Seroprevalence of xenotropic murine leukemia virus-related virus in normal and retrovirus-infected blood donors.

BACKGROUND: Xenotropic murine leukemia virus-related virus (XMRV) has been reported in patients with prostate cancer and chronic fatigue syndrome. Although results have been conflicting, the potential of XMRV as an infectious human retrovirus has raised concerns about transfusion safety. To address this issue, normal and retrovirus-infected blood donors were screened for evidence of XMRV infection. STUDY DESIGN AND METHODS: Plasma from 1000 US, 100 human immunodeficiency virus Type 1-infected Cameroonian, and 642 human T-lymphotropic virus Type I (HTLV-I)-infected or uninfected Japanese blood donors as well as 311 sexually transmitted disease diagnostic specimens were screened for antibodies to XMRV gp70 and p15E using chemiluminescent immunoassays (CMIAs). CMIA-reactive samples were evaluated by p30 CMIA, Western blot, and real-time reverse transcriptase polymerase chain reaction. RESULTS: XMRV seroreactivity was low (0%-0.6%) with the exception of the HTLV-I-infected donors (4.9%). Antibody was detected against only a single XMRV protein (p15E or gp70); none of the seroreactive samples had detectable XMRV pol or env sequences. The elevated seroreactivity in HTLV-I-infected donors was due to an increased p15E seroreactive rate (4.1%). Inspection of XMRV and HTLV sequences revealed a high level of conservation within the immunodominant region (IDR) of the transmembrane protein. In some cases, HTLV IDR peptide competitively reduced the XMRV p15E signal. CONCLUSIONS: Based on the low prevalence of seroreactivity, detection of antibody to only a single XMRV protein and the absence of XMRV sequences, this study finds no compelling evidence of XMRV in normal or retrovirus-infected blood donors. The increased p15E seroreactivity observed in HTLV infection is likely due to cross-reactive antibodies.

Human T cell leukemia virus type 1 up-regulation after simian immunodeficiency virus-1 coinfection in the nonhuman primate.

The effects that human T cell leukemia virus (HTLV) type 1 and simian immunodeficiency virus (SIV) coinfection have on HTLV-1 dynamics and disease progression were tested in a nonhuman primate model. Seven rhesus macaques were experimentally inoculated with HTLV-1, and a persistent infection was established. Coinfection with SIV/smB670 resulted in increased HTLV-1 p19 antigens in peripheral blood mononuclear cells and HTLV-1 proviral loads. Circulating CD2(+) and CD8(+) T lymphocytes increased over preinoculation levels, along with a progressive decrease in CD4(+) T cells, typical for terminal SIV disease. Finally documented was the striking emergence of up to 19% of HTLV-associated "flower cell" lymphocytes in the circulation, as seen in patients with adult T cell leukemia/lymphoma. CD8(+)CD25(+) T cell subpopulation increases were positively correlated with flower cell appearance and suggested their possible role in this process. We conclude that SIV may have the potential to up-regulate HTLV-1 and disease expression.

Comparison of antigenic sites of the envelope glycoprotein of the Iranian isolate of human T-cell leukemia virus type 1 with different subtypes of the virus.

