The Pathogenesis Of Tropical Spastic Paraparesis/human T-cell Leukemia Type I-associated Myelopathy

Tropical spastic paraparesis/human T-cell leukemia type I-associated myelopathy (TSP/HAM) is caused by a human T-cell leukemia virus type I (HTLV-I) after a long incubation period. TSP/HAM is characterized by a chronic progressive paraparesis with sphincter disturbances, no/mild sensory loss, the absence of spinal cord compression and seropositivity for HTLV-I antibodies. The pathogenesis of this entity is not completely known and involves a multivariable phenomenon of immune system activation against the presence of HTLV-I antigens, leading to an inflammatory process and demyelination, mainly in the thoracic spinal cord. The current hypothesis about the pathogenesis of TSP/HAM is: 1) presence of HTLV-I antigens in the lumbar spinal cord, noted by an increased DNA HTLV-I load; 2) CTL either with their lytic functions or release/production of soluble factors, such as CC-chemokines, cytokines, and adhesion molecules; 3) the presence of Tax gene expression that activates T-cell proliferation or induces an inflammatory process in the spinal cord; 4) the presence of B cells with neutralizing antibody production, or complement activation by an immune complex phenomenon, and 5) lower IL-2 and IFN-γ production and increased IL-10, indicating drive to a cytokine type 2 pattern in the TSP/HAM subjects and the existence of a genetic background such as some HLA haplotypes. All of these factors should be implicated in TSP/HAM and further studies are necessary to investigate their role in the development of TSP/HAM.331213951401Aboulafia, D.M., Clinical implications of human T-cell leukemia virus type I/II-associated diseases (1995) AIDS Reader, 5, pp. 118-125Uchiyama, T., Yodoi, J., Sagawa, K., Takatsuki, K., Uchino, H., Adult T-cell leukemia: Clinical and hematologic features of 16 cases (1977) Blood, 50, pp. 481-492Osame, M., Janssen, R., Kubota, H., Nishitani, H., Igata, A., Nagataki, S., Mori, M., Khabbaz, R., Nationwide survey of HTLV-I-associated myelopathy in Japan: Association with blood transfusion (1990) Annals of Neurology, 28, pp. 50-56Gessain, A., Barin, F., Vernant, J.C., Gout, O., Maurs, L., Calender, A., De The, G., Antibodies to human T-lyrnphotropic virus type-I in patients with tropical spastic paraparesis (1985) Lancet, 2, pp. 407-410Osame, M., Usuku, J., Izumo, S., Ijichi, N., Amitani, H., Igata, A., Matsumoto, M., Tara, M., HTLV-I-associated myelopathy: A new clinical entity (1985) Lancet, 1, pp. 1031-1032Gessain, A., Gout, O., Chronic myelopathy with human T-lymphotropic virus type I (HTLV-I) (1992) Annals of Internal Medicine, 117, pp. 933-946Iwasaki, Y., Pathology of chronic myelopathy associated with HTLV-I infection (TSP/HAM) (1990) Journal of Neurological Sciences, 96, pp. 103-123Seiki, M., Hattori, S., Hirayama, Y., Yoshida, M., Human adult T-cell leukemia virus: Complete nucleotide sequence of the provirus genome integrated in leukemia cell DNA (1983) Proceedings of the National Academy of Sciences, USA, 80, pp. 3618-3622Murphy, E.L., Blattner, W.A., HTLV-I-associated leukemia: A model for chronic retroviral diseases (1988) Annals of Neurology, 23, pp. S174-S180Piccardo, P., Ceroni, M., Rodgers-Johnson, P., Mora, C., Asher, D.M., Char, G., Gibbs C.J., Jr., Gajdusek, D.C., Pathological and immunological observations on tropical spastic paraparesis in patients from Jamaica (1988) Annals of Neurology, 23, pp. 156-160Azizuki, S., Nakasato, O., Higuchi, Y., Tanabe, K., Setoguchi, M., Yoshida, S., Miyazaki, Y., Okajima, T., Necropsy findings in HTLV-I associated myelopathy (1987) Lancet, 1, pp. 156-157Tendler, G.L., Greenberg, S.J., Blattner, W.A., Manns, A., Murphy, E., Fleisher, T., Hanchard, B., Waldmann, T.A., Transactivation