Human T-lymphotropic Retrovirus Research Articles

Novel PRMT5-mediated arginine methylations of HSP90A are essential for maintenance of HSP90A function in NDRG2low ATL and various cancer cells

N-myc downstream-regulated gene 2 (NDRG2) as a tumor suppressor is frequently downregulated in human T-lymphotropic retrovirus (HTLV-1)-infected adult T-cell leukemia (ATL) and variety of cancers, and negatively regulates PI3K signaling pathways through dephosphorylation of PTEN with protein phosphatase 2A (PP2A). We recently identified that protein arginine methyltransferase 5 (PRMT5) is one of novel NDRG2 binding proteins and the knockdown of PRMT5 induces cell apoptosis with degradation of several signaling molecules. To investigate how the apoptosis is induced by the knockdown PRMT5 expression, heat shock protein 90 alpha (HSP90A) was identified as a binding protein for NDRG2 or PRMT5 by immunoprecipitation-mass analysis. NDRG2/PP2A complex inhibited arginine methyltransferase activity of PRMT5 through dephosphorylation at Serine 335 (S335); however, in NDRG2low ATL-related cells, highly phosphorylated PRMT5 at S335 was mainly localized in cytoplasm with binding to HSP90A, resulting in enhancing arginine-methylation at the middle domain (R345 and R386). Since knockdown of PRMT5 expression or forced expression of HSP90A with alanine replacement of R345 or R386 induced apoptosis with the degradation of client proteins in NDRG2low ATL-related and other cancer cells, we here identified that the novel arginine methylations of HSP90A are essential for maintenance of its function in NDRG2low ATL and other cancer cells.

Proteomic analysis of plasma extracellular vesicles reveals mitochondrial stress upon HTLV-1 infection

Extracellular vesicles (EVs) can participate in intercellular communication and pathogenesis. EVs contain many cargos, including proteins, and the composition of EVs differs between cell-types and activation levels. Thus, plasma EVs can be used as a biomarker of systemic response to infection and/or disease progression. In this study, we aimed at describing alterations in the protein content of plasma EVs upon infection with the human T-lymphotropic retrovirus type 1 (HTLV-1). HTLV-1 is the etiological agent of a lymphoproliferative disease (ATL) and a series of inflammatory diseases, including a neurodegenerative inflammatory disease (HAM/TSP). We found that plasma EVs are more abundant and smaller in HTLV-1 asymptomatic carriers or HAM/TSP patients when compared to uninfected healthy donors. Moreover, EVs from HTLV-1 infected donors contain markers of metabolic and mitochondrial stress.

Functional comparison of antisense proteins of HTLV-1 and HTLV-2 in viral pathogenesis

The production of antisense transcripts from the 3′ long terminal repeat (LTR) in human T-lymphotropic retroviruses has now been clearly demonstrated. After the identification of the antisense strand-encoded human T-lymphotropic virus type 1 (HTLV-1) bZIP (HBZ) factor, we reported that HBZ could interact with CRE-binding protein (CREB) transcription factors and consequently turn off the important activating potential of the viral Tax protein on HTLV-1 5′ LTR promoter activity. We have recently accumulated new results demonstrating that antisense transcripts also exist in HTLV-2, -3, and -4. Furthermore, our data have confirmed the existence of encoded proteins from these antisense transcripts (termed antisense proteins of HTLVs or APHs). APHs are also involved in the down-regulation of Tax-dependent viral transcription. In this review, we will focus on the different molecular mechanisms used by HBZ and APH-2 to control viral expression. While HBZ interacts with CREB through its basic zipper domain, APH-2 binds to this cellular factor through a five amino acid motif localized in its carboxyl terminus. Moreover, unlike APH-2, HBZ possesses an N-terminal activation domain that also contributes to the inhibition of the viral transcription by interacting with the KIX domain of p300/CBP. On the other hand, HBZ was found to induce T cell proliferation while APH-2 was unable to promote such proliferation. Interestingly, HTLV-2 has not been causally linked to human T cell leukemia, while HTLV-1 is responsible for the development of the adult T cell leukemia/lymphoma. We will further discuss the possible role played by antisense proteins in the establishment of pathologies induced by viral infection.

