Acquired Immunodeficiency Syndrome: Sata T

Katano H, Sata T, Mori S. · Department of Pathology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan. · Curr Top Microbiol Immunol. · Pubmed #11443857 No free full text.

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Seki S, Kawada M, Takeda A, Igarashi H, Sata T, Matano T. · International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. · J Virol. · Pubmed #18337572 links to  free full text

Abstract: Cytotoxic T-lymphocyte (CTL) responses frequently select for immunodeficiency virus mutations that result in escape from CTL recognition with viral fitness costs. The replication in vivo of such viruses carrying not single but multiple escape mutations in the absence of the CTL pressure has remained undetermined. Here, we have examined the replication of simian immunodeficiency virus (SIV) with five gag mutations selected in a macaque possessing the major histocompatibility complex haplotype 90-120-Ia after its transmission into 90-120-Ia-negative macaques. Our results showed that even such a "crippled" SIV infection can result in persistent viral replication, multiple reversions, and AIDS progression.

Katano H, Sato Y, Hoshino S, Tachikawa N, Oka S, Morishita Y, Ishida T, Watanabe T, Rom WN, Mori S, Sata T, Weiden MD, Hoshino Y. · Department of Pathology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku, Tokyo 162-8640, Japan. · Microbes Infect. · Pubmed #18024124 links to  free full text

Abstract: Signal transducer and activator of transcription 3 (STAT3) is a DNA-binding transcription factor activated by multiple cytokines and interferons. High expression of STAT3 has also been implicated in cancer and lymphoma. Here, we show a case of B cell lymphoma in which a defective human immunodeficiency virus 1 (HIV-1) integrated upstream of the first STAT3 coding exon. The lymphoma cells with anaplastic large cell morphology formed multiple nodular lesions in the lung of an acquired immunodeficiency syndrome (AIDS) patient with Kaposi's sarcoma. The provirus had a 5' long terminal repeat (LTR) deletion, but the 3' LTR had stronger promoter activity than the STAT3 promoter in reporter assays. Immunohistochemistry showed increased expression of STAT3 in the nuclei of lymphoma cells. Transfection of STAT3 resulted in transient cell proliferation in primary B cells in vitro. Although this is a very rare case of HIV-1-integrated lymphoma, these data suggest that up-regulation of STAT3 caused by HIV-1 integration resulted in the development of B cell lymphoma in this special case.

Ueno T, Mitsuishi T, Kimura Y, Kato T, Hasegawa H, Katano H, Sata T, Kurane S, Kawana S. · Department of Dermatology, Nippon Medical School, Tokyo, Japan. · Eur J Dermatol. · Pubmed #17951139 links to  free full text

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Iwata N, Yoshida H, Tobiume M, Ono F, Shimazaki T, Sata T, Nakajima N. · Department of Pathology, National Institute of Infectious Disease, Tokyo, Japan. · J Neurovirol. · Pubmed #17454444 No free full text.

Abstract: The pathogenesis of neurologic dysfunctions caused by human immunodeficiency virus type 1 (HIV-1) infection is not yet well understood. Simian immunodeficiency virus (SIV) infection of macaques is an important animal model for HIV-1 infection. This is the first report to characterize brain progenitor cells (BPCs) isolated from embryonic brain of cynomolgus monkeys (Macaca fascicularis) by neurosphere assay and utilize BPC-derived cell culture for studying SIV infection. The self-renewal and multilineage differentiation properties of BPCs are convenient for planning viral infection experiments. The BPC-derived culture does not contain macrophage/microglial cells, fibroblasts, or endothelial cells. Thus, this culture is appropriate for studying direct relation between SIV infection and neuronal and glial cells. First, the authors characterized undifferentiated and differentiated simian BPCs by immunocytochemistry, flow cytometry analysis, real-time polymerase chain reaction (PCR), and reverse transcriptase (RT)-PCR. The BPCs induced to differentiate by the addition of 1% fetal bovine serum (FBS) were composed of heterogeneous cells expressing nestin, glial fibrillary acidic protein (GFAP), and/or tubulin beta III isoform (Tuj). None of them expressed the monocyte/macrophage/microglial marker. mRNA expression of CD4, CXCR4, CCR5, GPR1, STRL33, and APJ in both undifferentiated and differentiated BPCs were shown by RT-PCR method, suggesting that SIV would infect and replicate in this culture system. Then, it was confirmed that the neurotropic SIV strain, SIV17/E-Fr, replicated productively in BPC-derived cells. The SIV/17E-FrDelta nefGFP was inoculated to identify the infected cells and immunocytochemistry analysis revealed that green fluorescent protein (GFP)-expressing cells were mostly GFAP positive and coexpressed with SIV p27 antigen. Thus, BPC-derived cell culture system is applicable for studying SIV infection in glial and neuronal cells.