of mterleukin 2 and its receptor induces immune activation in human T-cell lymphotropic virus type I-associated myelopathy: Pathogenic implications and a rationale for immunotherapy (1990) Proceedings of the National Academy of Sciences, USA, 87, pp. 5218-5222Cheng, H., Tranok, J., Parks, W.P., Human immunodeficiency virus type 1 genome activation induced by human T-cell leukemia virus type 1 tax protein is through cooperation of NF-kB and tat (1998) Journal of Virology, 72, pp. 6911-6916Gessain, A., Saal, F., Gout, O., Daniel, M.T., Flandrin, G., De The, G., Peries, J., Sigaux, F., High human T-cell lymphotropic virus type I proviral DNA load with polyclonal integration in peripheral blood mononuclear cells of French West Indian, Guianese, and African patients with tropical spastic paraparesis (1990) Blood, 75, pp. 428-433Nagai, M., Usuku, K., Matsumoto, W., Kodama, D., Takenouchi, T.M., Hashiguchi, S., Ichinose, M., Osame, M., Analysis of HTLV-I proviral load in 202 TSP/HAM patients and 243 asymptomatic HTLV-I carriers: High proviral load strongly predisposes to TSP/HAM (1998) Journal of Neurovirology, 4, pp. 586-593Manns, A., Miley, J.W., Wilks, J.R., Morgan, O.C., Hanchard, B., Warfe, G., Cranston, B., Waters, D., Quantitative proviral DNA and antibody levels in the natural history of HTLV-I infection (1999) Journal of Infectious Diseases., 180, pp. 1487-1493Hara, H., Autoimmune mechanism in TSP/HAM (1994) Nippon Rinsho, 52, pp. 2919-2925Levin, M.C., Krichavsky, M., Berk, J., Foley, S., Rosenfeld, M., Dalmau, J., Chang, G., Jacobson, S., Neuronal molecular mimicry in immune-mediated neurologic disease (1998) Annals of Neurology, 44, pp. 87-98Hoffman, T.L., Doms, R.W., Chemokines and coreceptors in HIV/SIV-host interactions (1998) AIDS, 12 (SUPPL. A), pp. S17-S26Copeland, K.F.T., Heeney, J.L., T helper cell activation and human retroviral pathogenesis (1996) Microbiological Reviews, 60, pp. 722-742Oliva, A., Kinter, A.L., Vaccarezza, M., Rubbert, A., Catanzaro, A., Mo'r, S., Monaco, J., Fauci, A.S., Natural killer cells from human immunodeficiency virus (HIV)-in-fected individuals are an important source of CC-chemokines and suppress HIV-1 entry and replication in vitro (1998) Journal of Clinical Investigation, 102, pp. 223-231Umehara, F., Izumo, S., Takeya, M., Takahashi, K., Sato, E., Osame, M., Expression of adhesion molecules and monocyte chemcattractant protem-1 (MCP-1) in the spinal cord lesions in HTLV-I-associated myelopathy (1996) Acta Neuropathologica, 91, pp. 343-350Giraudon, P., Buart, S., Bernard, A., Belin, M.F., Cytokines secreted by glial cells infected with HTLV-I modulate the expression of matrix metalloproteinases (MMPs) and their natural inhibitor (TIMPs): Possible involvement in neurodegenerative processes (1997) Molecular Psychiatry, 2, pp. 107-110Greten, T.F., Slansky, J.E., Kubota, R., Soldan, S.S., Jaffee, E.M., Leist, T.P., Pardoll, D.M., Schneck, J.P., Direct visualization of antigen-specific T cells: HTLV-1 Taxi11-19-specific CD8(+) T cells are activated in peripheral blood and accumulate in cerebrospinal fluid from TSP/ HAM patients (1998) Proceedings of the National Academy of Sciences, USA, 95, pp. 7568-7573Biddison, W.E., Kubota, R., Kawanishi, T., Taub, D.D., Cruikshank, W.W., Center, D.M., Connor, E.W., Jacobson, S., Human T cell leukemia virus type I (HTLV-I)-specific CD8+ CTL clones from patients with HTLV-I-associated neurologic disease secrete proinflammatory cytokines, chemokmes, and matrix metalloproteinase (1997) Journal of Immunology, 159, pp. 2018-2025Hoffman, P.M., Dhib-Jalbut, S., Mikovits, J.A., Robbins, D.S., Wolf, A.L., Bergey, G.K., Lohrey, N.C., Ruscetti, F.W., Human