Paraparesia espástica tropical en un paciente con HTLV-I

The tropical spastic paraparesis associated to Human T-lymphotropic Retrovirus type 1 (HTLV-1) is a chronic, progressive myelopathy, characterized by bilateral involvement of the pyramidal tract with sphincter disorders. The main neuropathological features are chronic myelitis, perivascular injury, and parenchymal infiltration of the lymphocytes. A case is presented in this article and reviews the pathogeny, diagnosis and treatment of tropical spastic paraparesis.

Childhood leukemias and other hematopoietic malignancies: Interdependence between an infectious event and chromosomal modifications

A large number of epidemiological observations suggest an infectious origin of hematopoietic malignancies, including various forms of leukemia, nonHodgkin's lymphomas, Hodgkin's lymphomas and multiple myelomas. Incidence of nonHodgkin's lymphomas and Hodgkin's lymphomas, although not of leukemias, is substantially increased under immunosuppression. Specific chromosomal modifications (translocations) resulting in fusion genes frequently emerge as early, but not sufficient, events for malignant progression in most of these conditions. Presently less than 10% of the global incidence of leukemias and lymphomas can be linked to infections (Epstein-Barr virus, human T-lymphotropic retrovirus, human herpesvirus type 8 and Helicobacter pylori). For individual tumor types of the remaining more than 90%, several risk factors have been identified. They include occupational hazards, such as engagement in community services and agriculture, as well as time-space clustering. In childhood leukemias, a protective effect was noted for multiple infections during the first year of life and for at least 6 months of breastfeeding. A high socioeconomic state and absence of multiple contacts during the early phase of life have been described as risk factors. A hypothesis is presented here which combines these observations. It postulates a wide-spread viral infection, nontumorigenic when replication competent, but potentially leukemiogenic or carcinogenic when replication-incompetent viral genomes infect cells with specific chromosomal modifications. Existing data on polyoma-like virus types seem to render members of this or structurally related virus families as putative candidates for these malignancies.

