Agostino Pugliese

Role of nitric oxide in HIV-1 infection: friend or foe?

Nitric oxide (NO) is an important biologically active molecule that plays a key part in host defence against bacteria, protozoa, and tumour cells. NO has antiviral effects against several DNA viruses, such as murine poxvirus, herpes simplex virus, and Epstein-Barr virus, and some RNA viruses, such as coxsackievirus. In several studies, in vitro and in vivo, overproduction of NO has been noted in the presence of HIV-1 infection. Furthermore, increased NO production may contribute directly to the pathogenesis of HIV-1-associated dementia. The mechanisms of virus infection mediated by NO may be related to: direct antiviral effects of NO; impairment of antiviral defence mediated by T-helper-1 immune response by suppressing T-helper-1 functions; NO-induced cytotoxic effects by oxidative injury with cellular and organ dysfunctions; and NO-induced oxidative stress leading to rapid viral evolution with productions of drug-resistant and immunologically tolerant mutants. By contrast, there is some evidence of NO activity--directly, indirectly, or both--decreasing or blocking HIV-1 replication, through inhibition of viral enzymes, such as reverse transcriptase, protease, or cellular nuclear transcription factor (NF-kappa B) and long-terminal repeat-driven transcription. Therefore, although NO surely plays an important part in HIV-1 infection, that role is sometimes helpful and other times damaging to the host. Future challenges are to learn more about the beneficial and harmful effects of NO in HIV-1 infection, and how to selectively inhibit excessive NO production or to use NO-releasing drugs to decrease viral replication. This review discusses the role of NO in the pathogenesis of HIV-1 infection, inasmuch as its role against HIV-1 is unequivocal in inhibiting or increasing viral replication.

Serological Survey of Toscana Virus Infections in a High-Risk Population in Italy

ABSTRACT Toscana virus is the most important agent responsible for meningitis in central Italy. We report a serosurveillance study, using an immunoenzymatic assay, of 360 serum samples harvested from a high-risk population occupationally exposed to Toscana virus in two regions of Italy, Tuscany and Piedmont. The results indicates a seroprevalence of Toscana virus of 77.2% in the forestry workers, particularly in the Tuscany region. This fact is strictly correlated with the ecological niches specific for the survival of Toscana virus arthropod vector.

Reye's and Reye's-like syndromes

The review reports various questions about Reyes syndrome and Reyes‐like syndromes. Although there is a significant decrease in the classic Reyes syndrome cases, because of the reduced employment of salicylates in children (salicylate seems to be the most important inducing factor of the syndrome in paediatric subjects affected by viral infection), the problem is still of interest considering the presence of different Reyes‐like forms. All these pathological situations are associated with various aetiologic or predisposing causes that are examined in the text. Particular attention is placed on metabolic disorders, especially of fatty acid metabolism, and also of one amino acid. In fact, a latent form can also be the basis of possible biochemical disturbances induced by various exogenous factors such as viral infections, particularly of the respiratory tract (more rarely of bacterial aetiology), or produced by microbial toxins, or by chemical substances, including some therapeutic drugs. A full discussion of biochemical mechanisms of salicylate‐induced Reyes syndrome is reported. Finally a possible diagnostic differentiation from classic Reyes syndrome and Reyes‐like syndromes plus therapeutic prospects are briefly examined. Copyright

Platelets and HIV-1 infection: old and new aspects.

