Since human T-lymphotropic virus type 1 (HTLV-1)-associated diseases are associated with a high HTLV-1 load, reducing this load may treat or prevent disease. However, despite in vitro evidence that certain nucleoside/nucleotide analogue reverse transcriptase inhibitors (NRTIs) are active against HTLV-1, in vivo results have been disappointing. We therefore assayed the sensitivity of HTLV-1 primary isolates to a panel of RT inhibitors. HTLV-1 primary isolates were obtained, pre- and post- NRTI treatment, from patients with HTLV-1-associated myelopathy. Sensitivity to azidothymidine (AZT), lamivudine (3TC), tenofovir (TDF) and three phosphonated carbocyclic 2’-oxa-3’aza nucleosides (PCOANs) was assessed in a RT inhibitor assay. With the exception of 3TC, HTLV RT from primary isolates was less sensitive to all tested inhibitors than HTLV-1 RT from MT-2 cells. HTLV-1 RT from primary isolates and from chronically infected, transformed MT-2 cells was insensitive to 3TC. Sensitivity of primary isolates to RT inhibitors was not reduced following up to 12 months of patient treatment with AZT plus 3TC. The sensitivity of HTLV-1 primary isolates to NRTIs differs from that of cell lines and may vary among patients. Failure of NRTIs to reduce HTLV-1 viral load in vivo was not due to the development of phenotypic NRTI resistance. AZT and the three PCOANs assayed all consistently inhibited primary isolate HTLV-1 RT.

The human T-cell leukemia/lymphoma virus type 1 (HTLV-1) is an oncogenic retrovirus endemic in certain areas of the world including Japan and North and South America, where about 5% of the estimated 20 million HTLV-1-infected people develop HTLV-1-associated diseases (10,11,43), such as adult T-cell leukemia (ATL), human myelopathy/tropical spastic paraparesis (/TSP), or other minor inflammatory diseases. A number of studies have shown that HTLV-1 infects different types of cells (e.g., lymphocytes, monocytes, and fibroblasts) but preferentially T lymphocytes with a CD4 ϩ phenotype, which become immortalized following infection (26). In HTLV-1 infection viremia is essentially a "cytoviremia," since the virus is cell associated. In fact, cell-free virions are rarely infectious, and spreading of the virus in vivo does not require the extracellular release of viral particles. The spread of the virus within an individual host is most commonly recognized as being through the mitotic pathway, in which cell divisions and clonal expansion of infected cells ensure a constant level of viral load. However, recently it has been highlighted that the HTLV-1 viral load in vivo is also sustained by cell-tocell contact, involving intercellular viral spread. In particular, this "horizontal" spread allows the transfer of HTLV-1 infectious viral particles across the cell-cell junction by the generation of "virological synapses" between infected and uninfected cells (19,21). Transmission of HTLV-1 via cell-to-cell contact involves both integrin (3) and cytoskeleton proteins and participation of Env protein-cell receptor interactions (37). Either way, efficient transmission of HTLV-1 to noninfected cells implies reverse transcriptase (RT) dependency.In recent years, a number of strategies for therapeutic intervention have been pursued in the treatment of ATL or TSP, based on conventional chemotherapy or innovative approaches. However, until now, limited advances have been achieved in improving the therapy for HTLV-1-associated diseases. Therefore, symptomatic HTLV-1-infected patients still have inadequate treatment options with poor prognoses. Among the novel approaches for treating HTLV-1-related diseases, the use of topoisomerase 1 or 2 inhibitors in a pilot phase II study in refractory ATL did not provide satisfactory results (41). Similarly, treatments with the nucleoside analogue 2Ј deoxycoformycin (39) or inhibitors of AMP synthesis resulted in a limited response in ATL patients (42). Interestingly, studies based on a different strategy of chemotherapeutic intervention showed that ATL patients transiently responded to combined therapy with the nucleoside reverse transcriptase inhibitor (NRTI) azidothymidine (AZT) and interferon (IFN) (15) and that AZT treatment was beneficial to TSP patients (33), giving more encouraging results. In addition, a transient response to therapy with the NRTI lamivudine alone (38) or in combination with AZT (25) has been reported for human myelopathy/TSP. Moreover, IFN-␣ has been shown to have some ...