AIDS Vaccine Development: the Past, the Present, and the Future

AIDS was first reported in 1981 by Gottlieb MS et al at USC (University of California) Medical Center: Healthy homosexual men with pneumocystis carinii pneumonia and mucosal candidiasis had deficiency in CD4 T lymphocyte, a critical immune defense cell (1). In 1983, Dr. F. Barre-Sinoussi and L. Montagnier isolated a new human T-lymphotropic retrovirus, later named HIV-1(human immunodeficiency virus type 1) which turned out to be one of the causes of AIDS (2). Through their discovery, they received the 2008 Nobel Prize in Physiology or Medicine award. Discovery of the causative agent of AIDS had been the driving force to investigate its genomic structure, function, and replication mechanism. Most importantly, the development of a diagnostic kit contributed to the knowledge of AIDS as an infectious disease especially in the route of transmission. In addition, the development of antiretroviral drugs reduced the mortality of some HIV-infected individuals. However, high price and side effects of the current therapeutic drugs have not been beneficial for most AIDS patients. Thus, it has been generally accepted that the development of a low price and effective prophylactic AIDS vaccine is the only answer to stop the global epidemic. Despite tremendous efforts over the past 25 years, there is no promising candidate for an HIV vaccine. No one has even been able to design and develop a model leading to an effective vaccine. This review will introduce four major milestones in AIDS vaccine development to date which resulted in major social, economic and scientific impacts (Fig. 1). Figure 1 Time lines for HIV/AIDS pandemic and the development for AIDS vaccines. In 1989, the hopes for a HIV vaccine started from a highly effective formalin-inactivated whole SIV vaccine which was known to confer protection in macaques with AIDS (3). However, three years later, it was found that the protective effect was mediated by antigens (such as HLA and β2m) from the human cells used to grow the viral strain (4). In 1992, Dr. Ronald Desrosiers reported that a live attenuated SIV vaccine with a deletion in the nef gene can be efficient in treating AIDS of macaques (5). Unfortunately, three years later, Dr. Ruth Ruprecht found that this live attenuated vaccine had a safety issue in which the vaccine itself caused AIDS in neonatal macaques. For this reason, research into the development of a live attenuated vaccine has been no longer carried out (6). In 1990, Genentech reported that their recombinant glycoprotein gp120 subunit vaccine could induce protection in chimpanzees with HIV-1 (7). In phase I and II trial, they confirmed the safety and immunogenicity. However, when this vaccine was tested on 5,000 volunteers to test efficacy, vaccination failed to show reduction in HIV and thus was not able to become commercialized (8). Finally, Merck Co. reported that replication-incompetent adenoviral vaccine could elicit effective anti-viral T cell immune response against SHIV (pathogenic HIV-1 and SIV hybrid virus) in 2002 (9). Based on this positive result in monkeys, they entered clinical trial to evaluate the efficacy with almost 10,000 HIV-1 negative healthy volunteers. Disappointedly, in November 2007, they announced negative results on the interim report with 3,000 volunteers. This vaccine was ineffective in lowering plasma viremia postinfection and increased the risk of acquiring HIV-1 infection; therefore, further study on the vaccine was not pursued (10). There were five major vaccines introduced as possible treatments for AIDS: killed vaccine, live-attenuated vaccine, subunit vaccine, vectored vaccine, and DNA vaccine (Table I). Among them, DNA vaccine is the most promising AIDS vaccine since it was the only one that could provide a safe and protective immunity against HIV. Despite the safety concerns of the live attenuated vaccine, it is currently the only vaccine that is capable of inducing a protective immunity. Hence, the vaccine that has similar qualities and induces a strong response of the immune system similar to that of the live attenuated vaccine is the most probable to become a successful AIDS vaccine. In this regard, the fact that the DNA vaccine with electroporation (EP) does not have a vectored immunity makes it an excellent candidate because it can induce antibodies and a T cell response by continuous injections which are as powerful as live the attenuated vaccine. Therefore, there are high expectations for DNA vaccine with EP to develop successful AIDS vaccines commercially available in the near future. Table I The Potential of the five major AIDS vaccine candidates In order to develop an effective DNA vaccine with EP, the vaccine candidate should be evaluated thoroughly in terms of protective immunity in a small number of volunteers before entering large-scale phase IIb~III efficacy trials. More importantly, even before considering any clinical trials in humans, the efficacy test should be evaluated in the appropriate SIVmac-rhesus macaque challenge model that closely resembles the human case.

Human T-lymphotropic Virus Type I Tax Activates I-κB Kinase by Inhibiting I-κB Kinase-associated Serine/Threonine Protein Phosphatase 2A

I-kappa B kinase (IKK) is a serine/threonine kinase that phosphorylates I-kappa B alpha and I-kappa B beta and targets them for polyubiquitination and proteasome-mediated degradation. IKK consists of two highly related catalytic subunits, alpha and beta, and a regulatory gamma subunit, which becomes activated after serine phosphorylation of the activation loops of the catalytic domains. The human T-lymphotropic retrovirus type-I trans-activator, Tax, has been shown to interact directly with IKK gamma and activates IKK via a mechanism not fully understood. Here we demonstrate that IKK binds serine/threonine protein phosphatase 2A (PP2A), and via a tripartite protein-protein interaction, Tax, IKK gamma, and PP2A form a stable ternary complex. In vitro, PP2A down-regulates active IKK prepared from Tax-producing MT4 cells. In the presence of Tax, however, the ability of PP2A to inactivate IKK is diminished. Despite their interaction with IKK gamma, PP2A-interaction-defective Tax mutants failed to activate NF-kappa B. Our data support the notion that IKK gamma-associated PP2A is responsible for the rapid deactivation of IKK, and inhibition of PP2A by Tax in the context of IKK x PP2A x Tax ternary complex leads to constitutive IKK and NF-kappa B activation.