OBJECTIVE: Human T-cell leukemia virus type 1 (HTLV-1) is an enveloped retrovirus, which is associated with a T-cell malignancy known as adult T-cell leukemia (ATL). Variation in the HTLV-1 envelope nucleotide sequence has been extensively documented and has been used to classify HTLV-1 isolates into different subtypes. The virus occurs in at least 3 subtypes, which have been named A, B, and C. We conducted this study to compare the antigenic proprieties of the Iranian isolate of HTLV-1 with the homologous region of different subtypes of the virus. METHODS: This study took place in the Department of Biology, College of Sciences, Shiraz University, Iran in 2005. The predicted antigenic sites and secondary structure of the envelope glycoprotein of HTLV-1, present in Iran, have been compared with the antigenic sites and secondary structure of the homologous domains in subtypes A, B, C of the virus. To predict the epitopes of glycoproteins, 21 different scales were used. RESULTS: The number of helices in the Iranian isolate was equal to the number of these regions in all 3 subtypes, but the number of beta-sheets was more than other viruses. One potential glycosylation site, on all these studied envelope glycoproteins, was predicted. Antigenic sites in the Iranian isolate were almost similar to subtype A of the virus and the Iranian isolate of HTLV-1 may be belongs to subtype A. CONCLUSION: Our results indicate the similarities and differences between the Iranian and other subtypes of HTLV-1. Antigenic sites represent potential candidates for use in a peptide vaccine against HTLV-1 glycoproteins and since most of the properties of a particular protein depend on its structural properties, this type of study can help in better understanding of HTLV-1 isolates present in Iran.

Neuropathogenic murine leukemia virus TR1.3 induces selective syncytia formation of brain capillary endothelium.

Exposure of newborn BALB/c mice to murine leukemia virus (MLV) TR1.3 induces fusion of brain capillary endothelial cells (BCEC), loss of cerebral vessel integrity, hemorrhagic stroke, and death. Although TR1.3 infects endothelial cells in multiple organs, syncytia are only observed in BCEC. To determine if viral and cellular factors are responsible for selective syncytia formation, capillary endothelial cells (CEC) from multiple organs were assayed in vitro for MLV infection and cell fusion. Following incubation with virus, all CEC were infected to an equal extent as determined by expression of MLV envelope and infectious virus production; however, MLV-induced syncytia were only observed in TR1.3-infected BCEC cultures. These in vitro results mirror the in vivo pattern of TR1.3 MLV infection and neuropathology, and definitively show that selective fusion and pathology of BCEC by MLV is determined by properties unique to BCEC as contrasted to other endothelial cell types.

Detection of porcine endogenous retrovirus (PERV) using highly specific antisera against Gag and Env.

Porcine endogenous retroviruses (PERV) are considered an obstacle to the safe use of cells, tissues, and organs from pigs in the course of xenotransplantation. Thus, the detection of viral proteins and of a potential PERV infection is of major interest. Recently, we have published the generation of a highly specific antiserum directed against the nucleocapsid (p10) of PERV (Xenotransplantation 7 (2000), 221). Here we present new peptide-antisera specific to the capsid protein (p30) and the surface molecule of PERV class B (SU, gp70(B)) as well as the transmembrane moiety of the envelope protein (TM, p15E) of PERV which showed functionality in several immunological assays, such as immunoblots, immunofluorescence, and immunogold staining. Thus, these antisera can be used as tools for the identification of viral proteins in basic research as well as clinical trials.

Aberrant expression of HOXA9, DEK, CBL and CSF1R in acute myeloid leukemia.

Previous gene function analyses have indicated that HOXA9, DEK, CBL and CSF1R are aberrantly expressed in acute myeloid leukemia (AML). We analyzed the expression of these genes in a series of 41 adult patients with AML using quantitative real-time RT-PCR, and tested the association of the expression with the following hematologic and clinical parameters: age, FAB, immunophenotype and karyotype aberrations. A high proportion of the patients showed over- or underexpression of the analyzed genes. DEK was overexpressed in 98% of the cases, whereas CBL, CSF1R and HOXA9 were either overexpressed in 20%, 17% and 78% or underexpressed in 20%, 42% and 15% of the cases, respectively. Patients whose karyotype contained t(8;21)(q22;q22), showed lower relative expression of HOXA9 at a statistically significant level (p < 0.05). Bone marrow samples without expression of CD34 antigen were associated with either overexpression of DEK or HOXA9. Furthermore, an association was found between the AML-M2 subtype and lower expression of CBL, CSF1R or HOXA9, and between the AML-M5 subtype and CBL or CSF1R overexpression.