In this review we summarize the data on interaction of platelets with HIV-1 infection. Thrombocytopenia is a common finding among HIV-1 infected patients; several combined factors contribute to low peripheral platelet counts, which are present during all the stages of the disease. In addition, a relationship between platelet count, plasma viral load and disease progression has been reported, and this shows the potential influence platelets may have on the natural history of HIV-1 disease. Several lines of evidence have shown that platelets are an integral part of inflammation, and can be also potent effector cells of innate immune response as well as of adaptive immunity. Thus, we rewieved the role of inflammatory cytokines, and chemokines as activators of platelets during HIV-1 infection. Moreover, platelets show a direct interaction with HIV-1 itself, through different pathogenic mechanisms as binding, engulfment, internalisation of HIV-1, playing a role in host defence during HIV-1 infection, by limiting viral spread and probably by inactivating viral particles. Platelets may also play an intriguing role on endothelial dysfunction present in HIV-1 infection, and this topic begins to receive systematic study, inasmuch as interaction between platelets and endothelial cells is important in the pathogenesis of atherosclerosis in HIV-1 infected patients, especially in those patients treated with antiretroviral drugs. Finally, this review attempts to better define the state of this emerging issue, to focus areas of potential clinical relevance, and to suggest several directions for future research.

Phagocytic activity in human immunodeficiency virus type 1 infection.

Macrophages and neutrophils constitutes one of the main effectors of nonspecific immunity, phagocytosing conventional and opportunistic microorganisms and presenting their antigens to T lymphocytes. This consequently induces specific immune functions ([13][1], [91][2]). Moreover, activated

Interleukin-18: a proinflammatory cytokine in HIV-1 infection.

Interleukin (IL)-18 is a proinflammatory cytokine that plays an important role in both innate and adaptive immune responses against viruses and intracellular pathogens. Increased levels of circulating IL-18 from HIV-1 infected patients have been reported especially in the advanced and late stages of the disease, whereas in the initial stage serum levels of IL-18 were not increased. In contrast, low production of Il-18 was observed in vitro from peripheral blood mononuclear cells (PBMC) of HIV-1 infected patients, and these results were also observed in macaques infected with simian immunodeficiency virus (SIV). In addition, decreased IL-18 production from PBMC was significantly correlated with low production of IL-2. Furthermore, serum levels of IL-18 significantly decreased after highly active antiretroviral therapy. During the early stage of HIV-1 infection there is a decreased production of gamma interferon (IFN), IL-12 and IL-2 as well as not activation of IL-18 production and this leads to inhibition of Th1 immune response, whereas in the advanced stage of the disease, strong activation of IL-18 production along with persistent decreased production of gamma IFN, IL-12 and IL-2 may promote a Th2 immune response, which leads to persistent viral replication. Several studies have shown increased levels of IL-18 in HIV-seronegative subjects with obesity, insulin resistance and type II diabetes. Metabolic disorders, fat redistribution and cardiovascular manifestations are becoming more frequent in HIV-1 infected patients treated with antiretroviral drugs. Consequently, involvement of IL-18 in these disorders has been postulated and demonstrated in patients with lipodistrophy, or with hypertriglyceridemia. Finally, higher serum levels of IL-18 may represent an useful marker in HIV-1 infected patients with metabolic disorders and fat redistribution, as well as a sensitive predictor of cardiovascular complications in treated patients.

Impaired macrophage phagocytosis of apoptotic neutrophils in patients with human immunodeficiency virus type 1 infection.

ABSTRACT Dysfunction of neutrophils (polymorphonuclear leukocytes [PMNL]) and macrophagic cells occurs as a consequence of human immunodeficiency virus type 1 (HIV-1) infection. Macrophages contribute to the resolution of early inflammation ingesting PMNL apoptotic bodies. This study investigated macrophage ability to phagocytose PMNL apoptotic bodies in patients with HIV-1 infection in comparison with uninfected individuals and the effect of HIV Nef protein on apoptotic body phagocytosis to determine if phagocytic activity is impaired by HIV infection. Monocytes/macrophages were isolated from 10 HIV-1-infected patients and from five healthy volunteers, whereas PMNL were isolated from healthy volunteers. Macrophage phagocytosis of apoptotic PMNL was determined by staining of apoptotic bodies with fluorescein-conjugated concanavalin A or with fluorescein-labeled phalloidin. Our data show significant impairment of PMNL apoptotic body macrophage phagocytosis in subjects with HIV-1 infection presenting a concentration of CD4+ T lymphocytes of >200/mm3 and in particular in those with <200 CD4+ T lymphocyte cells/mm3. In addition, HIV-1 recombinant Nef protein is able to decrease phagocytosis of apoptotic PMNL from normal human macrophages in a dose-dependent manner. The results of our study suggest that impaired macrophage phagocytosis of PMNL apoptotic bodies may contribute to the persistence of the inflammatory state in HIV-infected subjects, especially during opportunistic infections that are often favored by defective phagocytic activity.