Dewan MZ, Terunuma H, Toi M, Tanaka Y, Katano H, Deng X, Abe H, Nakasone T, Mori N, Sata T, Yamamoto N. · Department of Molecular Virology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. · Cancer Sci. · Pubmed #16995875 No free full text.

Abstract: Natural killer (NK) cells are an important component of the innate immune response against microbial infections and tumors. Direct involvement of NK cells in tumor growth and infiltration has not yet been demonstrated clearly. Primary effusion lymphoma (PEL) cells were able to produce tumors and ascites very efficiently with infiltration of cells in various organs of T-, B- and NK-cell knock-out NOD/SCID/gammac(null) (NOG) mice within 3 weeks. In contrast, PEL cells formed small tumors at inoculated sites in T- and B-cell knock-out NOD/SCID mice with NK-cells while completely failing to infiltrate into various organs. Immunosupression of NOD/SCID by treatment with an antimurine TM-beta1 antibody, which transiently abrogates NK cell activity in vivo, resulted in enhanced tumorigenicity and organ infiltration in comparison with non-treated NOD/SCID mice. Activated human NK cells inhibited tumor growth and infiltration in NOG mice. Our results suggest that NK cells play an important role in growth and infiltration of PEL cells, and activated NK cells could be a promising immunotherapeutic tool against tumor or virus-infected cells either alone or in combination with conventional therapy. The rapid and efficient engraftment of PEL cells in NOG mice also suggests that this new animal model could provide a unique opportunity to understand and investigate the mechanism of pathogenesis and malignant cell growth.

Abe Y, Matsubara D, Gatanaga H, Oka S, Kimura S, Sasao Y, Saitoh K, Fujii T, Sato Y, Sata T, Katano H. · AIDS Clinical Center, Tokyo, Japan. · Pathol Int. · Pubmed #16984619 No free full text.

Abstract: The expression of Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8)-encoded proteins is herein demonstrated in Kaposi's sarcoma (KS) and multicentric Castleman's disease (MCD) in a single lymph node derived from a patient with acquired immunodeficiency syndrome. Immunohistochemistry revealed that both lytic and latent KSHV proteins were expressed in cells of the MCD lesion. KSHV-encoded viral interleukin-6 was also detected in follicular dendritic cells of the germinal center. Cytoplasmic localization of open reading frame 59 protein and latency-associated nuclear antigen suggested KSHV activation in the MCD lesion. Moreover, a high copy number of KSHV was detected in the blood. Clinically, pegylated-liposomal doxorubicin induced regression of not only KS, but also lymphadenopathy of the MCD lesion with a decrease in KSHV load and human interleukin-6 in the blood. To the best of the authors' knowledge this is the first case demonstrating differential expression of virus proteins in two KSHV-associated diseases, KS and MCD, in the same section. The case confirms lytic KSHV infection in MCD, and suggests that clinical symptoms of MCD might be closely linked with KSHV activation.

