Francesca Pica

Transmission of human herpesvirus 8: an update.

Purpose of review Human herpesvirus 8 is associated with neoplastic diseases in the immunocompromised host, including Kaposis sarcoma, multicentric Castleman disease and primary effusion lymphoma. Acquisition and control of human herpesvirus 8 infection have not yet been fully elucidated. This review focuses on the most recent findings on human herpesvirus 8 transmission. Recent findings Horizontal transmission by saliva appears the most common route not only in families in endemic regions, but also among high-risk groups in Western countries. Vertical, sexual, and blood and transplant-related transmission, however, remain of significant concern worldwide. Novel approaches to standardize and optimize the assessment of human herpesvirus 8 infection have been reported. New insights on the host immune cell mechanisms devoted to the control of human herpesvirus 8 infection have also been presented. Summary The increasing knowledge about the routes of human herpesvirus 8 transmission, which appear now more similar to those of other more ubiquitous human herpesviruses (i.e. Epstein–Barr virus and cytomegalovirus), the growing efforts in improving laboratory diagnosis and the caution in the research of new biological associations are the major recent findings. They constitute a fundamental background for directing more appropriate future research and achieving more stringent evidence useful for the control of human herpesvirus 8 spread and for the management of human herpesvirus 8-related diseases.

Clinical and psychosocial correlates of post-herpetic neuralgia

Post‐herpetic neuralgia is the most challenging and debilitating complication of herpes zoster in the immunocompetent host. Because the effect of treatment is disappointing once the syndrome has developed, it is important to know which factors predict post‐herpetic neuralgia occurrence to facilitate selection of herpes zoster patients with a higher risk of developing neuralgia and undertake preventative strategies. The present study aimed at identifying demographic, clinical and psychosocial correlates of post‐herpetic neuralgia in a sample of 219 immunocompetent patients, who were examined by dermatologists in private practice in Italy and who completed a questionnaire designed to evaluate their clinical and psychosocial profile at the time of clinical diagnosis of herpes zoster and at a follow‐up visit 6 months later. In a univariate analysis, post‐herpetic neuralgia was associated significantly with older age, longer duration of prodromal pain, greater acute pain intensity, greater extent of rash, presence of abnormal sensations and use of systemic antiviral therapy. Compared to the values at herpes zoster onset, at the follow‐up visit patients with post‐herpetic neuralgia presented with similar high mean scores of pain intensity, anxiety and depression and greatly reduced quality of life, whereas patients without neuralgia presented with improved scores. In a multivariate model, older age, greater acute pain intensity, greater extent of rash and longer duration of prodromal pain were independently associated with post‐herpetic neuralgia. The results of this study may help physicians to identify patients with a higher risk of developing post‐herpetic neuralgia and undertaking preventative strategies. J. Med. Virol. 80:1646–1652, 2008.

Thymosin alpha 1 in the treatment of cancer: from basic research to clinical application

Many studies have explored the effects of immunotherapy, alone or in combination with conventional therapies, on both experimental and human cancers. Evidence has been provided that combined treatments with thymosin alpha 1 (T alpha 1) and low doses of interferon (IFN) or interleukin (IL)-2 are highly effective in restoring several immune responses depressed by tumor growth and/or cytostatic drugs. In addition, when combined with specific chemotherapy, they are able to increase the anti-tumor effect of chemotherapy while markedly reducing the general toxicity of the treatment. The advantages of using this combined chemo-immunotherapeutic approach in experimental and human cancers are reviewed in this issue.

Combination treatment using thymosin α1 and interferon after cyclophosphamide is able to cure Lewis lung carcinoma in mice

