Human T-cell Lymphotrophic Virus Research Articles

Hypergammaglobulinemia and Corneal Opacities in Patients with Human T-Cell Lymphotrophic Virus Type–1

To investigate the relationship between serum immunoglobulin levels and corneal opacities in a cohort of patients with human T-cell lymphotrophic virus type-1 (HTLV-1). Retrospective case series. Complete ophthalmologic examination was performed on 44 patients with HTLV-1 infection (25 patients with adult T-cell leukemia/lymphoma [ATL], 18 patients with HTLV-1 that was associated myelopathy/tropical spastic paraparesis [HAM/TSP], and one patient who was asymptomatic). Corneal opacities were described by shape, size, color, and location. Serum immunoglobulin (Ig) levels (IgG, IgM, and IgA) were measured by nephelometry. Corneal opacities were identified in 15 of 25 patients (60%) with ATL and five of 18 patients (28%) with HAM/TSP. The prevalence of corneal opacities was associated statistically with elevated IgG level (P = .023) in patients with ATL, but not in patients with HAM/TSP (P > .99). Although the mechanism remains unclear, hypergammaglobulinemia is associated with the development of the corneal opacities in patients of African descent with ATL.

Seroprevalence of sexually transmitted infections among accepted and deferred blood donors in Jamaica

Critical donor selection and testing increases the safety of blood transfusion by excluding donors at risk of transmitting infections. This study investigated the seroprevalence of and risk factors for sexually transmitted infections (STIs) among accepted and deferred blood donors in Jamaica. A total of 1015 blood donors consisting of 794 (78%) accepted donors and 221 (22%) deferred donors presenting at the Central Blood Bank, Jamaica, over a six-month period, were recruited for this study. A standardized questionnaire was administered to each participant and a sample of blood obtained for detection of hepatitis B surface antigen, antibodies to Treponema pallidum, human immunodeficiency virus (HIV) and human T-cell lymphotrophic virus type-1 (HTLV-1). Deferred donors were three times more likely to be seropositive for STI than accepted donors (16.3% vs 5.2%, OR 3.57, 95% CI 2.16 - 5.90, p < 0.0001). Males had significant association between STI seropositivity and having fathered children with two or more women (p = 0.0085), unprotected sexual intercourse with several persons (p = 0.0326), and history of genital herpes (p = 0.0121). Significant risk factors identified among females were unprotected sex with several partners (p = 0.0385); having more than ten lifetime partners (p = 0.0105); and use of depoprovera (p = 0.0028). This study confirms higher rates of STI among deferred blood donors and supports the donor deferral system in Jamaica.

Development of a quantitative cell-based ELISA, for a humanized anti-IL-2/IL-15 receptor β antibody (HuMikβ 1), and correlation with functional activity using an antigen-transfected murine cell line

The HuMikβ 1, a humanized IgG1 monoclonal antibody directed toward the IL-2/IL-15 receptor β-chain (CD122), inhibits the actions of the inflammatory cytokine IL-15, and may be useful for immunotherapy of an array of autoimmune disorders as well as diseases associated with the retrovirus human T-cell lymphotrophic virus 1 (HTLV-1). In order to facilitate the production of material for clinical investigation, we developed a cell-based ELISA (CbELISA) for measuring the binding activity, as a potential biological activity marker, of the HuMikβ 1 monoclonal antibody to a transfected 32D mouse cell line (32Dβ) expressing IL-2Rβ antigen on the cell surface. There is specific binding of HuMikβ 1 to the transfected cell line, titrating out in the concentration range of 1–1000 ng/ml. Under identical conditions, there was no binding of HuMikβ 1 to the parent cell line 32D. Satisfactory binding curves with HuMikβ 1 were obtained with 32Dβ cells grown between 3 and 19 passages in culture and at seed densities of 2 × 10 5–4 × 10 6 cells/well. The binding was specific for Mikβ antibodies recognizing the IL-2/IL-15 receptor β subunit as demonstrated by binding of HuMikβ 1, Mikβ 2 and Mikβ 3 antibodies, and lack of binding of irrelevant humanized and chimeric antibodies and isotype-matched human IgG1 to the 32Dβ cell. Also, the human IgG1 and irrelevant humanized and chimeric antibodies did not interfere with the HuMikβ 1 binding. The assay could detect changes in binding activity of HuMikβ 1 antibody under stressful conditions (heat and low pH) and the results paralleled the effect of stress on the physicochemical characteristics. More importantly, the binding activity shows an apparent correlation to inhibition of IL-15-induced proliferation of 32Dβ cells with HuMikβ 1. In conclusion, the cell-based ELISA method represents a simple, reproducible accurate quantitative assay for monitoring HuMikβ 1 activity and could be used as a potency marker assay for monitoring the lot–lot consistency and functional stability of HuMikβ 1 product.

