To evaluate the relationships between body composition and physical frailty in community-dwelling HIV-infected older adults (HOA).
Academic hospital-based infectious disease clinic in Rochester NY
Community-dwelling HIV-infected adults >50 years of age.
Subjective and objective measures of functional status were evaluated by using the Physical Performance Test (PPT), graded treadmill test, knee strength, gait speed, balance and Functional Status Questionnaires (FSQ). Body composition was evaluated by using Dual Energy X-ray Absorptiometry (DXA) and Magnetic Resonance Imaging (MRI).
We studied 40 HOA on antiretroviral therapy (with mean: age 58 years, BMI 29, CD4 569 cells/ml, duration since HIV diagnosis 17 years; 28% female and 57% Caucasian) who were able to ambulate without assistive devices. Sixty percent (25/40) of the subjects met our standard criteria for physical frailty. Both frail (FR) and non-frail (NF) subjects were comparable in age, gender, CD4 count and viral load. Compared to NF HOA, FR HOA showed impairments in PPT, peak aerobic power (VO2peak), FSQ, walking speed, balance and muscle quality. Importantly, FR HOA had greater body mass index (BMI), fat mass and truncal fat with lipodystrophy. Moreover, PPT score was inversely related to both trunk fat (r=−0.34; p=0.045) and intermuscular fat (IMF) to total fat ratio (r=−60; p=0.02) after adjusting for covariates.
HOA represent an emerging cohort of older adults who frequently experience frailty at a much younger age compared to the general older population. Central obesity and fat redistribution are important predictors of frailty among community-dwelling HOA. These findings suggest that physical frailty in HOA may be amenable to lifestyle interventions, especially exercise and diet therapy.
HIV; older adults; frailty; function; obesity; lipodystrophy
Rationale: The National Quality Forum recently endorsed in-hospital mortality and intensive care unit length of stay (LOS) as quality indicators for patients in the intensive care unit. These measures may be affected by transferring patients to long-term acute care hospitals (LTACs).
Objectives: To quantify the implications of LTAC transfer practices on variation in mortality index and LOS index for patients in academic medical centers.
Methods: We used a cross-sectional study design using data reported to the University HealthSystem Consortium from 2008–2009. Data were from patients who were mechanically ventilated for more than 96 hours.
Measurements and Main Results: Using linear regression, we measured the association between mortality index and LTAC transfer rate, with the hospital as the unit of analysis. Similar analyses were conducted for LOS index and cost index. A total of 137 hospitals were analyzed, averaging 534 transfers to LTAC per hospital during the study period. Mean ± SD in-hospital mortality was 24 ± 6.4%, and observed LOS was 30.4 ± 8.2 days. The mean LTAC transfer rate was 15.7 ± 13.7%. Linear regression demonstrated a significant correlation between transfer rate and mortality index (R2 = 0.14; P < 0.0001) and LOS index (R2 = 0.43; P < 0.0001).
Conclusions: LTAC hospital transfer rate has a significant impact on reported mortality and LOS indices for patients requiring prolonged acute mechanical ventilation. This is an example of factors unrelated to quality of medical care or illness severity that must be considered when interpreting mortality and LOS as quality indicators.
National Quality Forum; American Thoracic Society; quality improvement
In contrast with human T-cell leukemia virus type 1 (HTLV-1) that causes ATL (adult T-cell leukemia), HTLV-2 has not been causally linked to malignant disease. The minus strand of the HTLV genomes encode the regulatory proteins HTLV-1 bZIP factor (HBZ) for HTLV-1 and antisense protein of HTLV-2 (APH-2) for HTLV-2. Unlike the viral proteins Tax1 and Tax2, both HBZ and APH-2 are constitutively expressed in infected cells suggesting that they may play important roles in the pathogenesis of these viruses. To date, very little is known about the function of APH-2 except that it inhibits Tax2-mediated transcription of HTLV-2 genes. In the present study, we investigated the role of APH-2 in basal and Tax2B-mediated activation of the AP-1 pathway.
We demonstrate that, unlike HBZ, APH-2 stimulates basal AP-1 transcription by interacting with c-Jun and JunB through its non-conventional bZIP domain. In addition, when Tax2 and APH-2 are co-expressed, they physically interact in vivo and in vitro and APH-2 acts as an inhibitor of Tax2-mediated activation of AP-1 transcription.
