead to hyperphenylalaninemia are never fatal (although devastating if untreated), newborn screening has been available for two generations, and dietary treatment has been considered for a long time as therapeutic and satisfactory. However, significant shortcomings of contemporary dietary treatment of PKU remain. A long list of various gene therapeutic experimental approaches using the classical model for human PKU, the homozygous enu2/2 mouse, witnesses the value of this model to develop treatment for a genetic liver defect. The list of experiments for proof of principle includes recombinant viral (AdV, AAV, and LV) and non-viral (naked DNA or LNP-mRNA) vector delivery methods, combined with gene addition, genome, gene or base editing, and gene insertion or replacement. In addition, a list of current and planned clinical trials for PKU gene therapy is included. This review summarizes, compares, and evaluates the various approaches for the sake of scientific understanding and efficacy testing that may eventually pave the way for safe and efficient human application.

Comparison of red blood cell transfusions and hemostatic transfusions and their relation to thromboses in pediatric patients receiving extracorporeal membrane oxygenation therapy.

OBJECTIVE: To evaluate the association of RBC transfusions with thrombosis in pediatric patients on extracorporeal membrane oxygenation (ECMO) and compare this with the transfusion of other blood products and their association with thrombosis. METHODS: This was a secondary analysis of the Bleeding and Thrombosis during ECMO (BATE) study, which was a multicenter prospective observational study involving patients less than 19 years of age treated with ECMO. RESULTS: 514 patients were analyzed, of which 282 (55%) were neonates (≤31 days) and 302 (58.7%) were male. When analyzing the entire cohort independently of other blood products, each 10 mL/kg of packed red blood cells (PRBCs) was associated with a 1.0% increase in the average number of thromboses (1.010; 1.008,1.013; p < .001). In neonates, each 10 mL/kg of PRBC was associated with a 0.9% increase in the average number of thromboses (1.009; 1.003,1.013; p < .001). In pediatric patients, each 10 mL/kg of PRBC was associated with a 1.2% increase in the average number of thromboses (1.012; 1.008,1.012; p < .001). The percent increase in the average number of thromboses was similar between PRBCs, platelets, and FFP, but increased significantly with cryoprecipitate. CONCLUSIONS: RBC transfusions and hemostatic transfusions are likely associated with thromboses in pediatric patients on ECMO.

Epigenomic regulation of human T-cell leukemia virus by chromatin-insulator CTCF.

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that causes an aggressive T-cell malignancy and a variety of inflammatory conditions. The integrated provirus includes a single binding site for the epigenomic insulator, CCCTC-binding protein (CTCF), but its function remains unclear. In the current study, a mutant virus was examined that eliminates the CTCF-binding site. The mutation did not disrupt the kinetics and levels of virus gene expression, or establishment of or reactivation from latency. However, the mutation disrupted the epigenetic barrier function, resulting in enhanced DNA CpG methylation downstream of the CTCF binding site on both strands of the integrated provirus and H3K4Me3, H3K36Me3, and H3K27Me3 chromatin modifications both up- and downstream of the site. A majority of clonal cell lines infected with wild type HTLV-1 exhibited increased plus strand gene expression with CTCF knockdown, while expression in mutant HTLV-1 clonal lines was unaffected. These findings indicate that CTCF binding regulates HTLV-1 gene expression, DNA and histone methylation in an integration site dependent fashion.

Postoperative Acute Kidney Injury by Age and Sex: A Retrospective Cohort Association Study.