SummaryA combination treatment with thymosin α1 (200 µg/kg) for 4 days, followed by a single injection of murine interferon α/β (3 × 104 international units/mouse), starting 2 days after cyclophosphamide treatment (200 mg/kg, single injection) demonstrated a dramatic and rapid disappearance of tumor burden in mice bearing Lewis lung carcinoma (3LL) tumor. The effectiveness of this new chemoimmunotherapy protocol was evident even on the long-term survival in a high percentage of animals, and was statistically significant when compared to treatment with the single agents in conjunction with chemotherapy or to chemotherapy itself. The same combination immunotherapy treatment strongly stimulated natural killer activity and cytotoxicity against autologus 3LL tumor cells in 3LL-tumor-bearing mice treated with cyclophosphamide, whereas treatments with each agent singly did not alter or only slightly modified the cytotoxic activity towards Yac-1 or 3LL target cells. Selective depletion with antibodies showed that killer cells stimulated by combination chemoimmunotherapy treatment bear phenotypic characteristics of asialo-GM1-positive cells. A histological study has shown a high number of infiltrating lymphoid cells in the tumors obtained from mice treated with combination chemoimmunotherapy.

A Systematic Analysis of Host Factors Reveals a Med23-Interferon-λ Regulatory Axis against Herpes Simplex Virus Type 1 Replication

Herpes simplex virus type 1 (HSV-1) is a neurotropic virus causing vesicular oral or genital skin lesions, meningitis and other diseases particularly harmful in immunocompromised individuals. To comprehensively investigate the complex interaction between HSV-1 and its host we combined two genome-scale screens for host factors (HFs) involved in virus replication. A yeast two-hybrid screen for protein interactions and a RNA interference (RNAi) screen with a druggable genome small interfering RNA (siRNA) library confirmed existing and identified novel HFs which functionally influence HSV-1 infection. Bioinformatic analyses found the 358 HFs were enriched for several pathways and multi-protein complexes. Of particular interest was the identification of Med23 as a strongly anti-viral component of the largely pro-viral Mediator complex, which links specific transcription factors to RNA polymerase II. The anti-viral effect of Med23 on HSV-1 replication was confirmed in gain-of-function gene overexpression experiments, and this inhibitory effect was specific to HSV-1, as a range of other viruses including Vaccinia virus and Semliki Forest virus were unaffected by Med23 depletion. We found Med23 significantly upregulated expression of the type III interferon family (IFN-λ) at the mRNA and protein level by directly interacting with the transcription factor IRF7. The synergistic effect of Med23 and IRF7 on IFN-λ induction suggests this is the major transcription factor for IFN-λ expression. Genotypic analysis of patients suffering recurrent orofacial HSV-1 outbreaks, previously shown to be deficient in IFN-λ secretion, found a significant correlation with a single nucleotide polymorphism in the IFN-λ3 (IL28b) promoter strongly linked to Hepatitis C disease and treatment outcome. This paper describes a link between Med23 and IFN-λ, provides evidence for the crucial role of IFN-λ in HSV-1 immune control, and highlights the power of integrative genome-scale approaches to identify HFs critical for disease progression and outcome.

In vivo cocaine administration influences lymphokine production and humoral immune response

SummaryThe effect of in vivo cocaine administration on in vitro mitogen-induced lymphokine production was examined. Splenocyte cultures from BALB/c mice treated with an acute (1 mg/kg) or daily cocaine administration (1 mg/kg/day for 7 consecutive days) were less responsive to induction of IFN-γ, IL-2 and IL-4 production by mitogen stimuli. We also evaluated the humoral immune response to both a T-dependent (HEL) and a T-independent antigen (rHBcAg). It was found that cocaine inhibits T-dependent antibody production only. This inhibition was greatest when cocaine was given during immunization. The results suggest that T-cell-mediated responses may be more affected by cocaine use/abuse.

Antitumor Effect of Thymosin α1/Interleukin-2 or Thymosin α1/Interferon α,β Following Cyclophosphamide in Mice Injected with Highly Metastatic Friend Erythroleukemia Cells

We investigated the effects of the systemic administration of thymosin alpha 1 plus relatively low doses of human recombinant interleukin-2 or very low doses of interferon alpha,beta in untreated and cyclophosphamide (CY)-treated DBA/2 mice challenged either subcutaneously or intravenously (i.v.) with Friend erythroleukemia cells (FLC). Both treatments resulted in the complete regression of subcutaneous tumor and cured a significative percentage of mice. They also increased the survival time of mice i.v. injected with large numbers of FLC. Neither immunotherapy alone nor CY, alone or in combination with single cytokines, produced similar effects. The antitumor action of these combined chemoimmunotherapy protocols seems to involve activation of the immune response since (a) a synergistic increase of the cytotoxicity of spleen cells was demonstrated in treated mice; (b) selective in vivo depletion of asialo-GM1, CD4, or CD8-positive cells abrogated this antitumor activity; and (c) a high lymphoid cell infiltration was found at the tumor site and in the livers of treated mice.

