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A Gessain

Publications and source records attributed to A Gessain.

At least 19 recordsLinked to original sources
PubMed2006

The tax protein from the primate T-cell lymphotropic virus type 3 is expressed in vivo and is functionally related to HTLV-1 Tax rather than HTLV-2 Tax.

Human T-cell leukemia virus and simian T-cell leukemia virus (STLV) form the primate T-cell lymphotropic viruses group. Human T-cell leukemia virus type 1 and type 2 (HTLV-1 and HTLV-2) encode the Tax viral transactivator (Tax1 and Tax2, respectively). Tax1 possesses an oncogenic potential and is responsible for cell transformation both in vivo and in vitro. We and others have recently discovered the existence of human T-cell lymphotropic virus type 3. However, there is currently no evidence for the presence of a Tax protein in HTLV-3-infected individuals. We show that the serum of an HTLV-3 asymptomatic carrier and the sera of two STLV-3-infected monkeys contain specific anti-Tax3 antibodies. We also show that tax3 mRNA is present in the PBMCs obtained from an STLV-3-infected monkey, demonstrating that Tax3 is expressed in vivo. We further demonstrate that Tax3 intracellular localization is very similar to that of Tax1 and that Tax3 binds to both CBP and p300 coactivators. Using purified Tax3, we show that the protein increases transcription from a 4TxRE G-free cassette plasmid in an in vitro transcription assay. In all cell types tested, including transiently transfected lymphocytes, Tax3 activates its own promoter STLV-3 long terminal repeat (LTR), which contains only two Tax Responsive Elements (TREs), and activates also HTLV-1 and HTLV-2 LTRs. In addition, Tax3 also activates the NF-kappaB pathway. We also show that Tax3 possesses a PDZ-binding sequence at its C-terminal end. Our results demonstrate that Tax3 is a transactivator, and that its properties are more similar to that of Tax1, rather than of Tax2. This suggests the possible occurrence of lymphoproliferative disorders among HTLV-3-infected populations.

Amino Acid Sequence↗
PubMed2005

[Epidemiological aspects of human herpesvirus 8 infection and of Kaposi's sarcoma].

HHV-8 belongs to the herpesviridae family, to the gammaherpesvirinae subfamily, and to the rhadinovirus genus. Whereas several viral homologues exist in non human primates, HHV-8 is the only rhadinovirus known in human. HHV-8 is mainly the etiological agent of the four clinico-epidemiological forms of Kaposi's sarcoma (classic, endemic, post-transplant, and epidemic/HIV associated). HHV-8 is not an ubiquitous virus. It is mainly endemic in areas of high endemicity for classic or endemic Kaposi's sarcoma including the Mediterranean area and most of East and Central Africa. Its prevalence varies in the adult population, from less than 5% in the USA and Northern Europe to more than 50% in some regions of the African continent and around 10 to 20% in Italy and Greece. One can estimate that several hundred million people are HHV-8 infected worldwide with at least 150 million on the African continent. Modes of infection seem different in low and highly endemic areas. In low endemic areas, HHV-8 is mainly present in the male homosexual population, where this herpesvirus is transmitted during sexual contacts. In contrast, in highly endemic areas, as Central Africa, HHV-8 transmission occurs mainly from mother to child and between siblings. Heterosexual transmission remains low as well as transmission through blood products. Saliva seems to play a major role in the viral transmission, and may be a reservoir for HHV-8.

Adult↗
PubMed2005

[New human retroviruses: HTLV-3 and HTLV-4].