BACKGROUND: Acute kidney injury (AKI) after noncardiac surgery is common and has substantial health impact. Preclinical and clinical studies examining the influence of sex on AKI have yielded conflicting results, although they typically do not account for age-related changes. The objective of the study was to determine the association of age and sex groups on postoperative AKI. The authors hypothesized that younger females would display lower risk of postoperative AKI than males of similar age, and the protection would be lost in older females. METHODS: This was a multicenter retrospective cohort study across 46 institutions between 2013 and 2019. Participants included adult inpatients without pre-existing end-stage kidney disease undergoing index major noncardiac, nonkidney/urologic surgeries. The authors' primary exposure was age and sex groups defined as females 50 yr or younger, females older than 50 yr, males 50 yr or younger, and males older than 50 yr. The authors' primary outcome was development of AKI by Kidney Disease-Improving Global Outcomes serum creatinine criteria. Exploratory analyses included associations of ascending age groups and hormone replacement therapy home medications with postoperative AKI. RESULTS: Among 390,382 patients, 25,809 (6.6%) developed postoperative AKI (females 50 yr or younger: 2,190 of 58,585 [3.7%]; females older than 50 yr: 9,320 of 14,4047 [6.5%]; males 50 yr or younger: 3,289 of 55,503 [5.9%]; males older than 50 yr: 11,010 of 132,447 [8.3%]). When adjusted for AKI risk factors, compared to females younger than 50 yr (odds ratio, 1), the odds of AKI were higher in females older than 50 yr (odds ratio, 1.51; 95% CI, 1.43 to 1.59), males younger than 50 yr (odds ratio, 1.90; 95% CI, 1.79 to 2.01), and males older than 50 yr (odds ratio, 2.06; 95% CI, 1.96 to 2.17). CONCLUSIONS: Younger females display a lower odds of postoperative AKI that gradually increases with age. These results suggest that age-related changes in women should be further studied as modifiers of postoperative AKI risk after noncardiac surgery.

Charge, Aspect Ratio, and Plant Species Affect Uptake Efficiency and Translocation of Polymeric Agrochemical Nanocarriers.

An incomplete understanding of how agrochemical nanocarrier properties affect their uptake and translocation in plants limits their application for promoting sustainable agriculture. Herein, we investigated how the nanocarrier aspect ratio and charge affect uptake and translocation in monocot wheat (Triticum aestivum) and dicot tomato (Solanum lycopersicum) after foliar application. Leaf uptake and distribution to plant organs were quantified for polymer nanocarriers with the same diameter (∼10 nm) but different aspect ratios (low (L), medium (M), and high (H), 10-300 nm long) and charges (-50 to +15 mV). In tomato, anionic nanocarrier translocation (20.7 ± 6.7 wt %) was higher than for cationic nanocarriers (13.3 ± 4.1 wt %). In wheat, only anionic nanocarriers were transported (8.7 ± 3.8 wt %). Both low and high aspect ratio polymers translocated in tomato, but the longest nanocarrier did not translocate in wheat, suggesting a phloem transport size cutoff. Differences in translocation correlated with leaf uptake and interactions with mesophyll cells. The positive charge decreases nanocarrier penetration through the leaf epidermis and promotes uptake into mesophyll cells, decreasing apoplastic transport and phloem loading. These results suggest design parameters to provide agrochemical nanocarriers with rapid and complete leaf uptake and an ability to target agrochemicals to specific plant organs, with the potential to lower agrochemical use and the associated environmental impacts.

Motivations for Seeking Cosmetic Enhancing Procedures of the Face: A Systematic Review.

BACKGROUND: Cosmetic enhancing procedures continue to grow in demand. Physicians should understand the complex factors that drive patient motivation for seeking such procedures. OBJECTIVE: In contrast to a lens of psychopathology, this review reveals the driving power of everyday intrapersonal, social, and behavioral factors that motivate interest in elective facial cosmetic procedures. MATERIALS AND METHODS: The review was conducted according to PRISMA guidelines and included studies with at least 50 adult patients seeking facial cosmetic enhancements between January 1, 2000, and July 1, 2022. RESULTS: Among 1,239 identified publications, 21 studies with 9,005 participants were selected for inclusion. The review documents everyday factors as patient motivators for pursuing cosmetic enhancements of the face, with the majority of work focusing on intrapersonal factors (17 of 21 studies), such as preventing aging or negative appearance based self-appraisals. For studies reporting social factors (15 of 21 studies), the most common motivators were the patient's social network and a desire to promote social standing. Behavioral factors revealed that social media and media consumption impact patient motivation for cosmetic enhancements (5 of 21 studies). CONCLUSION: In summary, this review demonstrates that patient motivations for facial cosmetic enhancements may be best understood through everyday intrapersonal, social, and behavioral factors.

Self-Reported Long-Term Side Effects of Isotretinoin: A Case Series.