Intracellular distribution of human T-cell leukemia virus type 1 Gag proteins is independent of interaction with intracellular membranes.

Retrovirus Gag proteins are synthesized on free ribosomes, and are sufficient to govern the assembly and release of virus particles. Like type C retroviruses, human T-cell leukemia virus type 1 (HTLV-1) assembles and buds at the plasma membrane. After immunofluorescence staining, HTLV-1 Gag proteins appear as punctuated intracellular clusters, which suggests that they are associated either with intracellular membranes or with the plasma membrane. However, colocalization experiments using a panel of markers demonstrated that Gag proteins were not associated with the membranes involved in the secretory or endocytosis pathway. Small amounts of Gag proteins were detected at the plasma membrane and colocalized with the envelope glycoproteins. Moreover, Gag proteins were excluded from streptolysin-O permeabilized cells and in this respect behaved like cytoplasmic proteins. This suggests that the trafficking of HTLV-1 Gag proteins through the cytoplasm of the host cell is independent of any cell membrane system.

Comparison of early plasma RNA loads in different macaque species and the impact of different routes of exposure on SIV/SHIV infection.

Various simian immunodeficiency virus (SIV)sm/mac and simian/human immunodeficiency virus (SHIV) strains are used in different macaque species to study AIDS pathogenesis, as well as to evaluate candidate vaccine and anti-retroviral drugs efficacy. In this study we investigated the effect of route of infection, species of macaques and nature of virus stock on early plasma viral RNA load. We monitored the plasma RNA concentrations of 63 rhesus (Macaca mulatta) and cynomolgus macaques (Macaca fascicularis) infected with well-characterised virus stocks administered either by oral, rectal, vaginal or intravenous (i.v.) routes. In SIV(mac)-infected macaques, no significant difference in plasma RNA loads was observed between the rectal, oral and i.v. routes of infection. Cynomolgus macaques developed lower steady state SIV plasma RNA concentrations compared with rhesus macaques and no significant difference was observed between rectal and i.v. routes of infection. In SHIV(89.6p)-infected macaques, no difference between species or between route of infection was observed with this particular chimeric virus.

Long-term effects of HTLV-1 on brain astrocytes: sustained expression of Tax-1 associated with synthesis of inflammatory mediators.

HTLV-1 is the causative agent of a chronic neurological disease, TSP/HAM. The persistently activated CTL response to the viral protein Tax-1 suggests the existence of persistent viral replication with continuous expression of Tax-1. Although CD4+ T-cell is the main target for HTLV-1, previous observations have indicated that the astrocyte, the major neural cell in close contact with blood vessel and thus with HTLV-1-infected T-cells infiltrating the CNS, may also be infected. We tested in vitro the hypothesis of persistent/restricted infection in human and rat astrocytes after transient contact with an infectious T-cell line (C91PL). Long-term analysis showed prolonged expression of Tax-1 in astrocytes, associated with secretion of inflammatory mediators (TNFalpha, IL1alpha, MMP-2, and MMP-9). These data suggest a possible contribution of Tax-1-expressing astrocytes to TSP/HAM pathogenesis.

Mitogenic phospholipase D activity is restricted to caveolin-enriched membrane microdomains.

Phospholipase D (PLD) activity is elevated in response to the oncogenic stimulus of several signaling oncogenes. PLD activity is also elevated in response to peptide growth factors, indicating that PLD likely plays an important role in mitogenic signaling. Many proteins that mediate mitogenic signaling are localized in caveolin-enriched membrane microdomains (CEMMs). We report here that the elevated PLD activity in NIH 3T3 cells transformed by activated oncogenic forms of Src, Ras, and Raf is largely restricted to the CEMMs. Likewise, the PLD activity stimulated by epidermal growth factor is also restricted to the CEMMs. Although both PLD1 and PLD2 were found in CEMMs, neither was particularly enriched in the CEMMs of the transformed relative to the parental cells, indicating that it is the specific activity of PLD that is increased in the CEMMs. An apparent PLD substrate specificity in transformed cells for phosphatidylcholine lacking arachidonate acyl groups is also explained by the localization of activity in the CEMMs where [(3)H]arachidonate-labeled PC was excluded. These data indicate that mitogenic signals through PLD are initiated in CEMMs where many signaling molecules colocalize.