T-cell leukemia virus type I infection of monocytes and microglial cells in primary human cultures (1992) Proceedings of the National Academy of Sciences, USA, 89, pp. 11784-11788Fox, R.J., Levin, M.C., Jacobson, S., Tumor necrosis factor alpha expression in the spinal cord of human T-cell lymphotrophic virus type I associated myelopathy/tropical spastic paraparesis patients (1996) Journal of Neurovirology, 2, pp. 323-329Nagai, M., Ijichi, S., Hall, W.W., Osame, M., Differential effect of TGF-beta 1 on the in vitro activation of HTLV-I and the proliferates response of CDS+ T lymphocytes in patients with HTLV-I-associated myelopathy (TSP/HAM) (1995) Clinical Immunology and Immunopathology, 77, pp. 324-331Saarloos, M.N., Koenig, R.E., Spear, G.T., Elevated levels of iC3b and C4d, but not Bb, complement fragments from plasma of persons infected with human T cell leukemia virus HTLVI with HTLV-I-associated myelopathy/tropical spastic paraparesis (1995) Journal of Infectious Diseases, 172, pp. 1095-1097Lira, J., Nakamura, M., Sawada, Y., Ohori, N., Itoyama, Y., Yamamoto, N., Sakaki, Y., Goto, I., Antibody titers to HTLV-Ip40tax protein and gag-env hybrid protein in HTLV-I-associated myelopathy/tropical spastic paraparesis: Correlation with increased HTLV-I proviral DNA load (1992) Journal of Neurological Sciences, 107, pp. 98-104Usuku, K., Sonoda, S., Osame, M., Yashiki, S., Takahashi, K., Matsumoto, M., Sawada, T., Igata, A., HLA haplotype-linked high immune responsiveness against HTLV-I in HTLV-I-associated myelopathy: Comparison with adult T-cell leukemia/lymphoma (1988) Annals of Neurology, 23, pp. 143-150Godoy, A.J., Itoyama, Y., Tokunaga, K., Hara, H., Kawaga, Y., Kiyokawa, H., Maeda, Y., Goto, I., Allolymphocytotoxic antibodies in sera from HTLV-I-associated myelopathy/tropical spastic paraparesis patients-putative anti-HLA antibodies (1994) Journal of Neurological Sciences, 125, pp. 62-69Uchiyama, T., Human T cell leukemia virus type I (HTLV-I) and human diseases (1997) Annual Review of Immunology, 15, pp. 15-37Manns, A., Hanchard, B., Morgan, O.S., Wilks, R., Cranston, B., Nam, J.M., Blank, M., Sonoda, S., Human leukocyte antigen class II alleles associated with human T-cell lymphotropic virus type I infection and adult T-cell leukemia/ lymphoma in a Black population (1998) Journal of the National Cancer Institute, 90, pp. 617-622Jeffery, K.J.M., Usuku, K., Hall, S.E., Matsumoto, W., Taylor, G.P., Procter, J., Bunce, M., Bangham, C.R.M., HLA alleles determine human T-lymphotropic virus-I (HTLV-I) proviral load and the risk of HTLV-I-associated myelopathy (1999) Proceedings of the National Academy of Sciences, USA, 96, pp. 3848-3853Bangham, C.R.M., Kermode, A.L., Hall, S.E., Daenke, S., The cytotoxic T-lymphocyte response to HTLV-I: The main determinant of disease? (1996) Seminars in Virology, 7, pp. 41-48Höllsberg, P., Pathogenesis of chronic progressive myelopathy associated with human T-cell lymphotropic virus type I (1997) Acta Neurologica Scandinavica, 169 (SUPPL.), pp. 86-93Elovaara, I., Koenig, S., Brewah, A.Y., Woods, R.M., Lehky, T., Jacobson, S., High human T cell lymphotropic virus type 1 (HTLV-1)-specific precursor cytotoxic T lymphocyte frequencies in patients with HTLV-1-associated neurological disease (1993) Journal of Experimental Medicine, 177, pp. 1567-1573Casseb, J., Hong, M.A., Salomão, S., Duarte, A.J.S., Gallo, D., Hendry, R.M., Comfection with human immunodeficiency virus and human T-cell lymphotropic virus type I: Reciprocal activation with clinical and immunological consequences (1997) Clinical Infectious Diseases, 25, pp. 1259-1260Casseb, J., Is HTLV-I more clever than HIV-I? (1998) Clinical Infectious Diseases, 27, pp. 1309-131