Snare-Assisted Trans-Brachial Stenting for the Cervical Internal Carotid Artery Stenosis of Patient with Aorto-Iliac Occlusion

We describe a case of endo-luminal stent placement with Snare-assist for a cervical internal carotid artery stenosis in which percutaneous access was obtained via the brachial artery. A 68-year-old man with known disease of the carotid, peripheral, and coronary arteries, with Human T-cell Lymphotrophic Virus type-1 (HTLV-1) Associated Myelopathy (HAM) presented for endoluminal revascularization of a severe, progressive right internal carotid artery stenosis, but with aorto-iliac occlusion. Transfemoral access was complicated by an aorto-iliac occlusion. A trans-brachial approach was successfully attempted, and a SMARTer stent (Cordis Endovascular, Miami Lakes, FL) was successfully placed through a 7-French Shuttle-SL guide sheath (Cook, Bloomington) under Snare-assist. The trans-brachial approach is becoming an increasingly viable alternative route for stent placement in patients with contra-indicated or complicated femoral access routes. As devices become increasingly more pliable and smaller, the trans-brachial route will be used with increasing frequency in the select patient population for stenting of both the cervical and intracranial circulation.

ALS syndrome in HTLV-I infection

Human T-cell lymphotrophic virus (HTLV)-I causes tropical spastic paraparesis/HTLV-I associated myelopathy (HAM/TSP) and may have other neurologic manifestations such as isolated peripheral neuropathy.1 An HTLV-I-associated ALS-like syndrome (ALS-S) has been rarely reported.2 We now describe the features of ALS-S in a cohort of HTLV-I infected individuals. From May 1992 to September 2004, 606 HTLV-I infected individuals who fulfilled international criteria for serologic positivity at both ELISA and Western blot tests were admitted to our institution. The clinical diagnosis of HAM/TSP was based on World Health Organization guidelines,3 which basically define it as a chronic, slowly progressive spastic paraparesis, with bladder disturbances, sensory symptoms, and low back pain. EMG of at least three limbs and nerve conduction studies were performed. Diagnosis of ALS-S was made by El Escorial criteria.4 Informed consent was obtained from all individuals. Of 606 infected individuals, 259 had some neurologic abnormality; 169 had HAM/TSP (65.2%) and 90 (34.7%) had other neurologic abnormalities. Five patients …

Phase I/II Combined Chemoimmunotherapy with Carcinoembryonic Antigen–Derived HLA-A2–Restricted CAP-1 Peptide and Irinotecan, 5-Fluorouracil, and Leucovorin in Patients with Primary Metastatic Colorectal Cancer