Oncogenic DNA viruses.

The early discoveries of Gross (1951) of viral causation of murine leukemias, the subsequent demonstration of retroviruses as the causative factors and the presence of similar viruses particularly in lymphoproliferative disorders in cattle, cats, and various rodent species, underlined for decades the justi®cation of attempts to search for similar agents in human cancers, subsequently identi®ed as retroviruses. When Stehelin et al. (1976) proved the cellular origin of retroviral oncogenes, it appeared to be almost odd to search for agents who possess their own oncogenes and may be involved in human cancers. Yet, until today, with the exception of the human Tlymphotropic retrovirus type I as causative agent of adult T-cell leukemia, endemic in the coastal regions of southern Japan, di€erent groups of viruses emerged as prime factors even for some common human cancers. Besides Hepatitis C, they all contain DNA as genetic material and belong to very di€erent virus families. Roughly 15% of the global cancer burden can be linked to these infections. An additional 5% can be attributed to bacterial (Helicobacter pylori) and parasitic infections (Schistosoma, Opistorchis, Clonorchis). DNA virus types known to be involved in human cancers are listed in Table 1.

Viruses in human cancers

It has been one of the surprising aspects, particularly of the past 2 decades, that widespread chronic diseases, previously thought to be due to metabolic imbalances or genetic modifications, are increasingly linked to infectious events. Besides atherosclerosis, now suspected to be caused by chlamydial infections, approximately 15% of global cancer incidence is aetiologically related to specific infections. Bacteria (Helicobacter pylori) and helminths (Schistosoma, Opistorchis, Clonorchis) contribute to the development of gastric, bladder and rectal cancers and to cholangiocarcinomas. Viruses, however, emerge as major causal cancer factors. In addition to hepatocellular carcinomas, linked to hepatitis B and C virus infections, specific types of papillomaviruses have been shown to cause a major human cancer, cancer of the cervix. They have also been implicated in a number of other anogenital, oropharyngeal, and cutaneous cancers. Epstein–Barr virus (EBV), the longest known human tumour virus (since 1964), human herpes virus types 8 (HHV-8), and human T-lymphotropic retrovirus type 1 (HTLV-1) represent additional identified human tumour viruses.

Seroepidemiological Prevalence of Human T-Cell Lymphotropic Virus Type I (HTLV-I) among Healthy Blood Donors in Eastern Saudi Arabia

Seroepidemiological Prevalence of Human T-Cell Lymphotropic Virus Type I (HTLV-I) among Healthy Blood Donors in Eastern Saudi Arabia

Seroepidemiological survey of human T-lymphotropic retrovirus among indigenous populations in Taiwan.

The prevalence of human T-lymphotropic retrovirus (HTLV) was examined in Taiwan's indigenous populations. In all, 797 healthy subjects in Taiwan including Han Chinese and nine indigenous populations (Ami, Atayal, Bunun, Saisiat, Paiwan, Puyuma, Rukai, Tsuo, and Yami) were examined for the presence of antibodies to HTLV by particle agglutination, indirect immunofluorescence and Western blot test. Two seropositive cases were found in this screening. One Saisiat male and a Han Chinese female were seropositive for HTLV. The Western blot profile indicated the virus was type-1 HTLV.

Absence of Human T-lymphotropic Retrovirus Type-1 (HTLV-1) in Different Populations of Mongolia

The prevalence of human T-lymphotropic retrovirus type-1 (HTLV-1) was surveyed in Mongolia. A total of 1100 blood samples from different ethnic groups of the Mongolian population were examined for the presence of antibodies to HTLV-1 by serological tests using particle agglutination and immunofluorescence. All sera tested proved negative and Mongolian populations are therefore considered to be free from HTLV-1 infection.