Human T cell leukemia/lymphoma virus Type 1 and 2 (HTLV-1 and HTLV-2), together with their simian counterparts (STLV-1, STLV-2 and STLV-3), belong to the Primate T lymphotropic viruses group (PTLV). HTLV-1 infects 15 to 20 million people worldwide, while STLV-1 is endemic in a number of simian species living in the Old World. Due to the high percentage of homologies between HTLV-1 and STLV-1 strains, it has now been widely accepted that most HTLV-1 subtypes arose from interspecies transmission between monkeys and humans. On the opposite, there is no close human homolog of the two STLV-2 strains that have been discovered in African bonobos chimpanzees. These results suggest that the interspecies transmission that lead to the present day HTLV-2 must have occurred in a distant past. STLV-3 viruses are very divergent, both from HTLV-1 and from HTLV-2. They are endemic in several monkey species that live in west, central and east Africa. Recently, two laboratories independently reported the discovery of the human homolog (HTLV-3) of STLV-3 in two inhabitants from south Cameroon whose sera exhibited HTLV indeterminate serologies. Together with STLV-3, these two viruses belong therefore to the PTLV-3 group. In addition, a fourth HTLV type (HTLV-4) was also discovered in the same geographical area. Current studies are aimed at determining the molecular characterization of these viruses. In particular, the possible oncogenic properties of their viral transactivator Tax is being investigated, as well as their modes of transmission and their possible association with human diseases.

Animals↗
PubMed2004

[HTLV1 infection and pregnancy].

OBJECTIVE: We report an epidemiological study with an analysis of the risk factors of the HTLV-1 seroprevalence in pregnant women and their children in the town of St Laurent du Maroni, French Guyana. MATERIAL AND METHOD: HTLV-1 seroprevalence and risk associated factors were first studied in all the pregnant women having delivered at St. Laurent between July 1991 and June 1993. Then, a retrospective analysis was performed in the children, aged between 18 months and 12 years old, born from HTLV-1 infected mothers, focusing especially on the duration of breast feeding and the level of HTLV-1 anti body titers and proviral load. RESULTS: The global HTLV-1 seroprevalence was 4.4% (75/1727) but it was more prevalent among ethnic groups of African origin such as the Noir Marron population (5.5%) and Haitians (6.3%). In the Noir-Marron population, which represents 70% of the studied population, HTLV-1 seropositivity was associated with a maternal age of>35 years, prior miscarriage, prior cesarean section, parity>4, gravidity>6 and negative rhesus factor. After logistic regression, HTLV-1 seropositivity remained associated with gravidity>6 and negative rhesus factor. Out of the 216 children born from 81 HTLV-1 infected mothers, only 21 were found to be HTLV-1 seropositive, giving a crude HTLV-1 transmission rate of 9.7% while among the 180 breast-fed children 10.6% were HTLV-1 seropositive. HTLV-1 seropositivity in children was associated with elevated maternal anti HTLV-1 antibody titer, high maternal HTLV-1 proviral load and child's gender, girls being more frequently HTLV-1 infected than boys. CONCLUSION: HTLV-1 infection, which can be responsible for severe pathologies in adults (adult T cell leukemia and tropical spastic paraparesis/HTLV-1 associated myelopathy) should be screened during pregnancy in women originating from high HTLV-1 endemic areas, as for France, mainly the French West Indies, French Guyana and Intertropical Africa. In case of HTLV-1 seropositivity, mothers should be informed on the risk of transmission and promotion of bottle feeding of their children should be strongly proposed.

Adult↗
PubMed2004

Human T-cell leukaemia/lymphoma virus type 1-associated infective dermatitis in Africa: a report of five cases from Senegal.