CITATION: Ghadimi TR, Martinez MJ, Rieder EA. Self-reported long-term side effects of isotretinoin: A case series. J Drugs Dermatol. 2023;22(4):423-424. doi:10.36849/JDD.2303.

A wavefront adaptive sensing beamformer for ocean acoustic waveguides.

This paper addresses robust adaptive beamforming for passive sonar in uncertain, shallow-water environments. Conventional beamforming is still common in passive sonar because adaptive beamformers suffer from signal mismatch in complex multipath environments. Existing approaches to robust adaptive beamforming try to model and account for the uncertainty in the beamformer's hypothesized signal subspace by using additional linear or quadratic constraints. Doing so, however, reduces the adaptivity of the beamformer and is prone to insufficiently suppressing interference. Instead, this paper uses blind source separation methods to adaptively estimate the complex spatial wavefronts of both targets and interference without requiring detailed physical modeling of the channel. By exploiting the different temporal spectra and/or frequency-selective multipath fading of targets and interference, this approach constructs a "signal-free" covariance matrix without imposing directional gain constraints. In doing so, the wavefront adaptive sensing (WAS) beamformer is able to separate targets from strong interference that is within the conventional beam width of the target. Simulation results in a realistic shallow-water channel are presented as well as results using the SWellEx96 S59 data with an injected target to show that the proposed WAS beamformer outperforms conventional and minimum variance adaptive beamformers in a shallow-water scenario.

Cell saver blood transfusions may be associated with a decrease in inflammation and improved outcome measures in pediatric cardiac surgery patients.

OBJECTIVE: Cardiopulmonary bypass (CPB) is a requisite for correction of congenital heart disease by open-heart surgery and induces a systemic inflammatory response that can lead to complications such as acute lung injury and acute kidney injury. In addition, blood transfusions are commonly required for this type of surgery, and they may further exacerbate this inflammatory response and increase morbidity and mortality. We hypothesized that, in contrast to red blood cells, intraoperative cell saver (CS) blood transfusions attenuate the post-CPB proinflammatory cytokine response. METHODS: Serum cytokine concentrations of IL-10, IL-1RA, IL-6, IL-8, and TNF-α were measured at four time points (preoperatively and postoperatively on postoperative days 0, 1, and 2). RESULTS: Anti-inflammatory IL-10 levels were significantly lower in the CS group on POD 0 than in the control group (mean 1083.2 pg/mL vs 2080.2 pg/mL, 95%CI 357.4-1636.6, p = .0026). Of the clinical parameters measured, mean BUN and creatinine levels on POD 2 were significantly lower in the CS group (13.79 vs 21.88, p = .004 and 0.45 vs 0.55, p = .055, respectively). In addition, the duration of milrinone use decreased by 80% in the CS group (0.20, 95%CI 0.04, 0.94; p = .048), the median time to extubation in hours was significantly lower in the CS group (3.5 vs 6.5; 95%CI -38.00, -0.50; p = .026), and hospital length of stay was decreased by 60% in the CS group (p = .003). CONCLUSIONS: CS transfusions in children may lower postoperative anti-inflammatory IL-10 levels, possibly due to an overall decrease in proinflammatory state, and may be associated with improvements in renal and pulmonary functions.

A 2-Year Longitudinal Study of Bone Mineral Density in Collegiate Distance Runners.