Elevated phosphorylation of AKT and Stat3 in prostate, breast, and cervical cancer cells.

We examined whether the persistent activation of AKT or Stat3 oncogene product is present in prostate, breast, and cervical cancer cells. We found that some prostate and breast cancer cell lines express high levels of phosphorylated AKT. Interestingly, the cancer cells, which only express low levels of phosphorylated AKT express high levels of phosphorylated Stat3. AKT or Stat3 is also highly phosphorylated in human papilloma virus-negative cervical cancer cells. Therefore, these results indicate that AKT and Stat3 are highly phosphorylated in some breast, prostate and cervical cancer cells, which may play a role in tumorigenesis of these cancers.

Establishment of a seronegative human T-cell leukemia virus type 1 (HTLV-1) carrier state in rats inoculated with a syngeneic HTLV-1-immortalized T-cell line preferentially expressing Tax.

Human T-cell leukemia virus type 1 (HTLV-1) causes T-cell malignancies in a small percentage of the population infected with the virus after a long carrier state. In the present study, we established a seronegative HTLV-1 carrier state in rats inoculated with a newly established HTLV-1-infected rat T cell line, FPM1. FPM1 originated from rat thymocytes cocultured with a human HTLV-1 producer, MT-2 cells, and expressed rat CD4, CD5, CD25, and HTLV-1 Tax. However, FPM1 scarcely expressed other major HTLV-1 structural proteins and failed to induce typical antibody responses against HTLV-1 in inoculated rats. In contrast, control rats inoculated with MT-2 cells generated significant levels of anti-HTLV-1 antibodies. HTLV-1 proviruses were detected in peripheral blood cells of syngeneic rats inoculated with FPM1 for more than 1 year. Analysis of the flanking region of HTLV-1 provirus integrated into host cells suggested that FPM1 cells remained in these animals over a relatively long period of time. However, a similar seronegative HTLV-1 carrier state was induced in the rats inoculated with mitomycin C-treated FPM1 cells and also in FPM1-inoculated allogeneic rats, suggesting that FPM1 could also transmit HTLV-1 into host cells in vivo. Our findings indicated that (i) HTLV-1-immortalized T cells which preferentially express HTLV-1 Tax persisted in vivo but failed to induce any diseases in immunocompetent syngeneic rats and that (ii) suboptimal levels of HTLV-1 for antibody responses allowed the establishment of persistent HTLV-1 infection.

Anti-HIV type 1 activity of wild-type and functional defective RANTES intrakine in primary human lymphocytes.

We have developed a genetic "intrakine" strategy to inactivate the CC-chemokine receptor 5 (CCR-5), the principal coreceptor for macrophage (M)-tropic HIV-1 viruses (Yang et al, 1997). The inactivation of CCR5 was achieved by targeting a modified CC-chemokine (RANTES) to the lumen of the endoplasmic reticulum (ER) to block the transport of the newly synthesized CCR-5. The transduced lymphocytes with the phenotypic CCR5 knockout were shown to be resistant to M-tropic HIV-1 infection. This study illustrated the feasibility of the intrakine strategy to block HIV-1 infection. In our current study, the potential clinical application of the intrakine approach was further evaluated in human peripheral blood lymphocytes (PBLs). PBLs were transduced with the RANTES intrakine gene by using retroviral vectors with the truncated low-affinity human nerve growth factor receptor (deltaNGFR) marker, and then isolated by an anti-NGFR antibody/magnetic bead method. The surface expression of CCR-5 in the transduced lymphocytes was dramatically inhibited, as demonstrated by flow cytometric assays. The transduced PBLs were shown to resist various types of M-tropic HIV-1 virus infection. The cell viability, cell proliferation rates, and cell surface markers of the intrakine-transduced PBLs were shown to be comparable to those of control PBLs. The transduced PBLs were also found to respond to the stimulation of various CXC- and CC-chemokines, other than RANTES. The transduced PBLs responded to tetanus antigen stimulation by increasing IL-2 production and cell proliferation. In addition, a functionally defective mutant of RANTES that retains its binding activity to CCR-5, but loses its signaling ability, was used to generate a mutant RANTES intrakine. The primary lymphocytes transduced with the mutant RANTES intrakine were found to be resistant to M-tropic HIV-1 infection. From these results, we conclude that the primary human lymphocytes transduced with either the wild-type or functionally defective RANTES intrakine are resistant to M-tropic HIV-1 infection, and maintain their basic biological functions. This study, therefore, indicates the potential clinical application of the intrakine approach for HIV-1 gene therapy.