This report is the first to document that HTLV-2 can modulate the AP-1 pathway. Altogether our results reveal that, in contrast with HBZ, APH-2 regulates AP-1 activity in a Tax2-dependant manner. As the AP-1 pathway is involved in numerous cellular functions susceptible to affect the life cycle of the virus, these distinct biological properties between HBZ and APH-2 may contribute to the differential pathogenic potential of HTLV-1 and HTLV-2.
HTLV-2; APH-2; Tax2; AP-1; Jun
The Epstein–Barr virus early antigen (EBV EA) complex consists of multiple proteins with potential significance for diagnosis of EBV-related diseases. In many individuals, detection of antibody to the early antigen (EA) is a sign of active infection, but 20% of healthy people may have this antibody for years. We studied the role of EA immunoglobulin G (IgG) in individuals with atypical antibody responses in the diagnosis of infectious mononucleosis (IM) and in EBV-infected transplant patients. EA IgG was present in 72% of confirmed IM patients. A trend was observed between high viral loads and the presence of EA IgG and between low viral loads and the absence of EA IgG in EBV-associated disease negative liver transplant recipients. Three assays that measure serum EA IgG were compared; enzyme-linked immunosorbent assay (ELISA), chemiluminescent immunoassay (CLIA), and immunoblot assay. The automated CLIA was found to be more accurate than the ELISA when using the immunoblot assay as a “gold standard” assay in the detection of EA IgG. There may be a potential role for EA IgG testing, together with EBV viral load, in the prediction of transplant recipients at risk of EBV-associated disease; however, EA IgG does not play a significant role in the differential diagnosis of EBV infection in immunocompetent individuals.
early antigen; Epstein–Barr virus; infectious mononucleosis; liver transplant
The trans-activator Tat protein is a viral regulatory protein essential for HIV-1 replication. Tat trafficks to the nucleoplasm and the nucleolus. The nucleolus, a highly dynamic and structured membrane-less sub-nuclear compartment, is the site of rRNA and ribosome biogenesis and is involved in numerous cellular functions including transcriptional regulation, cell cycle control and viral infection. Importantly, transient nucleolar trafficking of both Tat and HIV-1 viral transcripts are critical in HIV-1 replication, however, the role(s) of the nucleolus in HIV-1 replication remains unclear. To better understand how the interaction of Tat with the nucleolar machinery contributes to HIV-1 pathogenesis, we investigated the quantitative changes in the composition of the nucleolar proteome of Jurkat T-cells stably expressing HIV-1 Tat fused to a TAP tag. Using an organellar proteomic approach based on mass spectrometry, coupled with Stable Isotope Labelling in Cell culture (SILAC), we quantified 520 proteins, including 49 proteins showing significant changes in abundance in Jurkat T-cell nucleolus upon Tat expression. Numerous proteins exhibiting a fold change were well characterised Tat interactors and/or known to be critical for HIV-1 replication. This suggests that the spatial control and subcellular compartimentaliation of these cellular cofactors by Tat provide an additional layer of control for regulating cellular machinery involved in HIV-1 pathogenesis. Pathway analysis and network reconstruction revealed that Tat expression specifically resulted in the nucleolar enrichment of proteins collectively participating in ribosomal biogenesis, protein homeostasis, metabolic pathways including glycolytic, pentose phosphate, nucleotides and amino acids biosynthetic pathways, stress response, T-cell signaling pathways and genome integrity. We present here the first differential profiling of the nucleolar proteome of T-cells expressing HIV-1 Tat. We discuss how these proteins collectively participate in interconnected networks converging to adapt the nucleolus dynamic activities, which favor host biosynthetic activities and may contribute to create a cellular environment supporting robust HIV-1 production.