Yanagisawa Y, Sato Y, Asahi-Ozaki Y, Ito E, Honma R, Imai J, Kanno T, Kano M, Akiyama H, Sata T, Shinkai-Ouchi F, Yamakawa Y, Watanabe S, Katano H. · Department of Clinical Informatics, Tokyo Medical and Dental University, Japan. · J Pathol. · Pubmed #16741895 No free full text.

Abstract: Lymphoma usually forms solid tumours in patients, and high expression levels of adhesion molecules are observed in these tumours. However, Kaposi's sarcoma-associated herpesvirus (KSHV)-related primary effusion lymphoma (PEL) does not form solid tumours and adhesion molecule expression is suppressed in the cells. Inoculation of a KSHV-associated PEL cell line into the peritoneal cavity of severe combined immunodeficiency mice resulted in the formation of effusion and solid lymphomas in the peritoneal cavity. Proteomics using two-dimensional difference gel electrophoresis and DNA microarray analyses identified 14 proteins and 105 genes, respectively, whose expression differed significantly between effusion and solid lymphomas. Five genes were identified as having similar expression profiles to that of lymphocyte function-associated antigen 1, an important adhesion molecule in leukocytes. Among these, coronin 1A, an actin-binding protein, was identified as a molecule showing high expression in solid lymphoma by both DNA microarray and proteomics analyses. Western and northern blotting showed that coronin 1A was predominantly expressed in solid lymphomas. Moreover, KSHV-encoded lytic proteins, including viral interleukin-6, were highly expressed in effusion lymphoma compared with solid lymphoma. These data demonstrate that effusion and solid lymphomas possess distinctive gene and protein expression profiles in our mouse model, and suggest that differences in gene and protein expression between effusion and solid lymphomas may be associated with the formation of effusion lymphoma or invasive features of solid lymphoma. Furthermore, the results obtained using this combination of proteomics and DNA microarray analyses indicate that protein synthesis partly reflects, but does not correlate strictly with, mRNA production.

Minoda H, Usui N, Sata T, Katano H, Serizawa H, Okada S. · Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan. · Jpn J Ophthalmol. · Pubmed #16453181 No free full text.

Abstract: PURPOSE: To demonstrate human herpesvirus-8 (HHV-8) in Kaposi's sarcoma (KS) of the conjunctiva in a patient with acquired immunodeficiency syndrome (AIDS). METHODS: Clinical observation, pathologic findings of conjunctival specimens, immunohistochemical staining for HHV-8-specific antigen, polymerase chain reaction (PCR) analysis of HHV-8 DNA, and detection of specific antibody in patient's serum at appropriate times. RESULTS: In the conjunctival specimen, swollen endothelial-like cells were found with slit-like vessels. CD 31-positive cells were noted on the inner surface of the slit-like vessels, and HHV-8 latency-associated nuclear antigen was detected. The presence of HHV-8 DNA was demonstrated by PCR. Anti-HHV-8 antibody was found in the patient's serum. CONCLUSIONS: This is the first case report in the ophthalmology literature that provides histological, DNA, and serological evidence that HHV-8 is involved in the pathogenesis of conjunctival KS.

Tachiwana H, Shimura M, Nakai-Murakami C, Tokunaga K, Takizawa Y, Sata T, Kurumizaka H, Ishizaka Y. · Graduate School of Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku-ku, 169-8555 Tokyo, Japan. · Cancer Res. · Pubmed #16423988 links to  free full text

Abstract: Recent observations imply that HIV-1 infection induces chromosomal DNA damage responses. However, the precise molecular mechanism and biological relevance are not fully understood. Here, we report that HIV-1 infection causes double-strand breaks in chromosomal DNA. We further found that Vpr, an accessory gene product of HIV-1, is a major factor responsible for HIV-1-induced double-strand breaks. The purified Vpr protein promotes double-strand breaks when incubated with isolated nuclei, although it does not exhibit endonuclease activity in vitro. A carboxyl-terminally truncated Vpr mutant that is defective in DNA-binding activity is less capable of Vpr-dependent double-strand break formation in isolated nuclei. The data suggest that double-strand breaks induced by Vpr depend on its DNA-binding activity and that Vpr may recruit unknown nuclear factor(s) with positive endonuclease activity to chromosomal DNA. This is the first direct evidence that Vpr induces double-strand breaks in HIV-1-infected cells. We discuss the possible roles of Vpr-induced DNA damage in HIV-1 infection and the involvement of Vpr in further acquired immunodeficiency syndrome-related tumor development.