ABSTRACT: Brimacomb, OE, Martinez, MP, McCormack, WP, and Almstedt, HC. A 2-year longitudinal study of bone mineral density in collegiate distance runners. J Strength Cond Res 37(8): 1654-1659, 2023-The purpose of this investigation was to examine changes in bone mineral density (BMD) of male and female collegiate distance runners over 2 years. Bone mineral density of 29 collegiate distance runners (16 men and 13 women) were measured 5 times over 24 months using dual-energy x-ray absorptiometry (DXA) at the anterior-posterior (AP) and lateral (LAT) spine, femoral neck (FN), total hip (TH), whole body (WB), and ultradistal (UD) forearm. Repeated-measures multivariate analysis of covariance, with bone-free lean mass (BFLM) as covariate, was used to compare mean BMD values. Adjusted for BFLM, there were no significant differences ( p > 0.05) in BMD at any site between sexes. There were no significant differences at the AP or LAT spine, FN, or WB between visit 1 and 5 for either sex. There was a significant increase in BMD ( p = 0.044) at the UD forearm over 2 years in males. However, 56% of the men ( n = 9) had a Z-score < -1.0 at the UD forearm. Seven of 11 women had Z-scores < -1.0 at the LAT spine and 4 of 13 had Z-scores < -1.0 at the AP spine. There were no significant changes in BMD at any site over the 2-year time frame, except a significant increase in BMD at the nondominant forearm in men. The spine appears to be an area of concern for women in this study when examining Z-score results. Coaches and medical staff need to continually educate collegiate endurance athletes about the importance of achieving and maintaining BMD through their college years.

AN OUTBREAK OF FELINE INFECTIOUS PERITONITIS IN THREE RELATED SAND CATS (FELIS MARGARITA) IN HUMAN CARE.

Feline infectious peritonitis (FIP) is a systemic disease in felid species caused by infection with mutated forms of feline coronavirus (FCoV), and outbreaks can devastate exotic felid populations in human care. Feline infectious peritonitis was diagnosed in three of four related juvenile sand cats (Felis margarita) from a single institution over a 6-wk period. Case 1 was a 7-mon-old male found deceased with no premonitory signs. Case 2, an 8-mon-old male (littermate to Case 1), and Case 3, a 6-mon-old male (from a different litter with identical parentage), were evaluated for lethargy and anorexia 1 mon after Case 1. Both exhibited transient anisocoria and progressive lethargy, anorexia, and dehydration despite antibiotic and supportive treatment. Approximately 1 wk after initial presentation, Case 2 was humanely euthanized, and Case 3 was found deceased. Necropsy findings included intrathoracic and/or intra-abdominal lymphadenopathy (3/3 cases), bicavitary effusion (2/3), multifocal tan hepatic and intestinal nodules (1/3), and multifocal yellow renal nodules (1/3). Histologically, all cats had severe pyogranulomatous vasculitis in multiple organs, and the presence of FCoV antigen was confirmed using immunohistochemical staining. Next-generation sequencing of the virus from Case 3's affected kidney demonstrated ∼93% homology to the UG-FH8 virus, a serotype 1 feline alphacoronavirus isolated from Denmark. Future research will focus on comparative viral genomic sequencing with the goals of identifying potential sources of FCoV infection and identifying features that may have contributed to the development of FIP in this species.

Visible-Light-Mediated Controlled Radical Branching Polymerization in Water.

Hyperbranched polymethacrylates were synthesized by green-light-induced atom transfer radical polymerization (ATRP) under biologically relevant conditions in the open air. Sodium 2-bromoacrylate (SBA) was prepared in situ from commercially available 2-bromoacrylic acid and used as a water-soluble inibramer to induce branching during the copolymerization of methacrylate monomers. As a result, well-defined branched polymethacrylates were obtained in less than 30 min with predetermined molecular weights (36 000

CDK activity sensors: genetically encoded ratiometric biosensors for live analysis of the cell cycle.

Cyclin-dependent kinase (CDK) sensors have facilitated investigations of the cell cycle in living cells. These genetically encoded fluorescent biosensors change their subcellular location upon activation of CDKs. Activation is primarily regulated by their association with cyclins, which in turn trigger cell-cycle progression. In the absence of CDK activity, cells exit the cell cycle and become quiescent, a key step in stem cell maintenance and cancer cell dormancy. The evolutionary conservation of CDKs has allowed for the rapid development of CDK activity sensors for cell lines and several research organisms, including nematodes, fish, and flies. CDK activity sensors are utilized for their ability to visualize the exact moment of cell-cycle commitment. This has provided a breakthrough in understanding the proliferation-quiescence decision. Further adoption of these biosensors will usher in new discoveries focused on the cell-cycle regulation of development, ageing, and cancer.

Dermatomal Granulomatous Dermatitis and Vasculitis Following Herpes Zoster Ophthalmicus.