Hepatitis C virus (HCV) is a genetically diverse pathogen infecting approximately 2–3% of the world's population. Herein, we describe results of a large, multicentre serological and molecular epidemiological study cataloguing the prevalence and genetic diversity of HCV in five regions of Vietnam; Ha Noi, Hai Phong, Da Nang, Khanh Hoa and Can Tho. Individuals (n = 8654) with varying risk factors for infection were analysed for the presence of HCV Ab/Ag and, in a subset of positive specimens, for HCV RNA levels (n = 475) and genotype (n = 282). In lower risk individuals, including voluntary blood donors, military recruits and pregnant women, the prevalence of infection was 0.5% (n = 26/5250). Prevalence rates were significantly higher (p<0.001) in intravenous drug users (IDUs; 55.6%, n = 556/1000), dialysis patients (26.6%, n = 153/575) commercial sex workers (CSWs; 8.7%, n = 87/1000), and recipients of multiple blood transfusions (6.0%, n = 32/529). The prevalence of HCV in dialysis patients varied but remained high in all regions (11–43%) and was associated with the receipt of blood transfusions [OR: 2.08 (1.85–2.34), p = 0.001], time from first transfusion [OR: 1.07 (1.01–1.13), p = 0.023], duration of dialysis [OR: 1.31 (1.19–1.43), p<0.001] and male gender [OR: 1.60 (1.06–2.41), p = 0.026]. Phylogenetic analysis revealed high genetic diversity, particularly amongst dialysis and multi-transfused patients, identifying subtypes 1a (33%), 1b (27%), 2a (0.4%), 3a (0.7%), 3b (1.1%), 6a (18.8%), 6e (6.0%), 6h (4.6%), 6l (6.4%) and 2 clusters of novel genotype 6 variants (2.1%). HCV genotype 1 predominated in Vietnam (60%, n = 169/282) but the proportion of infections attributable to genotype 1 varied between regions and risk groups and, in the Southern part of Vietnam, genotype 6 viruses dominated in dialysis and multi-transfused patients (73.9%). This study confirms a high prevalence of HCV infection in Vietnamese IDUs and, notably, reveals high levels of HCV infection associated with dialysis and blood transfusion.
Recombination in Hepatitis C virus (HCV) is considered to be rare. In this study, we performed a phylogenetic analysis of 1278 full-length HCV genome sequences to identify potential recombination events. Nine inter-genotype recombinants were identified, all of which have been previously reported. This confirms the rarity of inter-genotype HCV recombinants. The analysis also identified five inter-subtype recombinants, four of which are documented for the first time (EU246930, EU246931, EU246932, and EU246937). Specifically, the latter represent four different novel recombination types (6a/6o, 6e/6o, 6e/6h, and 6n/6o), and this was well supported by seven independent methods embedded in RDP. The breakpoints of the four novel HCV recombinants are located within the NS5B coding region and were different from all previously reported breakpoints. While the locations of the breakpoints identified by RDP were not identical, they are very close. Our study suggests that while recombination in HCV is rare, this warrants further investigation.
Federal, professional and academic efforts are converging to address the preventive care needs of older Americans. Medicare is placing an increased emphasis on preventive care services for older adults. With the passage of the Affordable Care Act, access to preventive services has been enhanced by reducing out of pocket costs for older adults, and increasing reimbursement to health care providers. In 2010-2011 newly revised guidelines for Screening and Preventive Services have been issued by the United States Preventive Services Task Force (USPSTF) and the Centers for Disease Control and Prevention (CDC). In addition to these guidelines and the landmark changes in Medicare coverage, there are significant new attempts to modify national screening recommendations based on age and expected risk/benefit for older adults. These population-specific guidelines with new emphasis on functional status and multiple risk factor reduction are of increasing importance to an aging population where more conventional disease-focused guidelines are less suitable for maintaining physical function and quality of life. Evidence-based measures of physical performance appropriate for primary care office use are being developed and piloted. As a result of these policies, guidelines and tools, we have the ability to offer older adults more comprehensive, cost-effective screening and preventive measures than in any other previous time.
Screening; preventive services; older adults; Affordable Care Act; Medicare; USPSTF; ACOVE; gait speed
The optimal initial local treatment for patients with Graves’ ophthalmopathy (GO) is not fully characterized. The purpose of this retrospective study is to describe the clinical outcomes of RT as initial local therapy for GO and define predictors of the need for post-RT salvage bony decompressive surgery.
91 patients with active GO and without prior surgery were treated with RT as initial local therapy between 01/1999 and 12/2010, with a median follow-up period of 18.3 months (range 3.7 - 142 months). RT dose was 24 Gy in 12 fractions. 44 patients (48.4%) had prior use of steroids, with 31 (34.1%) being on steroids at the initiation of RT. The most common presenting symptoms were diplopia (79%), proptosis (71%) and soft tissue signs (62%).
84 patients (92.3%) experienced stabilization or improvement of GO symptoms. 58 patients (64%) experienced improvement in their symptoms. 19 patients (20.9%) underwent salvage post-RT bony decompressive surgery. Smoking status and total symptom score at 4 months were independent predictors of post-RT bony decompression with odds ratios of 3.23 (95% CI 1.03 – 10.2) and 1.59 (95% CI 1.06 – 2.4), respectively. Persistent objective vision loss at 4 months post-RT was the most important symptom type in predicting salvage decompression. Chronic dry eye occurred in 9 patients (9.9%) and cataracts developed in 4 patients (4.4%).