BACKGROUND: Infective dermatitis (ID) is a rare dermatological condition of childhood that has been linked to human T-cell leukaemia/lymphoma virus type 1 (HTLV-1). Most cases have been reported in the Caribbean. Although several million people are estimated to be infected by HTLV-1 in sub-Saharan Africa, no case of ID has been reported in this area. OBJECTIVES: To identify and to describe cases of HTLV-1-associated ID in Senegal, West Africa. METHODS: Over a 3-year period, a serological test for HTLV-1 was performed at a dermatological centre in Dakar, Senegal, in children who presented with a picture suggestive of ID. Complementary haematological, immunological and virological investigations were performed in infected children and in their mothers. RESULTS: Five patients with typical HTLV-1-associated ID were identified, of ages 17, 5, 4, 3 and 3 years; two patients belonged to the same family. They all presented with repeated flares of superinfected dermatitis involving typical sites of ID (mainly the scalp, external ears, nares and eyelids), associated with nasal discharge, and less commonly with a nonspecific papular rash on the face or trunk. Although oral antibiotic therapy always gave effective control of the symptoms, recurrences were constant. A persisting dry dermatitis of the retroauricular folds was common between flares. Infection in the oldest patient was associated with a chronic adult T-cell leukaemia/lymphoma. The mothers of three patients, and the grandmother of another, were all infected by HTLV-1 strains belonging to the Cosmopolitan molecular subtype, with a perfect nucleotide identity of long-terminal repeat and env gp21 genomic regions within each family. CONCLUSIONS: We present the clinical and virological features of the first reported African cases of HTLV-1-associated ID. When compared with data from the Caribbean, infectious features seemed particularly prominent. ID appears to be overlooked in sub-Saharan Africa, where it might be easily confused with common pyoderma. Breast feeding appears to be the origin of HTLV-1 contamination of the children.

Adolescent↗
PubMed2003

A novel, divergent simian T-cell lymphotropic virus type 3 in a wild-caught red-capped mangabey (Cercocebus torquatus torquatus) from Nigeria.

We present here a novel, distinct simian T-cell lymphotropic virus (STLV) found in a red-capped mangabey (Cercocebus torquatus) (CTO-NG409), wild-caught in Nigeria, that showed an HTLV-2-like Western blot (WB) seroreactivity. The complete genome (8920 bp) of CTO-NG409 STLV was related to but different from STLV-3/PHA-PH969 (13.5 %) and STLV-3/PPA-F3 (7.6 %), and STLV-3/CTO604 (11.3 %), found in Eritrean and Senegalese baboons, and red-capped mangabeys from Cameroon, respectively. Phylogenetic analysis of a conserved tax (180 bp) sequence and the env gene (1482 bp) confirmed the relatedness of STLV-3/CTO-NG409 to the STLV-3 subgroup. Molecular clock analysis of env estimated that STLV-3/CTO-NG409 diverged from East and West/Central African STLV-3s about 140,900+/-12,400 years ago, suggesting an ancient African origin of STLV-3. Since phylogenetic evidence suggests multiple interspecies transmissions of STLV-1 to humans, and given the antiquity and wide distribution of STLV-3 in Africa, a search for STLV-3 in human African populations with HTLV-2-like WB patterns is warranted.

Animals↗
PubMed2001

Arsenic trioxide induces apoptosis in human T-cell leukemia virus type 1- and type 2-infected cells by a caspase-3-dependent mechanism involving Bcl-2 cleavage.

Treatment of patients with adult T-cell leukemia-lymphoma (ATLL) using conventional chemotherapy has limited benefit because human T-cell leukemia virus type 1 (HTLV-1) cells are resistant to most apoptosis-inducing agents. The recent report that arsenic trioxide induces apoptosis in HTLV-1-transformed cells prompted investigation of the mechanism of action of this drug in HTLV-1 and HTLV-2 interleukin-2-independent T cells and in HTLV-1-immortalized cells or in ex vivo ATLL samples. Fluorescence-activated cell sorter analysis, fluorescence microscopy, and measures of mitochondrial membrane potential (Delta Psi m) demonstrated that arsenic trioxide alone was sufficient to induce programmed cell death in all HTLV-1 and -2 cells tested and in ATLL patient samples. I kappa B-alpha phosphorylation strongly decreased, and NF-kappa B translocation to the nucleus was abrogated. Expression of the antiapoptotic protein Bcl-X(L), whose promoter is NF-kappa B dependent, was down-regulated. The collapse of Delta Psi m and the release of cytochrome c to the cytosol resulted in the activation of caspase-3, as demonstrated by the cleavage of PARP. A specific caspase-3 inhibitor (Ac-DEVD-CHO) could reverse this phenotype. The antiapoptotic factor Bcl-2 was then cleaved, converting it to a Bax-like death effector. These results demonstrated that arsenic trioxide induces apoptosis in HTLV-1- and -2-infected cells through activation of the caspase pathway.