HIV-1 ancestry primordial expansions of RRE and RRE related sequences

The human T-lymphotropic retroviruses HTLV-I and HIV-1/-2 share a complementary patchwork homology in which the RRE regions of HIV-1 and -2 cover 78.1% of a 169 nucleotide (nt) region (PX1,2) positioned precisely between open reading frames PX I and PX II of ATLV (HTLV-I). The sequence character of the PX1,2 region is shown to be influenced by a primordial expansion, CTC2T, originating several hundred nucleotides upstream. A second primordial expansion, AGCU(U/C), is identified and shown to represent 52.1% of the HIV-1 RRE region. It is argued that prior to the present AIDS pandemic the efficiency of the rev receptor was enhanced by an ancestral recombination event.

A seroepidemiological study of HTLV-1 infection in Nepal.

A seroepidemiological survey of antibodies to human T-lymphotropic retrovirus type-1 (HTLV-1) was carried out among 413 residents of Chitwan, Dhapakhel and Katmandu in Nepal. Donor screening was first carried out by the gelatin particle agglutination (PA) tests and positive sera were retested by an improved PA test, indirect immunofluorescence (IF) and Western blotting (WB). Nine sera showed positive reaction in the first PA screening. Among these positive sera, 1 serum was positive in the improved PA test and the IF test but negative in the WB test. This study suggests that the prevalence of HTLV-1 in Nepalese people is negligible.

Effect of human T lymphotropic retrovirus-I exposure on cultured human glioma cell lines

Four different human tumor cell lines of glial origin have been exposed to a human T lymphotropic retrovirus (HTLV-I). All these cell lines were positive for the glial marker glial fibrillary acidic protein (GFAP). The presence of virus RNA was demonstrated by in situ hybridization using an HTLV-I, SStI-SStI viral insert as probe. Virus expression has been monitored through an indirect immunofluorescence assay using a monoclonal antibody against virus core protein p19. All the four glioma cell lines tested became positive for p19 after 2 weeks of co-cultivation and showed a clear alteration of GFAP expression.

Leukemic cells from a chronic T-lymphocytic leukemia patient proliferated in response to both interleukin-2 and interleukin-4 without prior stimulation and produced interleukin-2 mRNA with stimulation

Recently, interleukin-4 (IL-4) has been clarified as having T-cell growth factor activity; therefore, it becomes of interest whether IL-4, as well as interleukin-2 (IL-2), affects the proliferation of leukemic cells derived from mature T cells. In the present study, we describe a case of chronic T-lymphocytic leukemia (T-CLL) with monoclonal proliferation of human T-lymphotropic retrovirus (HTLV)-I or HTLV-II negative CD3(+)4(+)8(-) T cell expressing IL-2 receptors without stimulation. Radiolabeled IL-2 binding assay revealed 750 high-affinity and 6,750 low-affinity binding sites per cell. In accordance with the expression of high-affinity IL-2 receptors, the leukemic cells proliferated in response to exogenous IL-2 without prior stimulation. In addition, exogenous IL-4 also induced their proliferation. Moreover, IL-2 and IL-4 exerted a synergistic effect on the leukemic cell proliferation. Although the expression of IL-2 or IL-4 mRNA was not detected in fresh leukemic cells, the expression of IL-2 mRNA, but not IL-4 mRNA, was induced by phytohemagglutinin stimulation, and the leukemic cells proliferated. These findings suggest that not only IL-2, but also IL-4 are involved in the proliferation of leukemic cells of T- CLL.

Isolation of an HTLV-1-like retrovirus from patients with tropical spastic paraparesis.