Kato M, Igarashi H, Takeda A, Sasaki Y, Nakamura H, Kano M, Sata T, Iida A, Hasegawa M, Horie S, Higashihara E, Nagai Y, Matano T. · Department of Microbiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. · Vaccine. · Pubmed #15837216 No free full text.

Abstract: Recent prophylactic vaccine trials inducing virus-specific CD8+ T-cell responses have shown control of primary infections of a pathogenic simian-human immunodeficiency virus (SHIV) in macaques. In the chronic phase, therapeutic immunization replenishing virus-specific CD8+ T-cells is likely to contribute to sustained control of virus replication. In this study, we have administered a recombinant Sendai virus (SeV) vector into five rhesus macaques that had received prophylactic vaccinations and had controlled SHIV replication for more than 1 year after challenge. Our results indicate that virus-specific CD8+ T-cell responses can be expanded and broadened by therapeutic immunization with SeV vectors in the chronic phase after prophylactic vaccine-based control of primary immunodeficiency virus infections.

Kashiwase M, Yamauchi Y, Sata T, Nagata Y, Usui N, Mochizuki M, Fujino Y, Iwasaki T, Sato Y, Kurata T, Usui M. · Department of Ophthalmology, Tokyo Medical University, Japan. · Nippon Ganka Gakkai Zasshi. · Pubmed #15359904 No free full text.

Abstract: PURPOSE: We examined eyeballs collected from autopsied acquired immunodeficiency syndrome patients with cytomegalovirus (CMV) retinitis, and analyzed the precise pathogenesis of CMV retinitis. MATERIAL AND METHODS: Eyeballs were fixed with 10% buffered formalin embedded in paraffin. CMV antigens were investigated by histopathological and immunohistochemical analyses. Histopathological findings were compared with funduscopic images. RESULTS: CMV antigens remained in the necrotic area of the retina and many CMV immediate early antigens existed in intact parts of the inner retina showing almost intact structure, and around retinal vessels. CONCLUSIONS: The results suggest that CMV infects the inner retina first via the retinal vessels, although funduscopic examination may appear normal. It extends through the neuronal cells and glial cells horizontally and Muller cells vertically. CMV severely damages the retinal structure.

Lun WH, Takeda A, Nakamura H, Kano M, Mori K, Sata T, Nagai Y, Matano T. · AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan. · J Gen Virol. · Pubmed #15218180 links to  free full text

Abstract: Virus-specific cellular immune responses play an important role in the control of immunodeficiency virus replication. However, preclinical trials of vaccines that induce virus-specific cellular immune responses have failed to contain simian immunodeficiency virus (SIV) replication in macaques. A defective provirus DNA vaccine system that efficiently induces virus-specific CD8(+) T-cell responses has previously been developed. The vaccinated macaques showed reduced viral loads, but failed to contain SIVmac239 replication. In this study, macaques that showed partial control of SIV replication were followed up to see if or how they lost this control in the chronic phase. Two of them showed increased viral loads about 4 or 8 months after challenge and finally developed AIDS. Analysis of SIV-specific T-cell levels by detection of SIV-specific gamma interferon (IFN-gamma) production revealed that these two macaques maintained SIV-specific CD8(+) T cells, even after loss of control, but lost SIV-specific CD4(+) T cells when plasma viral loads increased. The remaining macaque kept viral loads at low levels and maintained SIV-specific CD4(+) T cells, as well as CD8(+) T cells, for more than 3 years. Additional analysis using macaques vaccinated with a Gag-expressing Sendai virus vector also found loss of viraemia control, with loss of SIV-specific CD4(+) T cells in the chronic phase of SIV infection. Thus, SIV-specific CD4(+) T cells that were able to produce IFN-gamma in response to SIV antigens were preserved by the vaccine-based partial control of primary SIV replication, but were lost with abrogation of control in the chronic phase.