Thymosin α1 and cancer: action on immune effector and tumor target cells

Since it was first identified, thymosin alpha 1 (Tα1) has been characterized to have pleiotropic effects on several pathological conditions, in particular as a modulator of immune response and inflammation. Several properties exerted by Tα1 may be attributable to a direct action on lymphoid cells. Tα1 has been shown to exert an immune modulatory activity on both T cell and natural killer cell maturation and to have an effect on functions of mature lymphocytes, including stimulating cytokine production and cytotoxic T lymphocyte–mediated cytotoxic responses. In previous studies we have shown that Tα1 increases the expression of major histocompatibility complex class I surface molecules in murine and human tumor cell lines and in primary cultures of human macrophages. In the present paper, we describe preliminary data indicating that Tα1 is also capable of increasing the expression of tumor antigens in both experimental and human tumor cell lines. This effect, which is exerted at the level of the target tumor cells, represents an additional factor increasing the antitumor activity of Tα1.

Thymosin alpha 1: from bench to bedside.

Abstract:  After the initial dramatic effects, observed in a Lewis lung carcinoma animal model, using a combination of thymosin alpha 1 (Tα1) and interferon (IFN) after cyclophosphamide, a number of other preclinical models in mice (Friend erythroleukemia and B16 melanoma) and in rats (DHD/K12 colorectal cancer liver metastasis) have confirmed the efficacy of the combination therapy with Tα1 and either IFN or IL‐2 plus chemotherapy. These results provided the scientific foundation for the first clinical trials using Tα1 in combination with BRMs and/or chemotherapy. Pivotal trials in advanced non‐small cell lung cancer (NSCLC) and melanoma with Tα1 and IFN‐α low doses after cis‐platinum or dacarbazine produced the first evidence of the high potentiality of this approach in the treatment of human cancer. The combination of Tα1 and IFN‐α was also used in patients affected by chronic B and C hepatitis including IFN‐nonresponders and infected by precore mutants or genotype 1b. Further studies demonstrated additional biological activities clarifying the mechanism of action of Tα1, partially explaining the synergism with IFN. It has been shown the capacity of activating infected dendritic cells through Toll‐like receptor signaling, thus influencing the inflammation balance, and of increasing the expression of tumor, viral, and major histocompatibility complex (MHC) I antigens. Dose–response studies suggested the possibility of improving the efficacy of this molecule reducing the overall toxic. Based on these information two clinical trials are ongoing: a large phase II on advanced melanoma patients treated with Tα1 at different doses after dacarbazine and a phase III one, on IFN‐resistant hepatitis C virus (HCV) patients treated with a triple combination (IFN, ribavirin, and Tα1).

Thymosin α1 in combination with cytokines and chemotherapy for the treatment of cancer

Abstract Multiple therapeutic approaches have been tested in different experimental tumour models and in human cancers. Most part of them are based on the hypothesis that the inhibition of tumour growth requires a strong immune response in which a main role is played by CTLs. It is known, however, that an efficient CTL response requires expression of tumour antigens, MHC class I surface molecules presentation, expression of different co-stimulatory molecules and a sustained generation and proliferation of specific cytotoxic CD8+ cells with an efficient CD4+ cooperation. In this context, our group has extensively explored a protocol of combined therapy consisting of the use of chemotherapeutic agents associated with thymosin α 1 (Tα1) and different cytokines, whose efficacy has been demonstrated in experimental models as well as in human cancers. In this manuscript, the main data supporting a pivotal role of Tα 1 in such combination protocols are reviewed. In particular, a special mention of the molecular mechanisms underlying the effects of Tα 1 on immune effector cells as well as on target tumour cells is provided. These data contribute to explain the mechanism of action of Tα1, when used in combination therapy, for the treatment of cancer and provide new insights in predicting further possible applications of this peptide in other pathological conditions.