Apoptosis↗
PubMed2001

Pooling of samples for seroepidemiological surveillance of human T-cell lymphotropic virus types I and II.

We evaluated a straight forward pooling strategy for antibody screening of HTLV-I/II, using panels of sera from various parts of the world including a total of 43 HTLV-I and 54 HTLV-II positive specimens. Four antibody screening assays were included in the evaluation: the HTLV-I/II GE 80/81 (Murex Diagnostics), the HTLV-I/HTLV-II Ab Capture ELISA (Ortho Diagnostics), the HTLV-I/II ELISA 3.0 (Genelabs Diagnostics) and the Serodia HTLV-I (Fujirebio). The Murex and Ortho assays represent a new generation of HTLV screening tests with a sandwich format incorporating both HTLV-I and HTLV-II synthetic and/or recombinant peptide antigens. The Genelabs assay is an indirect ELISA with recombinant HTLV-I and -II antigens and Serodia is a particle agglutination assay with HTLV-I whole viral lysate. Each HTLV-positive sample was included in pools of 1/1 up to 1/16, in two-fold steps made in normal HTLV-negative blood donor serum from one up to nine donors. For HTLV-I, with the exception of one false negative sample in dilution 1/16 with Genelabs ELISA, all assays were positive at all dilutions. The Murex assay had absorbance values at maximum levels for all samples at all dilutions. The other assays had gradually decreasing absorbance values although clearly above cut-off. For HTLV-II, the Murex assay correctly detected all samples to dilution 1/16 despite gradually decreasing signals. The Serodia assay had 100% sensitivity to dilution 1/4 while at 1/8 and 1/16 it decreased 82 and 80%, respectively. The Genelabs ELISA had gradually decreasing sensitivity for HTLV-II from 98 (1/1) to 33% (1/16) while the Ortho assay detected all specimens at all dilutions in a limited set of samples tested. Taken together, this evaluation has shown that pooling of samples may be an appropriate strategy for serosurveillance of HTLV. It is, however, crucial to limit the number of samples and to choose assays that allow the dilution caused by the pooling. Using the best performing assays in this evaluation for pools of e.g. five samples would leave a reasonable safety margin.

Agglutination Tests↗
PubMed2001

Molecular and phylogenetic analyses of 16 novel simian T cell leukemia virus type 1 from Africa: close relationship of STLV-1 from Allenopithecus nigroviridis to HTLV-1 subtype B strains.

A serological survey searching for antibodies reacting with human T-cell leukemia virus type 1 (HTLV-1) antigens was performed on a series of 263 sera/plasma obtained from 34 monkey species or subspecies, originating from different parts of Africa. Among them, 34 samples exhibited a typical HTLV-1 Western blot pattern. Polymerase chain reaction was performed with three primer sets specific either to HTLV-1/STLV-1 or HTLV-2 and encompassing gag, pol, and tax sequences, on genomic DNA from peripheral blood mononuclear cells of 31 animals. The presence of HTLV-1/simian T-cell leukemia virus type 1 (STLV-1) related viruses was determined in the 21 HTLV-1 seropositive animals tested but not in the 10 HTLV-1 seronegative individuals. Proviral DNA sequences from the complete LTR (750 bp) and a portion of the env gene (522 bp) were determined for 16 new STLV-1 strains; some of them originating from species for which no STLV-1 molecular data were available as Allenopithecus nigroviridis and Cercopithecus nictitans. Comparative and phylogenetic analyses revealed that these 16 new sequences belong to five different molecular groups. The A. nigroviridis STLV-1 strains exhibited a very strong nucleotide similarity with HTLV-1 of the subtype B. Furthermore, four novel STLV-1, found in Cercocebus torquatus, C. m. mona, C. nictitans, and Chlorocebus aethipos, were identical to each other and to a previously described Papio anubis STLV-1 strain (PAN 503) originating from the same primate center in Cameroon. Our data extend the range of the African primates who could be permissive and/or harbor naturally STLV-1 and provide new evidences of cross-transmission of African STLV-1 between different monkey species living in the same environment and also of STLV-1 transmissions from some monkeys to humans in Central Africa.