Sugimoto C, Tadakuma K, Otani I, Moritoyo T, Akari H, Ono F, Yoshikawa Y, Sata T, Izumo S, Mori K. · Tsukuba Primate Center for Medical Sciences, National Institute of Infectious Diseases, Tsukuba, Japan. · J Virol. · Pubmed #12634375 links to  free full text

Abstract: The pathogenesis of AIDS virus infection in a nonhuman primate AIDS model was studied by comparing plasma viral loads, CD4(+) T-cell subpopulations in peripheral blood mononuclear cells, and simian immunodeficiency virus (SIV) infection in lymph nodes for rhesus macaques infected with a pathogenic molecularly cloned SIVmac239 strain and those infected with its nef deletion mutant (Deltanef). In agreement with many reports, whereas SIVmac239 infection induced AIDS and depletion of memory CD4(+) T cells in 2 to 3 years postinfection (p.i.), Deltanef infection did not induce any manifestation associated with AIDS up to 6.5 years p.i. To explore the difference in SIV infection in lymphoid tissues, we biopsied lymph nodes at 2, 8, 72, and 82 weeks p.i. and analyzed them by pathological techniques. Maximal numbers of SIV-infected cells (SIV Gag(+), Env(+), and RNA(+)) were detected at 2 weeks p.i. in both the SIVmac239-infected animals and the Deltanef-infected animals. In the SIVmac239-infected animals, most of the infected cells were localized in the T-cell-rich paracortex, whereas in the Deltanef-infected animals, most were localized in B-cell-rich follicles and in the border region between the paracortex and the follicles. Analyses by double staining of CD68(+) macrophages and SIV Gag(+) cells and by double staining of CD3(+) T cells and SIV Env(+) cells revealed that SIV-infected cells were identified as CD4(+) T cells in either the SIVmac239 or the Deltanef infection. Whereas the many functions of Nef protein were reported from in vitro studies, our finding of SIVmac239 replication in the T-cell-rich paracortex in the lymph nodes supports the reported roles of Nef protein in T-cell activation and enhancement of viral infectivity. Furthermore, the abundance of SIVmac239 infection and the paucity of Deltanef infection in the T-cell-rich paracortex accounted for the differences in viral replication and pathogenicity between SIVmac239 and the Deltanef mutant. Thus, our in vivo study indicated that the nef gene enhances SIV replication by robust productive infection in memory CD4(+) T cells in the T-cell-rich region in lymphoid tissues.

Richardson RM, Tokunaga K, Marjoram R, Sata T, Snyderman R. · Department of Biochemistry, Meharry Medical College, 1005 Dr. D.B. Todd Jr. Boulevard, Nashville, TN 37208, USA. · J Biol Chem. · Pubmed #12594210 links to  free full text