We conducted a phase I/II randomized trial to evaluate the clinical and immunologic effect of chemotherapy combined with vaccination in primary metastatic colorectal cancer patients with a carcinoembryonic antigen-derived peptide in the setting of adjuvants granulocyte macrophage colony-stimulating factor, CpG-containing DNA molecules (dSLIM), and dendritic cells. HLA-A2-positive patients with confirmed newly diagnosed metastatic colorectal cancer and elevated serum carcinoembryonic antigen (CEA) were randomized to receive three cycles of standard chemotherapy (irinotecan/high-dose 5-fluorouracil/leucovorin) and vaccinations with CEA-derived CAP-1 peptide admixed with different adjuvants [CAP-1/granulocyte macrophage colony-stimulating factor/interleukin-2 (IL-2), CAP-1/dSLIM/IL-2, and CAP-1/IL-2]. After completion of chemotherapy, patients received weekly vaccinations until progression of disease. Immune assessment was done at baseline and after three cycles of combined chemoimmunotherapy. HLA-A2 tetramers complexed with the peptides CAP-1, human T-cell lymphotrophic virus type I TAX, cytomegalovirus (CMV) pp65, and EBV BMLF-1 were used for phenotypic immune assessment. IFN-gamma intracellular cytokine assays were done to evaluate CTL reactivity. Seventeen metastatic patients were recruited, of whom 12 completed three cycles. Therapy resulted in five complete response, one partial response, five stable disease, and six progressive disease. Six grade 1 local skin reactions and one mild systemic reaction to vaccination treatment were observed. Overall survival after a median observation time of 29 months was 17 months with a survival rate of 35% (6 of 17) at that time. Eight patients (47%) showed elevation of CAP-1-specific CTLs. Neither of the adjuvants provided superiority in eliciting CAP-1-specific immune responses. During three cycles of chemotherapy, EBV/CMV recall antigen-specific CD8+ cells decreased by an average 14%. The presented chemoimmunotherapy is a feasible and safe combination therapy with clinical and immunologic efficacy. Despite concurrent chemotherapy, increases in CAP-1-specific T cells were observed in 47% of patients after vaccination.

Functional Solubilization of Aggregation-prone HIV Envelope Proteins by Covalent Fusion with Chaperone Modules

The envelope proteins of human immunodeficiency virus (HIV) and human T-cell lymphotrophic virus (HTLV) mediate cell attachment and membrane fusion. For HIV-1, the precursor protein gp160 is cleaved proteolytically into two fragments, the surface-associated receptor binding subunit gp120 and the membrane spanning subunit gp41, which is involved in membrane fusion during virus entry. Soluble and immunoreactive variants of gp41 are essential for the reliable diagnosis of HIV-1 infections. Hitherto, gp41 was solubilized by adding detergents, or in acidic or alkaline solvents. We find that covalent fusions with SlyD or FkpA, two homodimeric Escherichia coli chaperones with peptidyl-prolyl isomerase activity, solubilize retroviral envelope proteins without compromising their immunological reactivity. gp41 from HIV-1, gp36 from HIV-2 and gp21 from HTLV could be expressed in large amounts in the Escherichia coli cytosol when fused with one or two subunits of SlyD or FkpA. The fusion proteins could be easily isolated and refolded, and showed high solubility and immunoreactivity, thus providing sensitive and reliable tools for diagnostic applications. Covalent fusions with SlyD or FkpA might be valuable generic tools for the solubilization and activation of aggregation-prone proteins.

HTLV-I Tax induces a novel interaction between p65/RelA and p53 that results in inhibition of p53 transcriptional activity

AbstractNuclear factor κB (NF-κB) activation plays a critical role in oncogenesis by human T-cell lymphotrophic virus type I (HTLV-I), the etiologic agent of adult T-cell leukemia (ATL), and is indispensable for maintenance of the malignant phenotype. In T lymphocytes, Tax-mediated p53 inhibition is dependent on Tax activation of the NF-κB pathway and is linked to p53 phosphorylation. We now report that blocking NF-κB transcriptional activation in HTLV-I–transformed cells restores p53 activity. Further, using mouse embryo fibroblast (MEF) null cells and antisense oligonucleotides to inhibit expression of NF-κB family members, we demonstrate that the p65 subunit of NF-κB is uniquely involved in p53 inhibition. Coimmunoprecipitation assays demonstrate an interaction between p65 and p53 in HTLV-I–transformed cells. In transient transfection assays, we demonstrate that Tax induces the p53-p65 interaction. Phosphorylation of p53 at serines 15 and 392 is critical for complex formation. Importantly, Tax-mediated p53 inhibition correlates with p65 and p53 interaction. By using chromatin immunoprecipitation (ChIP) assays, we find that in HTLV-I–transformed cells p53 and p65 form a complex on the inactive, p53-responsive murine double minute 2 (MDM2) promoter. Consistent with reduced transcriptional activity, transcription factor IID (TFIID) binding is not observed. These studies identify a unique mechanism for p53 regulation by the p65/RelA subunit of NF-κB.