Techniques used to identify the Brazilian variant of HIV-1 subtype B

The purpose of the present study was to compare the sensitivity and specificity of V3 enzyme immunoassay (solid phase EIA and EIA inhibition) and restriction fragment length polymorphism (RFLP) with the DNA sequencing "gold standard" to identify the Brazilian HIV-1 variants of subtype B and B"-GWGR. Peripheral blood mononuclear cells were collected from 61 HIV-1-infected individuals attending a clinic in São Paulo. Proviral DNA was amplified and sequentially cleaved with the Fok I restriction enzyme. Plasma samples were submitted to a V3-loop biotinylated synthetic peptide EIA. Direct partial DNA sequencing of the env gene was performed on all samples. Based on EIA results, the sensitivity for detecting B-GPGR was 70%, compared to 64% for the Brazilian variant B"-GWGR while, the specificity of B-GPGR detection was 85%, compared to 88% for GWGR. The assessment of RFLP revealed 68% sensitivity and 94% specificity for the B-GPGR strain compared to 84 and 90% for the B"-GWGR variant. Moreover, direct DNA sequencing was able to detect different base sequences corresponding to amino acid sequences at the tip of the V3 loop in 22 patients. These results show a similar performance of V3 serology and RLFP in identifying the Brazilian variant GWGR. However, V3 peptide serology may give indeterminate results. Therefore, we suggest that V3 serology be used instead of DNA sequencing where resources are limited. Samples giving indeterminate results by V3 peptide serology should be analyzed by direct DNA sequencing to distinguish between B-GPGR and the Brazilian variant B"-GWGR

Association between muscle strength and the cardiopulmonary status of individuals living with HIV/AIDS

OBJECTIVE: The purpose of this study was to compare aerobic function [anaerobic threshold (%VO2-AT), respiratory compensation point (%VO2-RCP) and peak oxygen uptake (VO2peak)] between physically active patients with HIV/AIDS and matched controls and to examine associations between disease status, poor muscle strength, depression (as estimated by the profile of mood states questionnaire) and the aerobic performance of patients. METHODS: Progressive treadmill test data for %VO2-AT (V-slope method), RCP and (VO2peak) were compared between 39 male patients with HIV/AIDS (age 40.6±1.4 years) and 28 male controls (age 44.4±2.1 years) drawn from the same community and matched for habitual physical activity. Within-patient data were also examined in relation to CD4+ counts (nadir and current data) and peak isokinetic knee torque. RESULTS: AT, RCP and (VO2peak) values were generally similar for patients and controls.Within the patient sample, binary classification suggested that AT, RCP and (VO2peak) values were not associated with either the nadir or current CD4+ count, but treadmill test variables were positively associated with peak isokinetic knee torque. CONCLUSION: The aerobic performance of physically active patients with HIV/AIDS is generally well conserved. Nevertheless, poor muscle strength is observed in some HIV/AIDS patients, which is associated with lower anaerobic power and (VO2peak), suggesting the possibility of enhancing the aerobic performance of patients with weak muscles through appropriate muscle-strengthening activities

Association between muscle strength and the\ud cardiopulmonary status of individuals living with\ud HIV/AIDS