RT is effective and well tolerated as initial local therapy for active GO, with only 21% of patients requiring decompressive surgery post RT. Most patients experience stabilization or improvement of GO symptoms, but moderate to significant response occurs in the minority of patients. Smoking status and total symptom severity at 4 months, primarily persistent objective vision loss, are the primary determinants of the need for post-RT salvage bony decompression. Patients who smoke or present with predominantly vision loss symptoms should be advised as to their lower likelihood of symptomatic response to RT and their increased likelihood of requiring post-RT decompressive surgery.
Radiation therapy; Graves’ disease; Orbital radiation; Graves’ ophthalmopathy; Graves’ orbitopathy
Hepatitis B (HBV) infection is endemic in Viet Nam, with up to 8.4 million individuals estimated to be chronically infected. We describe results of a large, multicentre seroepidemiological and molecular study of the prevalence of HBV infection and blood-borne viral coinfections in Viet Nam. Individuals with varying risk factors for infection (n = 8654) were recruited from five centres; Ha Noi, Hai Phong, Da Nang, Khanh Hoa and Can Tho. A mean prevalence rate of 10.7% was observed and levels of HBsAg were significantly higher in injecting drug users (IDUs) (17.4%, n = 174/1000) and dialysis patients (14.3%, n = 82/575) than in lower-risk groups (9.4%; p<0.001). Coinfection with HIV was seen in 28% of HBV-infected IDUs (n = 49/174) and 15.2% of commercial sex workers (CSWs; n = 15/99). HCV infection was present in 89.8% of the HBV-HIV coinfected IDUs (n = 44/49) and 40% of HBV-HIV coinfected CSWs (n = 16/40). Anti-HDV was detected in 10.7% (n = 34/318) of HBsAg positive individuals. Phylogenetic analysis of HBV S gene (n = 187) showed a predominance of genotype B4 (82.6%); genotypes C1 (14.6%), B2 (2.7%) and C5 (0.5%) were also identified. The precore mutation G1896A was identified in 35% of all specimens, and was more frequently observed in genotype B (41%) than genotype C (3%; p<0.0001). In the immunodominant ‘a’ region of the surface gene, point mutations were identified in 31% (n = 58/187) of sequences, and 2.2% (n = 4/187) and 5.3% (n = 10/187) specimens contained the major vaccine escape mutations G145A/R and P120L/Q/S/T, respectively. 368 HBsAg positive individuals were genotyped for the IL28B SNP rs12979860 and no significant association between the IL28B SNP and clearance of HBsAg, HBV viral load or HBeAg was observed. This study confirms the high prevalence of HBV infection in Viet Nam and also highlights the significant levels of blood-borne virus coinfections, which have important implications for hepatitis-related morbidity and development of effective management strategies.
To identify whether a history of cancer is associated with specific geriatric syndromes in older patients.
Patients and Methods
Using the 2003 Medicare Current Beneficiary Survey, we analyzed a national sample of 12,480 community-based elders. Differences in prevalence of geriatric syndromes between those with and without cancer were estimated. Multivariable logistic regressions were used to evaluate whether cancer was independently associated with geriatric syndromes.
Two thousand three hundred forty-nine (18%) reported a history of cancer. Among those with cancer, 60.3% reported one or more geriatric syndromes as compared with 53.2% of those without cancer (P < .001). Those with cancer overall had a statistically significantly higher prevalence of hearing trouble, urinary incontinence, falls, depression, and osteoporosis than those without cancer. Adjusting for possible confounders, those with a history of cancer were more likely to experience depression (adjusted odds ratio [OR], 1.15; 95% CI, 1.02 to 1.30; P = .023), falls (adjusted OR, 1.17; 95% CI, 1.04 to 1.32; P = .010), osteoporosis (adjusted OR, 1.21; 95% CI, 1.06 to 1.38; P = .004), hearing trouble (adjusted OR, 1.28; 95% CI, 1.08 to 1.52; P = .005), and urinary incontinence (adjusted OR, 1.42; 95% CI, 1.20 to 1.69; P < .001). Analysis of specific cancer subtypes showed that lung cancer was associated with vision, hearing, and eating trouble; prostate cancer was associated with incontinence and falls; cervical/uterine cancer was associated with falls and osteoporosis; and colon cancer was associated with depression and osteoporosis.