Cutaneous granulomatous dermatoses are uncommon sequelae of herpes zoster (HZ) infection that have been documented in the literature, with granulomatous vasculitis described in rare cases. Here, we report a patient with HZ ophthalmicus who developed edematous plaques with central scarring in a V1 dermatomal distribution with histopathological changes of a granulomatous dermatitis including features of granulomatous vasculitis. J Drugs Dermatol. 2022;21(10):1127-1128. oi:10.36849/JDD.6749.

Use of an adeno-associated virus serotype Anc80 to provide durable cure of phenylketonuria in a mouse model.

Phenylketonuria (PKU) is the most common inborn error of metabolism of the liver, and results from mutations of both alleles of the phenylalanine hydroxylase gene (PAH). As such, it is a suitable target for gene therapy via gene delivery with a recombinant adeno-associated virus (AAV) vector. Here we use the synthetic AAV vector Anc80 via systemic administration to deliver a functional copy of a codon-optimized human PAH gene, with or without an intron spacer, to the Pahenu2 mouse model of PKU. Dose-dependent transduction of the liver and expression of PAH mRNA were present with both vectors, resulting in significant and durable reduction of circulating phenylalanine, reaching near control levels in males. Coat color of treated Pahenu2 mice reflected an increase in pigmentation from brown to the black color of control animals, further indicating functional restoration of phenylalanine metabolism and its byproduct melanin. There were no adverse effects associated with administration of AAV up to 5 × 1012 VG/kg, the highest dose tested. Only minor and/or transient variations in some liver enzymes were observed in some of the AAV-dosed animals which were not associated with pathology findings in the liver. Finally, there was no impact on cell turnover or apoptosis as evaluated by Ki-67 and TUNEL staining, further supporting the safety of this approach. This study demonstrates the therapeutic potential of AAV Anc80 to safely and durably cure PKU in a mouse model, supporting development for clinical consideration.

Interaction between dilute water vapor and dodecane thiol ligated Au nanoparticles: Hydrated structure and pair potential of mean force.

The interaction between two ligated nanoparticles depends on whether they are isolated or immersed in a liquid solvent. However, very little is known about the influence of solvent vapor on the interaction between two ligated nanoparticles. Recent experiments yield the surprising result that the cyclic exposure of solvent free suspended monolayers of dodecane thiol ligated gold nanoparticles (AuNPs) to water vapor and dry nitrogen generates reversible cyclic decreases and increases in Young's modulus of the monolayer, implying corresponding cyclic changes in the AuNP-AuNP interaction. We examine how water vapor interacts with an isolated dodecane thiol dressed AuNP and how water vapor affects the interaction between a pair of nanoparticles, using all-atom molecular-dynamics simulations. We find that there is condensation of water molecules onto the ligand shell of an AuNP in the form of clusters of 100-2000 molecules that partially cover the shell, with most of the water in a few large clusters. A water cluster bridges the AuNPs, with a sensibly constant number of water molecules for AuNP-AuNP separations from the edge-to-edge contact up to center-to-center separations of 100 Å. The wet AuNP-AuNP interaction has a slightly deeper and wider asymmetric well than does the dry interaction, a change that is qualitatively consistent with that implied by the observed water vapor induced change in Young's modulus of a monolayer of these AuNPs. We find that macroscopic analyses of water drop-deformable surface interactions and dynamics provide both guidance to understanding and qualitatively correct predictions of the phenomena observed in our simulations.

Comparative virology of HTLV-1 and HTLV-2.

Human T cell leukemia virus type 1 (HTLV-1) was the first discovered human retrovirus and the etiologic agent of adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. Shortly after the discovery of HTLV-1, human T-cell leukemia virus type 2 (HTLV-2) was isolated from a patient with hairy cell leukemia. Despite possession of similar structural features to HTLV-1, HTLV-2 has not been definitively associated with lymphoproliferative disease. Since their discovery, studies have been performed with the goal of highlighting the differences between HTLV-1 and HTLV-2. A better understanding of these differences will shed light on the specific pathogenic mechanisms of HTLV-1 and lead to novel therapeutic targets. This review will compare and contrast the two oldest human retroviruses with regards to epidemiology, genomic structure, gene products, and pathobiology.