OBJECTIVE: The purpose of this study was to compare aerobic function [anaerobic threshold (%_VVO2-AT),\ud respiratory compensation point (%_VVO2-RCP) and peak oxygen uptake (_VVO2peak)] between physically active patients\ud with HIV/AIDS and matched controls and to examine associations between disease status, poor muscle strength,\ud depression (as estimated by the profile of mood states questionnaire) and the aerobic performance of patients.\ud METHODS: Progressive treadmill test data for %_VVO2-AT (V-slope method), RCP and (_VVO2peak) were compared\ud between 39 male patients with HIV/AIDS (age 40.6¡1.4 years) and 28 male controls (age 44.4¡2.1 years) drawn\ud from the same community and matched for habitual physical activity. Within-patient data were also examined in\ud relation to CD4+ counts (nadir and current data) and peak isokinetic knee torque.\ud RESULTS: AT, RCP and (_VVO2peak) values were generally similar for patients and controls.Within the patient sample,\ud binary classification suggested that AT, RCP and (_VVO2peak) values were not associated with either the nadir or\ud current CD4+ count, but treadmill test variables were positively associated with peak isokinetic knee torque.\ud CONCLUSION: The aerobic performance of physically active patients with HIV/AIDS is generally well conserved.\ud Nevertheless, poor muscle strength is observed in some HIV/AIDS patients, which is associated with lower anaerobic\ud power and (_VVO2peak), suggesting the possibility of enhancing the aerobic performance of patients with weak\ud muscles through appropriate muscle-strengthening activities

Living Invisible: HTLV-1-Infected Persons and the Lack of Care in Public Health

Human T-cell lymphotropic virus type 1 (HTLV-1) infection is commonly confounded with Human Immunodeficiency Virus (HIV) infection and it is unknown to many health professionals. It is endemic in many countries and there is no effective treatment available. Although a few individuals have severe symptoms, most patients remain asymptomatic throughout their lives. Further, HTLV-1 is considered a neglected public health problem and limited studies cover specific patients' needs and emotional experiences. To better understand how women and men living with HTLV-1 experience the disease and what issues exist in their healthcare processes, we conducted a qualitative study of both symptomatic and asymptomatic patients at an outpatient clinic at the Emílio Ribas Infectious Diseases Institute in São Paulo, Brazil. We found that the main focus of health staff was on illness risk, but not identifying infected relatives and preventing new infections. This point of view, ultimately neglected patients' complex demands, and overshadows the prevention of new infections and contributes to the lack of care in public health for HTLV-1 infected subjects. Furthermore, this perpetuates the infection among these populations and the patients experience an “invisibility” of their specific needs, such as reproductive rights and feel that their rights as citizens are ignored

HLA-C stability and AIDS progression

HLA-C stability influence AIDS progressio

Tuberculosis among HIV-1-infected subjects in a tertiary out-patient service in São Paulo city, Brazil

Atualmente, a tuberculose (TB) é considerada a doença infecciosa mais importante entre os pacientes infectados pelo HIV-1 nos países em desenvolvimento, como o Brasil. Análise retrospectiva dos casos de tuberculose ocorridos a partir de janeiro 1995 até dezembro de 2010 foi realizada em nossa coorte de 599 pacientes HIV positivos. O desfecho primário foi a ocorrência de TB ativa, e 41 casos da doença foram diagnosticados durante este período de 16 anos. As contagens médias do nadir de células T CD4 e ao momento do diagnóstico de TB foram de 146 e 217 células/mm³, respectivamente. A carga viral média de HIV foi de 5,19 log10 cópias/mL, e 59% dos pacientes estavam em tratamento com ART. A incidência de TB foi de 1,47 casos por 100 pessoas-ano, para um tempo total de seguimento da coorte de 2775 pessoas-ano. A probabilidade de sobreviver até 10 anos após o diagnóstico foi de 75% para pacientes com TB, em oposição a 96% para pacientes com outras doenças oportunistas não-TB (p = 0,03). A tuberculose pode ser considerada problema de saúde pública entre as pessoas que vivem com HIV no Brasil, apesar da ampla utilização de anti-retrovirais para o tratamento da infecção pelo HIV / AIDS.TB is currently considered to be the most important infectious disease among HIV-1-infected subjects in developing countries, such as Brazil. A retrospective analysis of TB cases was performed, occurring from January 1995 to December 2010 in our cohort of 599 HIV positive patients. The primary outcome was the occurrence of active TB. Forty-one TB cases were diagnosed over this period of 16 years, among 599 HIV positive patients in an open cohort setting in the city of Sao Paulo, Brazil. All-time lowest mean CD4 T cell count at the time of TB diagnosis was 146 and 186 cells/mm³, respectively. The mean HIV viral load was 5.19 log10 copies/mL, and 59% of the patients were on HAART. TB incidence was 1.47 per 100 person-years, for a total follow-up time of 2775 person-years. The probability of surviving up to 10 years after diagnosis was 75% for TB patients as opposed to 96% for patients with other, non-TB opportunistic diseases (p = 0.03). TB can be considered a public health problem among people living with HIV in Brazil despite of the widespread use of antiretrovirals for the treatment of HIV infection/AIDS