Elderly patients with cancer experience a higher prevalence of geriatric syndromes than those without cancer. Prospective studies that establish the causal relationships between cancer and geriatric syndromes are necessary.
Attenuation of visual activity in the superficial layers (SL) of the superior colliculus during saccades may contribute to reducing perceptual blur during saccades and also may help prevent subsequent unwanted saccades. GABAergic neurons in the intermediate, premotor, layer (SGI) send an inhibitory input to SL. This pathway provided the basis for a model proposing that the SGI premotor cells that project to brainstem gaze centers and discharge before saccades also activate neighboring GABAergic neurons that suppress saccade induced visual activity in SL.
The in vitro method allowed us to test this model. We made whole-cell patch clamp recordings in collicular slices from either rats or GAD67-GFP knock-in mice, in which GABAergic neurons could be identified by their expression of green fluorescence protein (GFP). Antidromic electrical stimulation of SGI premotor cells was produced by applying pulse currents where their axons congregate after exiting the superior colliculus. The stimulation evoked monosynaptic excitatory postsynaptic currents (EPSCs) in SGI GABAergic neurons that project to SL, as would be predicted if these neurons receive excitatory input from the premotor cells. Second, inhibitory postsynaptic currents (IPSCs) were evoked in SL neurons, some of which project to the visual thalamus. These IPSCs were polysynaptically mediated by the GABAergic neurons that were excited by the antidromically activated SGI neurons. These results support the hypothesis that collaterals of premotor neuron axons excite GABAergic neurons that inhibit SL visuosensory cells.
visuomotor integration; inhibitory feedback; in vitro slices; mice; rats
Hepatitis C virus (HCV) is capable of disrupting different facets of lipid metabolism and lipids have been shown to play a crucial role in the viral life cycle. The aim of this study was to examine the effect HCV infection has on the hepatocyte metabolome. Huh-7.5 cells were infected using virus produced by the HCV J6/JFH1 cell culture system and cells were harvested 24, 48, and 72-hours following infection. Metabolic profiling was performed using a non-targeted multiple platform methodology combining ultrahigh performance liquid chromatography/tandem mass spectrometry (UHPLC/MS/MS2) and gas chromatography/mass spectrometry (GC/MS). There was a significant increase in a number of metabolites involved in nucleotide synthesis and RNA replication during early HCV infection. NAD levels were also significantly increased along with several amino acids. A number of lipid metabolic pathways were disrupted by HCV infection, resulting in an increase in cholesterol and sphingolipid levels, altered phospholipid metabolism and a possible disruption in mitochondrial fatty acid transport. Fluctuations in 5′-methylthioadenosine levels were also noted, along with alterations in the glutathione synthesis pathway. These results highlight a number of previously unreported metabolic interactions and give a more in depth insight into the effect HCV has on host cell biochemical processes.
Adenovirus serotype 14; HAdV-14p1; molecular epidemiology; phylogenetics; restriction enzyme analysis; immunocompromised; immunocompetent; ARD; fatalities; viruses; Europe; research
Spinal metastasis is a problem that afflicts many cancer patients. Traditionally, conventional fractionated radiation therapy and/or surgery have been the most common approaches for managing such patients. Through technical advances in radiotherapy, high dose radiation with extremely steep drop off can now be delivered to a limited target volume along the spine under image-guidance with very high precision. This procedure, known as stereotactic body radiosurgery, provides a technique to rapidly treat selected spinal metastasis patients with single- or limited-fraction treatments that have similar to superior efficacies compared with more established approaches. This review describes current treatment systems in use to deliver stereotactic body radiosurgery as well as results of some of the larger case series from a number of institutions that report outcomes of patients treated for spinal metastatic disease. These series include nearly 1400 patients and report a cumulative local control rate of 90% with myelopathy risk that is significantly less than 1%. Based on this comprehensive review of the literature, we believe that stereotactic body radiosurgery is an established treatment modality for patients with spinal metastatic disease that is both safe and highly effective.
Treatment with a combination of interferon-α and arsenic trioxide ablates leukemia-initiating activity before reducing primary tumor bulk in a murine model of adult T cell leukemia.