Africa↗
PubMed2001

Molecular characterization and phylogenetic analysis of a human T cell leukemia virus type 2 strain from French Guiana.

Extensive studies have been carried out on native Amerindian populations living in French Guiana in an attempt to detect human T cell leukemia virus type 2 (HTLV-2). However, the first strain of this virus identified in this region was not detected in these populations, but in a Brazilian woman of Amerindian origin. Comparative analyses of the nucleotide sequences of 589 bp of the gp21 env gene and of 625 bp of the long terminal repeat (LTR) showed that this new HTLV-2 strain (HTLV-2 GUY) was of subtype A. Sequence comparison and phylogenetic analyses demonstrated that HTLV-2 GUY was closely related to a group of distinct variants of HTLV-2 subtype A strains originating mostly from Brazilian inhabitants and formerly called HTLV-2 subtype C. As there is a high level of immigration from Brazil in French Guiana, we carried out a seroepidemiological study of 175 Brazilians, mostly women (obtained from a serum databank) and 72 female Brazilian prostitutes living in French Guiana to determine whether HTLV-2 is likely to become an emerging infection in this area. No HTLV-2 infection was detected, indicating that this virus is unlikely to become prevalent in the near future.

Base Sequence↗
PubMed2001

Somatic mutation in human T-cell leukemia virus type 1 provirus and flanking cellular sequences during clonal expansion in vivo.

BACKGROUND: Human T-cell leukemia virus type 1 (HTLV-1), the causative agent of adult T-cell leukemia/lymphoma, shows intrapatient genetic variability. Although HTLV-1 can replicate via the reverse transcription of virion RNA to a double-stranded DNA provirus (the conventional manner for retroviruses), its predominant mode of replication is via the clonal expansion (mitosis) of the infected cell. This expansion is achieved by the viral oncoprotein Tax, which keeps the infected CD4 T lymphocyte cycling. Because Tax also interferes with cellular DNA repair pathways, we investigated whether somatic mutations of the provirus that occur during the division of infected cells could account for HTLV-1 genetic variability. METHODS: An inverse polymerase chain reaction strategy was designed to distinguish somatic mutations from reverse transcription-associated substitutions. This strategy allows the proviral sequences to be isolated together with flanking cellular sequences. Using this method, we sequenced 208 HTLV-1 provirus 3' segments, together with their integration sites, belonging to 29 distinct circulating cellular clones from infected individuals. RESULTS: For 60% of the clones, 8%-80% of infected cells harbored a mutated HTLV-1 provirus, without evidence of reverse transcription-associated mutations. Mutations within flanking cellular sequences were also identified at a frequency of 2.8 x 10(-4) substitution per base pair. Some of these clones carried multiple discrete substitutions or deletions, indicating progressive accumulation of mutations during clonal expansion. The overall frequency of somatic mutations increased with the degree of proliferation of infected T cells. CONCLUSIONS: These data indicate that, in vivo, HTLV-1 variation results mainly from postintegration events that consist of somatic mutations of the proviral sequence occurring during clonal expansion. The finding of substitutions in flanking sequences suggests that somatic mutations occurring after integration, presumably coupled with selection, help move the cellular clones toward a transformed phenotype, of which adult T-cell leukemia/lymphoma is the end point.

Adult↗
PubMed2001

Human T cell leukemia virus Type I (HTLV-I) infection induces greater expansions of CD8 T lymphocytes in persons with HTLV-I-associated myelopathy/tropical spastic paraparesis than in asymptomatic carriers.

A quantitative study of the T cell receptor repertoire was performed ex vivo on CD4 and CD8 T cell subsets of human T cell leukemia virus type I (HTLV-I)-infected asymptomatic carriers and patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Indexes of oligoclonality that compiled all repertoire modifications were calculated for peripheral blood mononuclear cells and for CD4 and CD8 T cell subsets. Both patients with HAM/TSP and asymptomatic carriers had greater T lymphocyte expansions than did uninfected donors, which was independent of age and at least twice higher in the CD8 than in the CD4 cell compartment. Some expanded CD8 T cells corresponded to cytotoxic T lymphocytes directed against various epitopes of the immunodominant Tax protein. Patients with HAM/TSP had significantly higher CD8 cell expansions than did asymptomatic carriers. These results highlight the prognostic value of measuring CD8 T cell expansions during follow-up of HTLV-I infection.