Serologic Assessment of Type 1 and Type 2 Immunity in Healthy Japanese Adults

Abstract We assessed the informativeness of several serologic biomarkers of immune function using serum specimens collected in the Miyazaki Cohort Study from subjects who were seronegative for anti–human T-cell lymphotrophic virus I and anti–hepatitis C virus. To broadly characterize type 1 immune status, we measured EBV antibody titers, because titer profiles associated with cellular immune suppression are well described. We also tested for three type 2 biomarkers: total serum IgE, soluble CD23, and soluble CD30. Nonreactivity to a tuberculin purified protein derivative (PPD) skin test is indicative of diminished delayed-type hypersensitivity (type 1) responsiveness in the study population due to a history of tuberculosis exposure or Bacillus Calmette-Guérin vaccination. We therefore evaluated the serologic markers as predictors of PPD nonreactivity using logistic regression. Subjects whose EBV antibody profiles were consistent with deficient type 1 immunity were more than thrice as likely to be PPD nonreactive as persons with “normal” antibody titers. Elevated total IgE was also strongly associated with PPD nonreactivity (odds ratio 3.4, 95% confidence interval 1.2-9.9); elevated soluble CD23 had a weaker, but positive, odds ratio, whereas soluble CD30 levels were not predictive of PPD status. Therefore, PPD nonreactivity is associated, in this population, with a pattern of serum biomarkers that is indicative of diminished type 1 and elevated type 2 immunity. We conclude that, with the exception of soluble CD30, the serologic markers are informative for the characterization of type 1/type 2 immune status using archived sera from study populations of healthy adults.

RETRACTED: Inhibition of proliferation and induction of apoptosis by 2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide in adult T-cell leukemia cells

Human T-cell lymphotrophic virus type-1 (HTLV-1) is a retrovirus which causes adult T-cell leukemia (ATL), an aggressive malignancy of activated T-cells. So far, there is no proven therapy for this disease. The compound 2-benzoyl-3-phenyl-6,7-dichloro quinoxaline 1,4-dioxide (DCQ) has been shown to exhibit a wide range of antibacterial activities and to induce antiproliferation and apoptosis of human colon cancer cell lines. In the present study, we investigated the in vitro effects of DCQ in HTLV-1 positive (C91-PL and HuT-102) and negative (CEM and Jurkat) malignant T-cells. The results indicate that DCQ induced growth inhibition in all four cell lines examined in a dose-dependent manner. The inhibitory effect was mainly due to the induction of apoptosis which was verified by flow cytometry analyses and ELISA-based apoptosis assays. The role of transforming growth factor (TGF) in mediating the antiproliferative and apoptotic effects of DCQ in ATL cells was investigated. Interestingly, in three of the four cell lines used, DCQ increased the TGF-beta1 transcript levels and decreased TGF-alpha mRNA, but did not induce changes in TGF-beta2 expression. DCQ treatment also induced an upregulation of p53 and p21 protein levels, key mediators of cell cycle arrest and apoptosis. The anti-apoptotic Bcl-2alpha protein level was found to be reduced. These findings indicate that DCQ inhibits the growth of ATL cell lines, at least in part, by inducing apoptosis mediated by the modulation of TGF expression, the upregulation in p53 and p21 proteins and downregulation in Bcl-2alpha expression. The present findings suggest that DCQ merits further investigation as a potential therapeutic agent for this incurable disease.

Natural course of voiding function in patients with human T-cell lymphotrophic virus type 1-associated myelopathy

Objectives: Patients with human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) frequently experience voiding dysfunction. In patients with HAM/TSP, the major symptoms are gait disturbance and voiding dysfunction. However, the detailed natural course of voiding function and the management of their urination has not previously been investigated. We examined the correlation between voiding function and clinical features and evaluated the management of urination, in the patients with HAM/TSP. Patients and Methods: The voiding function of 47 patients (7 males, 40 females, aged 29–89 years, mean: 60.9 years) with HAM/TSP was analyzed retrospectively. All HAM/TSP patients are positive for HTLV-1. Patients were referred to a neurologist for analysis of bladder function. In the present study, we analyzed their clinical details, age at disease onset, voiding function and alterations in the management of their urination. Furthermore, we investigated the relationship between urological management and the clinical features of HAM/TSP. Results: Of the 47 patients, 20 (42.5%) were able to void with or without drug therapy. Thirty-four (72.3%) experienced clean intermittent self-catheterization (CIC), with 25 of these 34 continuing CIC, 7 changing to voiding and 2 changing to management with the Foley catheter. No relationship was noted between disruption of voiding function and either age or gender. However, significant inverse correlation was observed between the age at disease onset and the time to CIC ( r=−0.77, P=0.00001). Conclusions: These data suggest that the younger a patients is at HAM/TSP onset, the longer voiding function will be maintained.