Abstract: Human immunodeficiency virus type 1 (HIV-1) entry into CD4(+) cells requires the chemokine receptors CCR5 or CXCR4 as co-fusion receptors. We have previously demonstrated that chemokine receptors are capable of cross-regulating the functions of each other and, thus, affecting cellular responsiveness at the site of infection. To investigate the effects of chemokine receptor cross-regulation in HIV-1 infection, monocytes and MAGIC5 and rat basophilic leukemia (RBL-2H3) cell lines co-expressing the interleukin-8 (IL-8 or CXCL8) receptor CXCR1 and either CCR5 (ACCR5) or CXCR4 (ACXCR4) were generated. IL-8 activation of CXCR1, but not the IL-8 receptor CXCR2, cross-phosphorylated CCR5 and CXCR4 and cross-desensitized their responsiveness to RANTES (regulated on activation normal T cell expressed and secreted) (CCL5) and stromal derived factor (SDF-1 or CXCL12), respectively. CXCR1 activation internalized CCR5 but not CXCR4 despite cross-phosphorylation of both. IL-8 pretreatment also inhibited CCR5- but not CXCR4-mediated virus entry into MAGIC5 cells. A tail-deleted mutant of CXCR1, DeltaCXCR1, produced greater signals upon activation (Ca(2+) mobilization and phosphoinositide hydrolysis) and cross-internalized CXCR4, inhibiting HIV-1 entry. The protein kinase C inhibitor staurosporine prevented phosphorylation and internalization of the receptors by CXCR1 activation. Taken together, these results indicate that chemokine receptor-mediated HIV-1 cell infection is blocked by receptor internalization but not desensitization alone. Thus, activation of chemokine receptors unrelated to CCR5 and CXCR4 may play a cross-regulatory role in the infection and propagation of HIV-1. Since DeltaCXCR1, but not CXCR1, cross-internalized and cross-inhibited HIV-1 infection to CXCR4, the data indicate the importance of the signal strength of a receptor and, as a consequence, protein kinase C activation in the suppression of HIV-1 infection by cross-receptor-mediated internalization.

Nakajima N, Ionescu P, Sato Y, Hashimoto M, Kuroita T, Takahashi H, Yoshikura H, Sata T. · Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan. · Am J Pathol. · Pubmed #12547697 links to  free full text

Abstract: In situ hybridization is one of the most important techniques to visualize gene expression at the cellular level in various tissues. The in situ hybridization-AT tailing (ISH-AT) method uses a specially designed and synthesized oligonucleotide probe that has (AT)10 on the 3' side. This (AT)10 of the probe is elongated by DeltaTth DNA polymerase in the presence of dATP, dTTP, and labeled dUTP in the tissue after hybridization. Through this process the target is labeled with many hapten molecules. In this study, we detected human immunodeficiency virus type 1 RNA in formalin-fixed and paraffin-embedded tissues obtained from autopsied patients with acquired immunodeficiency syndrome by combining ISH-AT with the catalyzed signal amplification (CSA) system (ISH-AT-CSA), although we failed to detect signals from the same samples by conventional in situ hybridization using RNA probes (RISH) with CSA (RISH-CSA). We demonstrated that the ISH-AT-CSA method was superior to RISH-CSA in terms of both sensitivity and specificity, and that it was applicable to fluorescence in situ hybridization and double staining with immunohistochemistry for the characterization of cell phenotypes.

Rosales CM, McLaughlin MD, Sata T, Katano H, Veno PA, de Las Casas LE, Miranda RN. · Department of Pathology, Truman Medical Center, University of Missouri-Kansas City, Kansas City, Missouri, USA. · AIDS Patient Care STDS. · Pubmed #12542930 No free full text.

Abstract: Kaposi's sarcoma (KS) and bacillary angiomatosis (BA) may be histologically similar. A precise diagnosis is required because of the different management of these diseases. KS or BA involving bone marrow is rare in patients with and without acquired immune deficiency syndrome (AIDS). We report the case of a 40-year-old human immunodeficiency virus (HIV)-positive homosexual male who presented with small KS lesions in the skin and BA in the bone marrow that histologically were similar. Laboratory evaluation revealed anemia and thrombocytopenia; CD4 count was 103/mm3, and the viral load was 750,000 HIV-1 mRNA copies per milliliter in plasma. Bartonella henselae, the etiologic agent of BA, was isolated from a blood culture. DNA sequences of human herpesvirus-8 (HHV-8), the putative etiologic agent of KS, were identified by polymerase chain reaction (PCR) in skin and bone marrow specimens, but antibody anti-HHV-8-encoded protein ORF73, localized signals only in the skin-KS lesion. The patient received clarithromycin and cefotetan for the BA, and antiretroviral therapy for the HIV infection. The skin lesions gradually regressed, the HIV-1 mRNA copy number decreased to less than 400 per milliliter and the CD4 lymphocyte count increased to 665/mm3. In conclusion, vascular lesions of BA and KS may be clinically and histologically similar, both may be associated with advanced AIDS, and an accurate diagnosis is required because of their different management.

