HTLV-1 Tax protects against CD95-mediated apoptosis by induction of the cellular FLICE-inhibitory protein (c-FLIP)

The HTLV-1 transactivator protein Tax is essential for malignant transformation of CD4 T cells, ultimately leading to adult T-cell leukemia/lymphoma (ATL). Malignant transformation may involve development of apoptosis resistance. In this study we investigated the molecular mechanisms by which HTLV-1 Tax confers resistance toward CD95-mediated apoptosis. We show that Tax-expressing T-cell lines derived from HTLV-1-infected patients express elevated levels of c-FLIP(L) and c-FLIP(S). The levels of c-FLIP correlated with resistance toward CD95-mediated apoptosis. Using an inducible system we demonstrated that both resistance toward CD95-mediated apoptosis and induction of c-FLIP are dependent on Tax. In addition, analysis of early cleavage of the BH3-only Bcl-2 family member Bid, a direct caspase-8 substrate, revealed that apoptosis is inhibited at a CD95 death receptor proximal level in Tax-expressing cells. Finally, using siRNA we directly showed that c-FLIP confers Tax-mediated resistance toward CD95-mediated apoptosis. In conclusion, our data suggest an important mechanism by which expression of HTLV-1 Tax may lead to immune escape of infected T cells and, thus, to persistent infection and transformation.     

Broad human immunodeficiency virus (HIV)-specific T cell responses to conserved HIV proteins in HIV-seronegative women highly exposed to a single HIV-infected partner

Eighteen highly exposed but persistently seronegative (HEPS) women (HW) and their human immunodeficiency virus (HIV) type 1-seropositive male partners were studied for HIV-specific T cells and other host factors. Circulating HIV-specific T cells were measured by interferon-gamma enzyme-linked immunospot assays, using recombinant vaccinia virus vectors expressing HIV proteins. Nine (50%) of the HW and all HIV-seropositive persons had HIV-specific T cell responses. Only 2 (22%) of the HEPS responders recognized Env, compared with 94% of HIV-seropositive persons. A high percentage (75%) of the HW with HIV-specific T cell responses reported recent HIV exposure. Remarkably, however, long-lived HIV-specific T cells were detected in 2 HW who had an extended period (>3.9 years) of no HIV exposure. These findings have important implications for HIV vaccine design.     

Efficient and non-toxic gene transfer to cardiomyocytes using novel generation amplicon vectors derived from HSV-1

OBJECTIVE: The feasibility of gene transfer to myocardial tissue using viral vectors was investigated over the last few years. In this study we report gene transfer using a recently described improved of Herpes simplex virus (HSV-1)-derived amplicon vectors and demonstrate that these vectors are a powerful and potentially very interesting tool for gene transfer into neonatal primary as well as in adult cardiac myocytes. METHODS AND RESULTS: Non-pathogenic HSV-1 amplicon vectors simultaneously expressing GFP and LacZ were constructed using a novel helper system that yields essentially helper-free vector particles. These vectors were used to infect either cultured primary neonatal rat cardiomyocytes or adult cardiac tissue. Transgenic expression was quantified using a FACS (GFP) or X-gal staining (LacZ). Infection of primary cardiomyocytes showed efficient transduction even at very low multiplicity of infection (MOI), and expression increased with the infectious dose. By investigating release of lactate dehydrogenase (LDH) or spontaneous beating of the cells, we failed to detect cytotoxic effects in cardiomyocytes infected at high MOI. Thin slices of adult cardiac tissue placed in medium containing vectors also showed very good levels of transduction, without any evidence of toxic effects. CONCLUSIONS: Helper-free amplicon vectors very efficiently transduce genes into cardiomyocytes. Our results indicate similar or better transduction efficiencies than those reported using other vector systems. Furthermore, the very high transgenic capacity of amplicon vectors (up to 150 kbp) makes these vectors a unique and very suitable system to transduce large genomic sequences into cardiomyocytes.     