Diagnosis and therapeutic strategies in Alzheimer's disease (AD) might greatly benefit of the present multidisciplinary approach for studying the molecular pathogenesis of the disorder. Gene expression profile at peripheral level could be a promising tool for pathogenic studies as well as for early diagnosis of AD. A dysregulated inflammatory response, as well as other systemic disorders, have been described in AD. Therefore, we investigated the expression, at peripheral level, of a number of genes involved in the inflammatory, oxidative stress and proliferative response of a well defined, small cohort of sporadic AD patients. Firstly, the mRNA expression of inflammatory, stress and proliferation/ differentiation genes were evaluated, using SuperArray, in mitogen-stimulated peripheral blood mononuclear cells (PBMC) from a group of 12 well-characterized, sporadic AD patients with various levels of dementia, by comparison with aged-matched controls. Real-time RT-PCR confirmed the trend of alteration in 16 genes out of the 36 supposed to be dysregulated in AD patients, by the preliminary screening. The expression level of the NFKB1(p105/50Kd) gene was significantly higher in AD with respect to adult age-matched controls (AA) and was related to the Mini-Mental State Examination (MMSE) score of the same patients. In addition, the expression of various NF-κB target genes and of both NF-κBp50 and NF-κBp65 DNA-binding activity were increased in PBMC from AD patients in comparison with those from AA. Our results suggest that NF-κB activation at peripheral blood cell level could be a potential new hallmark of AD progression and sustain a rationale to more deeply investigate the therapeutic potential of specific NF-κB inhibitors in AD.

Peripheral blood mononuclear cells (PBMCs) from healthy individuals can be infected by human Tlymphotropic virus type 1 (HTLV-1) upon cocultivation of the PBMCs with irradiated HTLV-1-transformed human MT-2 cells. This model system closely mimics HTLV-1 transmission through cell-to-cell contact.Carbohydrate-binding agents (CBAs) such as the ␣(1,3)/␣(1,6)mannose-specific Hippeastrum hybrid agglutinin and the GlcNAc-specific Urtica dioica agglutinin, and also the small, nonpeptidic ␣(1,2)-mannose-specific antibiotic pradimicin A, were able to efficiently prevent cell-to-cell HTLV-1 transmission at nontoxic concentrations, as evidenced by the lack of appearance of virus-specific mRNA and of the viral protein Tax Human T-lymphotropic virus type 1 (HTLV-1) is a member of the genus Deltaretrovirus of the family Retroviridae and is associated with various pathologies (35). The most common characterized pathologies are oncological transformation (i.e., adult T-cell leukemia [ATL] and cutaneous T-cell lymphoma) and neurological abnormalities (i.e., tropic spastic paraparesis). The virus is spread in areas of endemicity in Japan, Central America, and South America. Its worldwide spread encompasses around 20 million infected individuals (12,13,26). The main routes of HTLV-1 infection in vivo consist of mother-to-infant transmission (mainly through breast-feeding), parenteral infection, and viral transmission through sexual intercourse (20,26,27). HTLV-1 infection occurs predominantly by infection of CD4 ϩ T lymphocytes, followed by random integration of the provirus into the cellular genome (11). HTLV-1 infection in vivo results in a lifelong infection that is characterized by low, if any, viremia. Therefore, in the absence of a sustained extracellular phase during the replication cycle of HTLV-1, survival and propagation of the virus within the host seem to be mainly ensured by two modalities: (i) the reverse transcriptase (RT)-independent mitotic pathway and (ii) cell-to-cell contacts allowing the virus to migrate from infected to uninfected cells through an RT-dependent route. However, the mechanisms involved in the entry of HTLV-1 into the cell have not been fully elucidated. HTLV-1 transmission benefits from the formation of cellular conjugates through the generation of biological synapses and involvement of the cytoskeleton (17). Although the glucose transporter GLUT-1 has been identified as a cellular receptor for HTLV-1 (22), other studies indicate that the interaction with this receptor is not sufficient by itself for viral entry into the cell (18,29). The structural component of HTLV-1 presumably required for receptor recognition is composed of the envelope glycoprotein (gp46) and a noncovalently associated transmembrane anchor protein (gp21), derived from a common gp63 precursor (21). gp46 is among the smallest retroviral envelope proteins known, and it exhibits little sequence variability (19). Studies have revealed that all four potential N-glycosylation sites (28) in gp46 are used and that the glycans are m...

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