Chlamydia trachomatis, herpes simplex virus 2, and human T-cell lymphotrophic virus type 1 are not associated with grade of cervical neoplasia in Jamaican colposcopy patients.

A few recent studies have suggested that other sexually transmitted infections may increase the likelihood of a human papillomavirus (HPV) infection progressing to high-grade cervical neoplasia and cancer. The goal was to assess whether exposures to Chlamydia trachomatis, human T-cell lymphotrophic virus type 1 (HTLV-I), and/or human simplex virus type 2 (HSV-2) are greater in colposcopy patients with cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) than in patients with low-grade cervical neoplasia (CIN1). Sequential patients (n=447) attending a colposcopy clinic in Kingston, Jamaica, a country with high cervical cancer rates and high HTLV-I prevalence, were tested for (1) HPV DNA by L1 consensus primer (MY09/11) polymerase chain reaction assays, (2) C trachomatis DNA by ligase chain reaction, (3) C trachomatis antibodies by both microimmunofluorescence and a peptide (VS4) enzyme linked immunosorbent assay (ELISA), (4) HTLV-I antibodies by ELISA confirmed by western blotting, and (5) HSV-2 antibodies by a recombinant HSV-2-specific ELISA. Odds ratios and 95% confidence intervals were estimated with use of multinomial logistic regression models. HPV DNA detection was associated with grade of cervical neoplasia but other evaluated sexually transmitted infections were not. HTLV-I, C trachomatis, and/or HSV-2 were not associated with severity of cervical neoplasia in Jamaican women.

Lack of association of Human T-cell lymphotrophic virus type 1(HTLV-1) infection and rheumatoid arthritis in an endemic area.

In South Africa the association of HTLV-1 infection with myelopathy is well described in Kwa Zulu Natal, which is an endemic area for HTLV-1 infection. Japan also has a high background prevalence of HTLV-1 infection, and a significant association of HTLV-1 infection with rheumatoid arthritis has been reported. This study was undertaken to determine whether there was an association with HTLV-1 infection among black Africans with rheumatoid arthritis (RA) in Kwa Zulu Natal, South Africa. A randomly selected group of 110 black people with RA were studied. The age, sex and duration of disease were recorded and a rheumatoid factor test was performed. The presence of antibodies to HTLV-1 was assessed using an enzyme-linked immunosorbent assay. The integration of proviral DNA in peripheral blood monocytes was also studied using the polymerase chain reaction (PCR). Control data were available from a previously reported community-based study of 1018 subjects from the same geographical area. None of the 110 patients studied were positive for HTLV-1 infection by serology or by PCR. Although HTLV-1 infection is reported as a possible triggering agent for RA in Japan, we failed to detect any excess of HTLV-1 infection in black Africans with RA. Our findings are in agreement with observations in the USA and Europe.

Non-HTLV-1-associated primary gastric T-cell lymphomas show cytotoxic activity: clinicopathological, immunohistochemical characteristics and TIA-1 expression in 31 cases.