Safety and tolerability of oral daily and intermittent ibandronate are not influenced by age

OBJECTIVE: The risk of osteoporosis increases exponentially with age. Elderly patients, who are often frail, have declining functional status and take multiple medications, and require osteoporosis therapies that are not only effective, but also very well tolerated. Ibandronate is a potent nitrogen-containing bisphosphonate that can be given intermittently with extended between-dose intervals. Oral daily and intermittent ibandronate (interval between doses > 2 mo) was found to significantly reduce the risk of new morphometric vertebral fractures by 62% and 50%, respectively, compared with calcium and vitamin D supplementation alone. We investigated the effect of age on the safety profile of oral daily and intermittent ibandronate, with particular emphasis on the upper gastrointestinal (GI) safety profile of ibandronate. METHODS: A predefined subgroup analysis examined the tolerability of oral ibandronate in women aged < 70 and > or = 70 years. RESULTS: The incidence of adverse events in patients aged > or = 70 years receiving oral daily and intermittent ibandronate was similar and comparable to placebo. The incidence of upper GI adverse events, including dyspepsia and esophagitis, was also similar between the 2 treatment groups and placebo. CONCLUSION: Older patients (> or = 70 yrs) receiving oral daily and intermittent ibandronate are at no greater risk of adverse events than older patients receiving placebo. Older patients were at no greater risk of upper GI adverse events than younger patients or patients receiving placebo. As a result of the good efficacy and tolerability observed in this trial, a once-monthly oral regimen of ibandronate is in late-stage clinical development.     

Safety evaluation of olaparib for treating ovarian cancer

Introduction: Olaparib (Lynparza®) is an oral, small molecule, poly (ADP-ribose) polymerase inhibitor that has become the first ‘personalized’ therapy available for patients with BRCA mutation-positive ovarian cancer (OC). A capsule formulation of the drug has recently received approval for use in this population for platinum-sensitive recurrent disease for maintenance therapy following platinum-based chemotherapy in Europe and as third- or fourth-line platinum-sensitive therapy in the USA.

Areas covered: This article reviews the development of olaparib in OC with a focus on safety evaluation. Data are based on published literature and reports available from the olaparib development program database.

Expert opinion: Oral olaparib 400 mg twice daily has acceptable tolerability when administered as maintenance monochemotherapy in women with relapsed OC. The common toxicities – nausea/vomiting, fatigue and anemia – are mild or moderate in severity and appear consistent across subgroups (BRCA carriers/wild-type). Though the risk is low, long-term monitoring of patients is warranted to determine the potential risk for hematological complications such as anemia, myelodysplastic syndrome or acute myeloid leukemia.     

HLA-A amino acid polymorphism and delayed kidney allograft function

Delayed allograft function (DGF) is a common adverse event in postrenal transplantation. The etiology of DGF is thought to include both nonimmunologic (donor age, cold ischemia time, and recipient race) and immunologic factors. We examined the association of DGF with amino acid mismatches at 66 variable sites of the HLA-A molecule in a prospective cohort study of 697 renal transplant recipients of deceased donors. Using a multivariate logistic regression model adjusted for nonimmunologic risk factors, we show that combinations of a few amino acid mismatches at crucial sites of HLA-A molecules were associated with DGF. In Caucasian recipients, a mismatch at position 62, 95, or 163, all known to be functionally important within the antigen recognition site, was associated with an increased risk for DGF. Furthermore, a decreased risk for DGF was associated with a mismatch at HLA-A family-specific sites (149, 184, 193, or 246), indicating that evolutionary features of HLA-A polymorphism separating HLA-A families and lineages among donor-recipient pairs may correlate with the magnitude of alloreactivity influencing the development of DGF. These findings suggest that amino acid polymorphisms at functionally important positions at the antigen recognition site of the HLA-A molecule have a significant influence on DGF.