Anti-inflammatory response of IL-4, IL-10 and TGF-beta in patients with systemic inflammatory response syndrome.

The systemic inflammatory response syndrome (SIRS) is an inflammatory process seen in association with a large number of clinical infective and non-infective conditions. The aim of this study was to investigate the role of anti-inflammatory cytokines such as interleukin-4 (IL-4), interleukin-10 (IL-10), and transforming growth factor-beta (TGF-beta). Serum levels of IL-4, IL-10 and TGF-beta were determined in 45 patients with SIRS: 38 patients had SIRS of infectious origin, whereas seven patients had non-infectious SIRS. Twenty healthy subjects were used as controls. Serum levels of IL-4, IL-10 and TGF-beta were determined by an immunoenzyme assay. A significant increase of IL-4 was observed in these patients at the time of diagnosis and 5 days later. In contrast, serum levels of IL-10 were not increased at the time of diagnosis, but a slight decrease was noted after 5 days. Serum levels of TGF-beta were not increased at time of diagnosis, and a slight increase was observed after 5 days. Serum levels of IL-4 were significantly higher in patients with infectious SIRS at the time of diagnosis, whereas no significant difference between infectious and non-infectious SIRS was noted for serum levels of IL-10 and TGF-beta at the time of diagnosis and 5 days later. During SIRS, serum levels of IL-4 were significantly increased with a significant correlation between IL-4 and mortality, and only levels of IL-4 were significantly increased in the SIRS caused by infectious stimuli.

Emerging and re-emerging viral infections in Europe

Emerging viral infections are becoming a serious problem in Europe in the recent years. This is particularly true for severe acute respiratory syndrome (SARS), West Nile virus (WNV) disease, Toscana virus (TOSV) disease, and potentially for avian influenza virus (H5N1). In contrast, emergence or re‐emergence of severe viral infections, including tick borne encephalitis virus, and viral haemorrhagic fever caused by Hantavirus and dengue virus have been frequently reported in several European countries. Laboratory diagnosis of these viral infections based on viral isolation or detection by immune electron microscopy, immunoassay and polymerase chain reaction (PCR) has dramatically improved in the recent years, and SARS represents a good example of a diagnostic approach to emerging viral infections. Finally, old and new promising agents are in the pipeline of pharmaceutical companies to treat emerging viral infections. However only prevention based on large epidemiological studies, and research and development of new vaccines may be able to control and eventually eradicate these deadly viral infections. Copyright

Modulation of surface transferrin receptors in lymphoid cells de novo infected with human immunodeficiency virus type-1.

To investigate whether transferrin receptor (CD71) expression is affected by acute HIV‐1 infection, three different lymphoid cell lines (MT‐4, SUPT‐1, H9) were infected with HIV‐1 and tested for surface CD71 expression after different incubation periods depending on cell survival after infection. We found that expression of surface CD71 was lower in cells infected with HIV‐1 than in uninfected controls: the timing and extent of this down‐modulation depended apparently on the different susceptibility of the cell lines to HIV‐1 infection and cytopathogenicity. Citrate, a molecule capable of chelating iron, dose‐dependently prevented down‐modulation of surface CD71 in HIV‐1 infected cells as well as viral cytopathic effects. We conclude that (i) expression of surface transferrin receptors is down‐modulated by acute HIV‐1 infection in T lymphoid cells, that (ii) this cell phenotypic modulation is associated with the cytopathic effects of the virus, and that (iii) these phenomena are modulated by iron chelation. These results support the view that iron metabolism may be an important area for interaction between HIV‐1 and human cells. Copyright