Most primary gastrointestinal lymphomas are of B-cell origin and T-cell origin is very rare. Recent studies have suggested that human T-cell lymphotrophic virus type 1 (HTLV-1) may be involved in the development of primary gastric T-cell lymphoma. We analysed 31 patients with primary gastric T-cell lymphoma in south-west Japan, an area endemic for HTLV-1, and determined their phenotypes, genotypes, and HTLV-1 status. Here we present 31 cases of primary gastric T-cell lymphoma in a HTLV-1-endemic area in Japan and analyse the clinical status, histology, phenotype and virus status. The median age at onset of primary gastric T-cell lymphoma was 57 years with a gender ratio of M:F = 1.58:1. Six of the 31 primary gastric T-cell lymphoma cases had HTLV-1 proviral DNA (five males, one female), nine of the 31 cases were positive for anti-adult T cell leukaemia antibody, without examination of HTLV-1 proviral DNA (five males, four females), eight were non-HTLV-1-associated primary gastric T-cell lymphoma (four males, four females) and the other eight cases were unknown. Primary gastric T-cell lymphoma usually presented as a large ulcerated tumour at the corpus to the antrum and histologically consisted of anaplastic large cell type (n = 2), pleomorphic large cell type (n = 3), pleomorphic medium and large cell type (n = 14), pleomorphic medium cell type (n = 11), and angioimmunoblastic T-cell lymphoma type (n = 1). There were no clear macroscopic and microscopic differences between HTLV-1-associated and non-HTLV-1-associated primary gastric T-cell lymphoma. Most patients died within 2 years of diagnosis, and both types of primary gastric T-cell lymphoma (with and without HTLV-1) were associated with poor prognosis. Cytotoxic marker analysis showed that HTLV-1-associated lymphomas were negative for TIA-1, while non-HTLV-1-associated lymphomas were positive for TIA-1. Our results suggest that in HTLV-1-endemic areas, patients with HTLV-1-associated primary gastric T-cell lymphoma should be managed carefully and that TIA-1 seems to be useful for identifying the aetiology of this lesion.

Prevalence of blood-borne infectious diseases in blood donors in Ghana.

Transfusion-transmissible infections among 808 blood donors in Ghana were investigated in 1999. Antibody seroprevalences of 3.8, 0.7, 8.4, and 13.5%, respectively, for human immunodeficiency virus, human T-cell lymphotrophic virus type 1, hepatitis C virus (HCV), and Treponema pallidum were obtained. The seroprevalence of HCV infection was confirmed to be 0.9% after supplementary testing, and the transfusion risk potential of these pathogens was demonstrated.

Skin and Soft Tissue Infections in Injection Drug Users.

Skin and soft tissue infections (SSTIs) are common among injection drug users (IDUs). Subcutaneous and intramuscular injection ("skin-popping") and the injection of "speedballs" (a mixture of heroin and cocaine) are important risk factors for SSTIs in this patient population. Female IDUs appear to be at greater risk of SSTIs than male IDUs, probably because of more difficult venous access. There are conflicting data regarding the impact of HIV and human T-cell lymphotrophic virus II infection on the risk of SSTIs in IDUs; however, an expanding body of evidence suggests that immunosuppressive effects of the drugs themselves may play a role. Most information regarding the microbiology of SSTIs in IDUs comes from data on skin and subcutaneous abscesses, where Staphylococcus aureus and organisms that originate from the oral flora predominate. Clonal outbreaks and uncommon infections including tetanus, wound botulism, and a sepsis/myonecrosis syndrome due to Clostridium species have been recently reported in IDUs.

Human T‐Cell Lymphotrophic Virus Infection in Organ Donors: A Need to Reassess Policy?

Human T-cell lymphotrophic virus (HTLV)-I/II infection has been considered a contra-indication to organ donation due to the risk of transmission of infection and the subsequent development of either adult T-cell leukemia or HTLV-I-associated myelopathy. However, neither the incidence of HTLV-I/II infection in organ donors nor the risk of transmission of HTLV-I/II by solid organ transplantation has been defined. Further, it is not known if HTLV infection contributes to significant morbidity in solid organ recipients. The purpose of this study was to evaluate the incidence of HTLV-I/II infection in organ donors in USA and to determine if transplanting these organs resulted in HTLV-related morbidity or mortality. We utilized the UNOS database to: (i) identify organ donors that were positive for HTLV-I or II infection between 1988 and 2000, and (ii) evaluate outcomes in the recipients of these organs. There were 25 HTLV-I/II-positive organ donors reported to UNOS between 1988 and 2000. Based on organ donors with a known HTLV-I/II status, the prevalence of HTLV-I infection in organ donors is 0.027% and the prevalence of HTLV-II is 0.064%. Twenty-two organs were transplanted from these HTLV-positive donors. There have been no reports of HTLV-I/II-related disease in the recipients with a median follow-up of 11.9 months. At our center, over the last 1.5 years there have been four multiorgan donors with false-positive HTLV-I/II screening assays, which resulted in the decision not to use organs from these donors. Based on the minimal chance of HTLV-related disease following transplantation of HTLV-I/II organs in this series, we recommend that careful consideration be given to transplanting organs from HTLV-I/II-positive organ donors.