Relationship between anti-Tax antibody responses and cocultivatable virus in HTLV-I-infected rabbits.

The presence of anti-Tax antibody responses in human T cell leukemia virus type I (HTLV-I)-infected individuals has been correlated with increased proviral load, increased risk of transmitting infection, and increased risk of developing tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM). In this study, a rabbit model of HTLV-I infection was used to determine whether anti-Tax antibody responses could predict the presence of virus with the potential to replicate. Seven of 14 HTLV-I-infected rabbits developed anti-Tax antibody responses. The onset of Tax reactivity was variable, but once detected remained constant throughout the remainder of the 60-week course of the study. All anti-Tax antibody positive rabbits produced virus as measured by p19 expression upon coculture, while p19 was detected in only one of the Tax antibody negative animals. Thus the presence of an anti-Tax antibody response correlates with p19 expression following cocultivation, and may be a useful predictor of virus replication in HTLV-I infected individuals.

An improved method for generating retroviral producer clones for vectors lacking a selectable marker gene.

Most retroviral vectors used in preclinical and clinical studies contain a selectable marker gene to facilitate the generation of producer clones. However, the expression of such genes in target cells is often undesirable since this may modify cellular phenotype and invoke a host immune response. Unfortunately, the efficient identification of high-titer producer clones for vectors lacking a selectable marker gene continues to be problematic and lacking for a standard methodology. Despite recent improvements in the screening techniques for identifying high-titer producer clones without the aid of a selectable marker, a solution to the fundamental problem of the very low frequency occurrence of high-titer clones within the starting cell population has not emerged. We have developed a strategy which greatly increases the frequency of virus-producing clones, including those with high-titer, within the population of transduced cells to be screened. This approach relies on the use of high-titer vector preparations generated in 293T cells by co-transfection of retroviral packaging and vector plasmids. Viral preparations of a vector lacking a selectable marker were used to repeatedly transduce exponentially growing packaging cells at a high multiplicity of infection (MOI). Each cell in the resulting polyclonal population of producer cells contained multiple copies of the unrearranged vector genome. Greater than 95% of the clones derived from this population produced vector particles as judged by slot blot analysis of viral RNA from conditioned media. Numerous clones with estimated titers of 10(5)-10(6) were identified. These titers were confirmed using a standard vector genome transmission assay. This approach significantly enhances the ability, without large scale screening, to easily identify high-titer clones lacking a selectable marker and should facilitate the routine use of simplified gene marking and therapeutic vectors.

Rapid syncytium formation between human T-cell leukaemia virus type-I (HTLV-I)-infected T-cells and human nervous system cells: a possible implication for tropical spastic paraparesis/HTLV-I associated myelopathy.