Dilnur P, Katano H, Wang ZH, Osakabe Y, Kudo M, Sata T, Ebihara Y. · Second Department of Pathology, Tokyo Medical University, Japan. · Pathol Int. · Pubmed #11844050 No free full text.

Abstract: We report 17 cases of the classic type of Kaposi's sarcoma in Xinjiang, which is located in the north-western area of China surrounded by Mongolia in the east, Russia in the north and Kazakhstan in the west. Fifteen of the patients were of the Uygur people. All patients were male and did not have acquired immunodeficiency syndrome. Most of the lesions were found in the lower and/or upper extremities, with 16 patients showing multiple lesions. Immunohistochemical examination of the lesions revealed that human herpesvirus 8 (HHV-8)-encoded latency-associated nuclear antigen was expressed in the nuclei of spindle-shaped tumor cells. HHV-8 DNA was detected by polymerase chain reaction in all seven cases examined. Phylogenetic tree analysis revealed that DNA sequences of the HHV-8-encoded K1 gene in the seven Kaposi's sarcoma cases were classified as subtype C that was common in the Mediterranean, the Middle East and East Asian countries. In addition, using immunofluorescence we investigated the seroprevalence of HHV-8 in 73 Uygur patients with diseases other than Kaposi's sarcoma. Surprisingly, the serological study revealed that 34 of the patients (46.6%) were positive for antibodies against HHV-8, suggesting that HHV-8 infection is widespread in Xinjiang area. The occurrence of the classic type of Kaposi's sarcoma with a high seropositivity rate implies that Xinjiang is the most endemic area for HHV-8 infection in the world known to date. Considering that Xinjiang is located at the middle point of the Silk Road that used to extend from Rome to China, these data imply that the virus may have been in circulation in this area due to the migration of the people via the Silk Road.

Katano H, Sato Y, Sata T. · Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan. · Cancer. · Pubmed #11753987 links to  free full text

Abstract: BACKGROUND: Kaposi sarcoma (KS) and primary effusion lymphoma (PEL) cells express human herpesvirus-8 (HHV-8)-encoded latency-associated nuclear antigen (LANA) (open reading frame [ORF] 73 protein), suggesting that LANA plays an important role in the pathogenesis of HHV-8-associated malignancies. Recently, the binding of LANA to p53 was demonstrated in vitro. In the current study, the authors investigated the association between p53 and LANA expression with apoptosis in HHV-8-associated malignancies in vivo. METHODS: Twenty-six cases of KS, 1 case of HHV-8-associated solid lymphoma, 2 PEL cell lines, and an HHV-8-associated lymphoma engrafted in severe combined immunodeficiency (SCID) mice were examined. Immunohistochemistry using the catalyzed signal amplification system was employed to detect LANA and p53 on paraffin embedded tissues and the immunofluorescence technique was used on cell lines. To detect apoptosis, the TdT-mediated dUTP nick end labeling (TUNEL) method was used. For mutation analysis of p53, exons 5-9 of the p53 gene were amplified by polymerase chain reaction and examined by direct sequencing. RESULTS: Immunohistochemistry revealed that LANA and p53 were expressed in the tumor cells of all these specimens, and apoptotic cells were rarely detected in them using the TUNEL method. Immunofluorescence assay revealed that LANA colocalized with p53 in the nuclei of PEL cells. Sequencing analysis indicated that there was no mutation in the deduced amino acid sequences of p53 in KS tissues. CONCLUSIONS: These data suggest colocalization of p53 and LANA and the inhibition of apoptosis in HHV-8-associated malignancies in vivo, supporting the results found in vitro that p53 inhibition by LANA suppresses cell death, as reported previously. These results also suggest that the p53 pathway is crucial in the pathogenesis of HHV-8-associated malignancies.