Adult↗
PubMed2001

Sporadic inclusion body myositis in a patient with human T cell leukemia virus type 1-associated myelopathy.

Sporadic inclusion body myositis is a disease of unknown pathogenesis in which a viral etiology has long been suspected. We report a case that occurred in a patient with human T cell leukemia virus type 1-associated myelopathy. The diagnosis was confirmed by histopathological studies of the deltoid muscle. Nucleic acids amplification and in situ hybridization indicated the presence of integrated proviral DNA and viral mRNA transcripts in the lesions.

Adult↗
PubMed2001

A novel gamma 2-herpesvirus of the Rhadinovirus 2 lineage in chimpanzees.

Old World monkeys and, recently, African great apes have been shown, by serology and polymerase chain reaction (PCR), to harbor different gamma2-herpesviruses closely related to Kaposi's sarcoma-associated Herpesvirus (KSHV). Although the presence of two distinct lineages of KSHV-like rhadinoviruses, RV1 and RV2, has been revealed in Old World primates (including African green monkeys, macaques, and, recently, mandrills), viruses belonging to the RV2 genogroup have not yet been identified from great apes. Indeed, the three yet known gamma2-herpesviruses in chimpanzees (PanRHV1a/PtRV1, PanRHV1b) and gorillas (GorRHV1) belong to the RV1 group. To investigate the putative existence of a new RV2 Rhadinovirus in chimpanzees and gorillas we have used the degenerate consensus primer PCR strategy for the Herpesviral DNA polymerase gene on 40 wild-caught animals. This study led to the discovery, in common chimpanzees, of a novel gamma2-herpesvirus belonging to the RV2 genogroup, termed Pan Rhadino-herpesvirus 2 (PanRHV2). Use of specific primers and internal oligonucleotide probes demonstrated the presence of this novel gamma2-herpesvirus in three wild-caught animals. Comparison of a 1092-bp fragment of the DNA polymerase obtained from these three animals of the Pan troglodytes troglodytes subspecies, one from Gabon and the two others from Cameroon, revealed <1% of nucleotide divergence. The geographic colocalization as well as the phylogenetic "relationship" of the human and simian gamma2-herpesviruses support the model according to which herpesviruses have diversified from a common ancestor in a manner mediating cospeciation of herpesviruses with their host species. By demonstrating the existence of two distinct Rhadinovirus lineages in common chimpanzees, our finding indicates the possible existence of a novel human gamma2-herpesvirus belonging to the RV2 genogroup.

Animals↗
PubMed2001

Serological, epidemiological, and molecular differences between human T-cell lymphotropic virus Type 1 (HTLV-1)-seropositive healthy carriers and persons with HTLV-I Gag indeterminate Western blot patterns from the Caribbean.