Tropical spastic paraparesis/HTLV-I associated myelopathy (TSP/HAM), is characterized by infiltration of human T cell leukaemia virus type-I (HTLV-I)-infected T-cells, anti-HTLV-I cytotoxic T cells and macrophages into the patients' cerebrospinal fluid and by intrathecally formed anti-HTLV-I antibodies. This implies that the disease involves a breakdown of the blood-brain barrier. Since astrocytes play a central role in establishing this barrier, the authors investigated the hypothesis that the HTLV-I infected T cells disrupt this barrier by damaging the astrocytes. The present study revealed the HTLV-I-producing T cells conferred a severe cytopathic effect upon monolayers of astrocytoma cell line in co-cultures. Following co-cultivation, HTLV-I DNA and proteins appeared in the monolayer cells, but after reaching a peak their level gradually declined. This appearance of the viral components was proved to result from a fusion of the astrocytic cells with the virus-producing T cells, whereas their subsequent decline reflected the destruction of the resulting syncytia. This fusion could be specifically blocked by anti HTLV-I Env antibodies, indicating that it was mediated by the viral Env proteins expressed on the surface of the virus-producing cells. Similar fusion was observed between the HTLV-I-producing cells and certain other human nervous system cell lines. If such fusion of HTLV-I-infected T cells occurs also with astrocytes and other nervous system cells in TSP/HAM patients, it may account, at least partially, for the blood-brain barrier breakdown and some of the neural lesions in this syndrome.

Identification of a core functional and structural domain of the v-Ski oncoprotein responsible for both transformation and myogenesis.

The v-ski oncogene promotes cellular transformation and myogenic differentiation. In quail embryo fibroblasts the two properties are displayed simultaneously and terminal muscle differentiation occurs only among cells already transformed by v-ski. To understand how the two phenotypes are derived from a single gene, we have undertaken to identify functionally important regions in v-ski and to test whether these regions can promote one phenotype without the other. We have generated both random and targeted mutations in v-ski and evaluated the effects of these mutations on expression, intracellular location, transformation, and myogenesis. Among a total of 26 mutants analysed, we have not found complete separation of the myogenic and transforming properties. Mutations in the region of v-Ski encoded by exon 1 of c-ski frequently abolish both its transformation and muscle differentiation activities, whereas mutations outside of this region are always tolerated. When expressed in cells from a minigene containing only the exon 1 sequence, the protein displays the transforming and myogenic activities similar to v-Ski. These results argue that the amino acid sequence encoded by exon 1 contains the core functional domain of the oncoprotein. To determine whether this functional domain has a structural counterpart, we have fragmented the v-Ski protein by limited proteolysis and found a single proteolytically stable domain spanning the entire exon 1-encoded region. Physical studies of the polypeptide encoded by exon 1 confirms that it folds into a compact, globular protein. The finding that both the transforming and myogenic properties of v-Ski are inseparable by mutation and are contained in a single domain suggests that they are derived from the same function.

Use of immunohistochemistry and polymerase chain reaction for detection of oncornaviruses in formalin-fixed, paraffin-embedded fibrosarcomas from cats.

OBJECTIVE: To determine whether there was intralesional infection or expression of FeLV or feline sarcoma virus in suspected vaccine-associated fibrosarcomas in cats. DESIGN: Prospective case series. SAMPLE POPULATION: 130 suspected vaccine-associated fibrosarcomas from cats and 1 multicentric fibrosarcoma from 1 cat. PROCEDURE: Excisional biopsy specimens were fixed in formalin and embedded in paraffin. Expression of FeLV antigen was assessed, using a polyclonal goat anti-FeLV glycoprotein 70 (gp 70) serum and an avidinbiotin immunoperoxidase staining technique. The FeLV genome was detected with a polymerase chain reaction (PCR), using primers targeted to a conserved sequence in the untranslated region of the long terminal repeat (LTR) of the FeLV. RESULTS: FeLV gp 70 and LTR sequence were detected in a multicentric fibrosarcoma. All 130 of the suspected vaccine-associated fibrosarcomas were FeLV gp 70 negative on the basis of immunohistochemical test results: 100 fibrosarcomas also were examined by use of PCR and were negative for FeLV LTR region. CLINICAL IMPLICATIONS: Exogenous retroviruses, FeLV, and feline sarcoma virus were not detected in these suspected vaccine-associated fibrosarcomas, using immunohistochemistry and PCR. Additional testing will be required to determine the nature of genomic alterations that are involved in the oncogenesis of vaccine-associated fibrosarcomas in cats.