Non-cytotoxic 1,2,3-triazole tethered fused heterocyclic ring derivatives display Tax protein inhibition and impair HTLV-1 infected cells

Human T cell lymphotropic virus type 1 (HTLV-1) is a human retrovirus that infects approximately 10–20 million people worldwide and causes an aggressive neoplasia (adult T-cell leukemia/lymphoma - ATL). Therapeutic approaches for the treatment of ATL have variable effectiveness and poor prognosis, thus requiring strategies to identify novel compounds with activity on infected cells. In this sense, we initially screened a small series of 25 1,2,3-triazole derivatives to discover cell proliferation inhibitors and apoptosis inducers in HTLV-1-infected T-cell line (MT-2) for further assessment of their effect on viral tax activity through inducible-tax reporter cell line (Jurkat LTR-GFP). Eight promising compounds (02, 05, 06, 13, 15, 21, 22 and 25) with activity ≥70% were initially selected, based on a suitable cell-based assay using resazurin reduction method, and evaluated towards cell cycle, apoptosis and Tax/GFP expression analyses through flow cytometry. Compound 02 induced S phase cell cycle arrest and compounds 05, 06, 22 and 25 promoted apoptosis. Remarkably, compounds 22 and 25 also reduced GFP expression in an inducible-tax reporter cell, which suggests an effect on Tax viral protein. More importantly, compounds 02, 22 and 25 were not cytotoxic in human hepatoma cell line (Huh-7). Therefore, the discovery of 3 active and non-cytotoxic compounds against HTLV-1-infected cells can potentially contribute, as an initial promising strategy, to the development process of new drugs against ATL

DETERMINATION OF VIRAL TROPISM BY GENOTYPING AND PHENOTYPING ASSAYS IN BRAZILIAN HIV-1-INFECTED PATIENTS

The clinical application of CCR5 antagonists involves first determining the coreceptor usage by the infecting viral strain. Bioinformatics programs that predict coreceptor usage could provide an alternative method to screen candidates for treatment with CCR5 antagonists, particularly in countries with limited financial resources. Thus, the present study aims to identify the best approach using bioinformatics tools for determining HIV-1 coreceptor usage in clinical practice. Proviral DNA sequences and Trofile results from 99 HIV-1-infected subjects under clinical monitoring were analyzed in this study. Based on the Trofile results, the viral variants present were 81.1% R5, 21.4% R5X4 and 1.8% X4. Determination of tropism using a Geno2pheno[coreceptor] analysis with a false positive rate of 10% gave the most suitable performance in this sampling: the R5 and X4 strains were found at frequencies of 78.5% and 28.4%, respectively, and there was 78.6% concordance between the phenotypic and genotypic results. Further studies are needed to clarify how genetic diversity amongst virus strains affects bioinformatics-driven approaches for determining tropism. Although this strategy could be useful for screening patients in developing countries, some limitations remain that restrict the wider application of coreceptor usage tests in clinical practice