Chronic HTLV-I (human T cell lymphotropic virus type I) infection may cause adult T cell leukemia/lymphoma (ATL), a disease with dismal long-term prognosis. The HTLV-I transactivator, Tax, initiates ATL in transgenic mice. In this study, we demonstrate that an As2O3 and IFN-α combination, known to trigger Tax proteolysis, cures Tax-driven ATL in mice. Unexpectedly, this combination therapy abrogated initial leukemia engraftment into secondary recipients, whereas the primary tumor bulk still grew in the primary hosts, only to ultimately abate later on. This loss of initial transplantability required proteasome function. A similar regimen recently yielded unprecedented disease control in human ATL. Our demonstration that this drug combination targeting Tax stability abrogates tumor cell immortality but not short-term growth may foretell a favorable long-term efficiency of this regimen in patients.
Human cytomegalovirus (HCMV) strains may be genotyped based on polymorphisms that exist within the UL144 gene, which is one of 19 viral genes lost in attenuated laboratory strains. In the present study, UL144 genotypes in congenitally infected babies (congenital cytomegalovirus [cCMV]) were determined, and the relationship between the genotype, viral load, cytokine profile, and patient developmental outcome was investigated. All cCMV infections identified during 2006 and 2007 were included (n = 29). A portion of the infants were clinically assessed at birth and at 12 to 18 months postinfection for cCMV clinical sequelae (n = 18/29). The plasma viral load (PVL) was requested for 23/29 patients, and the UL144 genotype was determined (n = 27/29). The cytokine profile in patient plasma or serum was assessed (n = 20/29). UL144 genotypes A, B, and C were detected within the cCMV population at 33.3%, 29.6%, and 25.9%, respectively. UL144 A and C were associated with a high PVL (P < 0.04). Furthermore, a significant association between the developmental outcome and UL144 A and C was observed (P < 0.04). Only patients infected with UL144 B and A/B were described as having a normal clinical outcome. In addition, a significant correlation between interleukin 10 (IL-10) levels and the PVL was observed (P < 0.04); however, there was no association between the genotype and the cytokine profile. The present study determined that the specific detection of UL144 genotypes A and C was indicative of serious cCMV infection and more likely to lead to long-term cCMV-associated clinical manifestations. The inclusion of HCMV UL144 genotyping along with the recommended PVL monitoring following cCMV diagnosis may aid prediction of the clinical outcome.
Prostate cancer is the most common malignancy in older men. With the aging of the population, the number of older men with prostate cancer will grow rapidly. Androgen deprivation therapy (ADT) is the mainstay of treatment for men with systemic disease and is increasingly utilized as primary therapy or in combination with other therapies for localized disease. Side effects of therapy are multifold and include hot flashes, osteoporosis, and adverse psychological and metabolic effects. Recent research has illustrated that ADT can negatively impact the functional, cognitive, and physical performance of older men. Patients with prostate cancer, despite recurrence of the disease, have a long life expectancy and may be subjected to the side effects of ADT for many years. This review highlights the complications of ADT and approaches to management. We also provide recommendations for assessment and management of ADT complications among the most vulnerable and frail older male patients.
Disability; Geriatric assessment; Prostate cancer; Vulnerable elders; Functional impairment; Androgen deprivation; Quality of life; Complications
The HIV-1 regulatory protein Rev, which is essential for viral replication, mediates the nuclear export of unspliced viral transcripts. Rev nuclear function requires active nucleocytoplasmic shuttling, and Rev nuclear import is mediated by the recognition of its Nuclear Localisation Signal (NLS) by multiple import factors, which include transportin and importin β. However, it remains unclear which nuclear import pathway(s) predominate in vivo, and the cellular environment that modulates Rev nucleocytoplasmic shuttling remains to be characterised.
In our study, we have identified the cellular protein HIC (Human I-mfa domain-Containing protein) as a novel interactor of HIV-1 Rev. We demonstrate that HIC selectively interferes with Rev NLS interaction with importin β and impedes its nuclear import and function, but does not affect Rev nuclear import mediated by transportin. Hence, the molecular determinants mediating Rev-NLS recognition by importin β and transportin appear to be distinct. Furthermore, we have employed HIC and M9 M, a peptide specifically designed to inhibit the transportin-mediated nuclear import pathway, to characterise Rev nuclear import pathways within different cellular environments. Remarkably, we could show that in 293T, HeLa, COS7, Jurkat, U937, THP-1 and CEM cells, Rev nuclear import is cell type specific and alternatively mediated by transportin or importin β, in a mutually exclusive fashion.
Rev cytoplasmic sequestration by HIC may represent a novel mechanism for the control of Rev function. These studies highlight that the multivalent nature of the Rev NLS for different import receptors enables Rev to adapt its nuclear trafficking strategy.