PEST-dependent cytoplasmic retention of v-Rel by I(kappa)B-alpha: evidence that I(kappa)B-alpha regulates cellular localization of c-Rel and v-Rel by distinct mechanisms.

Association of c-Rel with the inhibitor of kappaB-alpha (IkappaB-alpha) protein regulates both cellular localization and DNA binding. The ability of v-Rel, the oncogenic viral counterpart of avian c-Rel, to evade regulation by p40, the avian IkappaB-alpha protein, contributes to v-Rel-mediated oncogenesis. The yeast two-hybrid system was utilized to dissect Rel:IkappaB-alpha interactions in vivo. We find that distinct domains in c-Rel and v-Rel are required for association with p40. Furthermore, while the ankyrin repeat domain of p40 is sufficient for association with c-Rel, both the ankyrin repeat domain and the PEST domain are required for association with v-Rel. Two amino acid differences between c-Rel and v-Rel that are principally responsible for PEST-dependent association of v-Rel with p40 were identified. These same amino acids were principally responsible for PEST-dependent cytoplasmic retention of v-Rel by p40. The presence of mutations in c-Rel that were sufficient to confer PEST-dependent association of the mutant c-Rel protein with p40 did not increase the weak oncogenicity of c-Rel. However, the introduction of these two c-Rel-derived amino acids into v-Rel markedly reduced the oncogenicity of v-Rel. Deletion of the NLS of either c-Rel or v-Rel did not abolish association with p40, but did confer PEST-dependent association of c-Rel with p40. Surprisingly, deletion of the nuclear localization signal in v-Rel did not affect oncogenicity by v-Rel. Analysis of several mutant c-Rel and v-Rel proteins demonstrated that association of Rel proteins with p40 is necessary but not sufficient for cytoplasmic retention. These results are not consistent with the hypothesis that p40 regulates cellular localization of v-Rel and c-Rel by the same mechanism. Rather, these results support the hypothesis that p40 regulates cellular localization of v-Rel and c-Rel by distinct mechanisms.

Identification of human T cell leukemia/lymphoma virus type I antibodies, DNA, and protein in patients with polymyositis.

OBJECTIVE: To investigate a possible association between human T cell leukemia/lymphoma virus type I (HTLV-I) and polymyositis (PM). METHODS: Sera and muscle biopsy samples from 9 Jamaican PM patients were compared with specimens from American HTLV-I-positive PM patients and normal controls. Sera were evaluated for HTLV antibodies by enzyme-linked immunosorbent assay and Western blot. The biopsy samples were analyzed for HTLV-I/II DNA by polymerase chain reaction and were also immunohistochemically stained for HTLV gp46 envelope protein. RESULTS: Seven of the 8 Jamaican PM patients from whom sera were available were HTLV-I seropositive. The muscle biopsies of all 9 Jamaican patients demonstrated severe lymphocytic infiltration, cellular degeneration, myofiber atrophy, and fibrosis. Each muscle biopsy specimen contained HTLV-I DNA. Two of 6 samples demonstrated intense staining for HTLV-I gp46 in many of the invading mononuclear cells and weak staining for HTLV-I gp46 in many of the invading mononuclear cells and weak staining in the adjacent myocytes. Two other specimens were weakly positive for gp46 in rare mononuclear cells. All control specimens were negative for the presence of HTLV-I DNA and protein. CONCLUSION: HTLV-I is associated with an inflammatory muscle disease characterized by direct invasion of the affected muscle by HTLV-I-infected mononuclear cells.