Regulation of IκB Kinase (IKK)γ/NEMO Function by IKKβ-mediated Phosphorylation

The IkappaB kinase (IKK) complex includes the catalytic components IKKalpha and IKKbeta in addition to the scaffold protein IKKgamma/NEMO. Increases in the activity of the IKK complex result in the phosphorylation and subsequent degradation of IkappaB and the activation of the NF-kappaB pathway. Recent data indicate that the constitutive activation of the NF-kappaB pathway by the human T-cell lymphotrophic virus, type I, Tax protein leads to enhanced phosphorylation of IKKgamma/NEMO by IKKbeta. To address further the significance of IKKbeta-mediated phosphorylation of IKKgamma/NEMO, we determined the sites in IKKgamma/NEMO that were phosphorylated by IKKbeta, and we assayed whether IKKgamma/NEMO phosphorylation was involved in modulating IKKbeta activity. IKKgamma/NEMO is rapidly phosphorylated following treatment of cells with stimuli such as tumor necrosis factor-alpha and interleukin-1 that activate the NF-kappaB pathway. By using both in vitro and in vivo assays, IKKbeta was found to phosphorylate IKKgamma/NEMO predominantly in its carboxyl terminus on serine residue 369 in addition to sites in the central region of this protein. Surprisingly, mutation of these carboxyl-terminal serine residues increased the ability of IKKgamma/NEMO to stimulate IKKbeta kinase activity. These results indicate that the differential phosphorylation of IKKgamma/NEMO by IKKbeta and perhaps other kinases may be important in regulating IKK activity.

A case-control study of risk factors associated with human T-cell lymphotrophic virus type-I seropositivity in blood donors from Guadeloupe, French West Indies.

An age- and gender-specific distribution characterizes human T-cell lymphotrophic virus type-I (HTLV-I) seropositivity in Guadeloupe (French West Indies). Further epidemiological studies are required to identify other possible risk factors associated with this retroviral infection. A nested case-control study was conducted between 1997 and 1999 among blood donors. A total of 102 HTLV-I-positive subjects were matched (at a ratio of 1 : 3) by gender, age (+/-5 years) and donor status (new or regular) to 306 HTLV-I-negative controls. Information was obtained through a questionnaire assessing both environmental and behavioural variables. Factors independently associated with HTLV-I infection included a low level of education [odds ratio (OR) 6.61, confidence interval (CI) 2.89-15.15], black ethnicity (OR 3.28, CI 1.01-10.65), two or more sex partners in the previous 3 years (OR 2.43, CI 1.16-5.10), early age at first sexual intercourse (0.84 risk reduction per additional year, CI 0.76-0.93), a history of sexually transmitted diseases (OR 2.29, CI 1.0-5.34) and positive Chlamydia serology (OR 1.95, CI 1.03-3.68). These data provide a wide spectrum of features associated with HTLV-I seropositivity, especially sexual risk factors. It strongly suggests that heterosexual intercourse is an important route of HTLV-I transmission in Guadeloupe, even among low-risk populations such as blood donors.

The IL-2/IL-15 receptor systems: targets for immunotherapy.

Although interleukin-2 (IL-2) and -15 (IL-15) share two receptor subunits and many functions, at times they provide contrasting contributions to T-cell-mediated immune responses. IL-2, through its pivitol role in activation-induced cell death (AICD), is involved in peripheral tolerance through the elimination of self-reactive T cells. In contrast, in general IL-15 manifests antiapoptotic actions and inhibits IL-2-mediated AICD. IL-15 stimulates persistence of memory phenotype CD8+ T cells, whereas IL-2 inhibits their expression. Humanized monoclonal antibodies that recognize IL-2Ra, the private receptor for IL-2, are being employed to inhibit allograft rejection and to treat T-cell leukemia/lymphoma. Therapies directed toward inhibiting the actions of the inflammatory cytokine, IL-15, are proposed for an array of autoimmune disorders as well as diseases associated with the retrovirus human T-cell lymphotrophic virus 1.