Tropical spastic paraparesis (TSP) is a slowly progressive myelopathy associated with increased serum and cerebrospinal fluid antibodies to the human T-lymphotropic retrovirus type I (HTLV-I) (ref. 1), and has been observed in many regions of the world. A similar condition known as HTLV-I-associated myelopathy occurs in the Kagoshima prefecture of Japan. Recent but controversial reports suggest involvement of virus related to HTLV-I in multiple sclerosis. Magnetic resonance imaging and electrophysiological studies indicate that TSP lesions are like multiple sclerosis in that they are disseminated throughout the nervous system. Complete virus from patients with TSP has proved difficult to isolate using techniques successful in adult T-cell leukaemia cases associated with HTLV-I. Here we report the isolation of an HTLV-I-like virus from T-cell lines derived from the peripheral blood and cerebrospinal fluid of TSP patients. The monoclonal antibody OKT3 was used to generate non-transformed T-cell lines that express HTLV-I antigens. Infectious virus was demonstrated by co-cultivation and complete, replicating virions were visualized ultrastructurally.

A seroepidemiological survey of HTLV-1 in the Philippines.

The prevalence of human T-lymphotropic retrovirus type-1 (HTLV-1) was examined in the Asian Pacific area to search for endemic foci outside Japan. A total of 1323 sera from healthy subjects in the Philippines including Filipino lowlanders, Mongoloid slash-and-burn agriculturalists and the Mongoloid aboriginal hunter-gatherers (Aeta group and Mamanwa group) were examined for the presence of antibodies to HTLV-1 by the indirect immunofluorescence test and by the Western blot technique using HTLV-1 carrying cells. Nineteen out of 20 HTLV-1 antibody carriers found in the present study are clustered in the Aeta group of Mongoloid aboriginal hunter-gatherers who have until recently been isolated in the remote mountainous areas of Luzon Island since their arrival in the Philippines during the last glacial era (12,000-15,000 years ago). This finding supports the theory that HTLV-1 originated in Mongoloid racial groups during prehistoric times.

Quasi-periodic primary structructures of core proteins of human T-lymphotropic leukemia retroviruses

Fourier analysis, previously introduced by Liquori et al. (1983, 1986), has been applied to the primary structures of two core proteins of human T-lymphotropic leukemia retroviruses HTLV-I and HTLV-II. The resulting autocorrelation functions display striking patterns that can be interpreted in terms of an approximately fourfold quasi-periodicity of the primary structures. Self-alignments of the amino acid sequences containing a few gaps are consistent with the above finding and suggest that the tertiary structure of these two homologous core proteins contains alpha-helical and delta-helical segments, the latter being characteristic of the threefold helix present in collagen structure.

The origins of HIV-1 and HTLV-4/HIV-2.

More sophisticated knowledge of the different strains of seemingly closely related retroviruses is essential to understanding acquired immunodeficiency syndrome (AIDS) and developing a successful vaccine. Distinct exogenous human retroviruses include human immunodeficiency virus type 1 (HIV-1), the etiologic agent in AIDS; human T-lymphotropic virus type 1 (HTLV-1), which has been linked with adult T-cell leukemia/lymphoma; and HTLV-II, a virus closely linked to HTLV-I but not definitively implicated in human disease. Closely related to HIV-1 is simian T-lymphotropic virus type 3 (STLV-3 mac). 30-70% of over 1000 African green monkeys tested possess antibodies to STLV-3 proteins. Of interest is the contrasting pathogenicity of HTLV-3 in seropositive Asian macques and African green monkeys; the former always have clinical or pathological evidence of immunosuppressive disease, while the latter remain healthy. Given the apparent ability of African green monkeys to mount an effective immune response against infection with STLV-3, this retrovirus offers a model system for the study of AIDS pathogenesis. It was hypothesized that STLV-3 is a distant progenitor of the AIDS virus, and that HIV-1 may have originated in Africa through the chance transmission of a simian virus to humans. A 4th human T-lymphotropic retrovirus, isolated from healthy Senegalese prostitutes in 1985 and termed HTLV-4/HIV-2, has viral proteins similar to those of STLV-3 and HIV-1. Although HTLV-4/HIV-2 is prevalent among high risk groups in West Africa, it is not associated with immunosuppression; this suggests a unique species-specific pathogenicity similar to that in STLV-3.