To investigate the significance of serological human T-cell lymphotropic virus type 1 (HLTV-1) Gag indeterminate Western blot (WB) patterns in the Caribbean, a 6-year (1993 to 1998) cross-sectional study was conducted with 37,724 blood donors from Guadeloupe (French West Indies), whose sera were routinely screened by enzyme immunoassay (EIA) for the presence of HTLV-1 and -2 antibodies. By using stringent WB criteria, 77 donors (0.20%) were confirmed HTLV-1 seropositive, whereas 150 (0.40%; P < 0.001) were considered HTLV seroindeterminate. Among them, 41.3% (62) exhibited a typical HTLV-1 Gag indeterminate profile (HGIP). Furthermore 76 (50.7%) out of the 150 HTLV-seroindeterminate subjects were sequentially retested, with a mean duration of follow-up of 18.3 months (range, 1 to 70 months). Of these, 55 (72.4%) were still EIA positive and maintained the same WB profile whereas the others became EIA negative. This follow-up survey included 33 persons with an HGIP. Twenty-three of them (69.7%) had profiles that did not evolve over time. Moreover, no case of HTLV-1 seroconversion could be documented over time by studying such sequential samples. HTLV-1 seroprevalence was characterized by an age-dependent curve, a uniform excess in females, a significant relation with hepatitis B core (HBc) antibodies, and a microcluster distribution along the Atlantic coast of Guadeloupe. In contrast, the persons with an HGIP were significantly younger, had a 1:1 sex ratio, did not present any association with HBc antibodies, and were not clustered along the Atlantic façade. These divergent epidemiological features, together with discordant serological screening test results for subjects with HGIP and with the lack of HTLV-1 proviral sequences detected by PCR in their peripheral blood mononuclear cell DNA, strongly suggest that an HGIP does not reflect true HTLV-1 infection. In regard to these data, healthy blood donors with HGIP should be reassured that they are unlikely to be infected with HTLV-1 or HTLV-2.

Adolescent↗
PubMed2001

Immunogenicity and protective efficacy of recombinant human T-cell leukemia/lymphoma virus type 1 NYVAC and naked DNA vaccine candidates in squirrel monkeys (Saimiri sciureus).

We assessed the immunogenicities and efficacies of two highly attenuated vaccinia virus-derived NYVAC vaccine candidates encoding the human T-cell leukemia/lymphoma virus type 1 (HTLV-1) env gene or both the env and gag genes in prime-boost pilot regimens in combination with naked DNA expressing the HTLV-1 envelope. Three inoculations of NYVAC HTLV-1 env at 0, 1, and 3 months followed by a single inoculation of DNA env at 9 months protected against intravenous challenge with HTLV-1-infected cells in one of three immunized squirrel monkeys. Furthermore, humoral and cell-mediated immune responses against HTLV-1 Env could be detected in this protected animal. However, priming the animal with a single dose of env DNA, followed by immunization with the NYVAC HTLV-1 gag and env vaccine at 6, 7, and 8 months, protected all three animals against challenge with HTLV-1-infected cells. With this protocol, antibodies against HTLV-1 Env and cell-mediated responses against Env and Gag could also be detected in the protected animals. Although the relative superiority of a DNA prime-NYVAC boost regimen over addition of the Gag component as an immunogen cannot be assessed directly, our findings nevertheless show that an HTLV-1 vaccine approach is feasible and deserves further study.

Animals↗
PubMed2001

Human T-cell lymphotropic virus type 1 Tax represses c-Myb-dependent transcription through activation of the NF-kappaB pathway and modulation of coactivator usage.

The proto-oncogene c-myb is essential for a controlled balance between cell growth and differentiation. Aberrant c-Myb activity has been reported for numerous human cancers, and enforced c-Myb transcription can transform cells of lymphoid origin by stimulating cellular proliferation and inhibiting apoptotic pathways. Here we demonstrate that activation of the NF-kappaB pathway by the HTLV-1 Tax protein leads to transcriptional inactivation of c-Myb. This conclusion was supported by the fact that Tax mutants unable to stimulate the NF-kappaB pathway could not inhibit c-Myb transactivating functions. In addition, inhibition of Tax-mediated NF-kappaB activation by coexpression of IkappaBalpha restored c-Myb transcription, and Tax was unable to block c-Myb transcription in a NEMO knockout cell line. Importantly, physiological stimuli, such as signaling with the cellular cytokines tumor necrosis factor alpha, interleukin 1 beta (IL-1beta), and lipopolysaccharide, also inhibited c-Myb transcription. These results uncover a new link between extracellular signaling and c-Myb-dependent transcription. The mechanism underlying NF-kappaB-mediated repression was identified as sequestration of the coactivators CBP/p300 by RelA. Interestingly, an amino-terminal deletion form of p300 lacking the C/H1 and KIX domains and unable to bind RelA retained the ability to stimulate c-Myb transcription and prevented NF-kappaB-mediated repression.

Animals↗