Suda T, Katano H, Delsol G, Kakiuchi C, Nakamura T, Shiota M, Sata T, Higashihara M, Mori S. · Department of Pathology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. · Pathol Int. · Pubmed #11696169 No free full text.

Abstract: Multicentric Castleman's disease (MCD) is a clinicopathologically defined entity characterized by systemic lymphadenopathy with unique pathomorphology such as angiosclerosis, blood vessel proliferation in and around follicles, and plasmacytosis. While its pathogenesis has remained unclarified for many years, identification of the human herpesvirus 8 (HHV-8) in at least some MCD cases has opened new perspectives in this field. Because previous reports have described many inconsistencies regarding HHV-8 positivity in MCD, we intended to clarify this issue by the introduction of more convincing methodologies. For this investigation, we introduced two antibodies produced in our laboratories that recognize a latent gene product ORF73 and a lytic gene product ORF59, together with two well-recognized methods, in situ hybridization for the detection of lytic phase transcript T1.1/nut-1, and genomic polymerase chain reaction (PCR). Eighty-two cases of MCD were collected from Japan (n = 75) and France (n = 7). In three cases, the patients were suffering from acquired immunodeficiency syndrome (AIDS). Immunohistochemistry and in situ hybridization showed identical results: only three out of 82 cases were positively stained, and all the positive cases were found to be the patients with AIDS. Genomic PCR was done in 43 cases, and only one case produced positive results: the only AIDS case among the 43 cases studied by genomic PCR. Histopathologically, the HHV-8-positive cases showed the highest intensity of angiosclerosis and germinal center / perifollicular vascular proliferation, while plasmacytosis was not severe in the HHV-8-positive cases. Some of the HHV-8-negative MCD cases displayed similar histopathology, but at a far less intense level, except for the plasmacytosis. These results suggest that: (i) all three of the HHV-8-positive MCD patients in the present group are the patients with AIDS; and (ii) HHV-8-positive MCD patients develop typical but marked angiosclerosis and vascular proliferation that might be differentiated from HHV-8-negative MCD patients, who showed far less intense changes.

Kashiwase M, Sata T, Yamauchi Y, Minoda H, Usui N, Iwasaki T, Kurata T, Usui M. · Department of Ophthalmology, Tokyo Medical University, Japan. · Ophthalmology. · Pubmed #10768344 No free full text.

Abstract: OBJECTIVE/BACKGROUND: To identify the etiologic agent of rapidly progressive outer retinal necrosis (PORN) in a 32-year-old man with acquired immunodeficiency syndrome (AIDS), who had retinitis developed from cytomegalovirus (CMV). Multiple yellowish spots appeared in the deep retina without evidence of intraocular inflammation or retinal vasculitis, diagnosed clinically as PORN. Death occurred after failure of multiple organs. DESIGN: Case report. METHODS: Both globes were taken at autopsy, fixed in formalin, and examined histopathologically and immunohistochemically to identify causative agents in the retinal lesions. MAIN OUTCOME MEASURE: Immunohistochemistry. RESULTS: All layers of the retina were severely damaged and contained focal calcification. Cytomegalic inclusion bodies were found in cells in the damaged retina of the right eye. Immunohistochemical studies for herpesviruses revealed the presence of CMV antigens in the right retina at the posterior pole and herpes simplex virus type 1 (HSV-1)-specific antigen in the periphery of both retinas. No varicella-zoster virus (VZV) antigen was detected in either retina. CONCLUSIONS: PORN has been described as a variant of necrotizing herpetic retinopathy, occurring particularly in patients with AIDS. Although the etiologic agent has been reported to be VZV, HSV-1 can be an etiologic agent.

Otani I, Mori K, Sata T, Terao K, Doi K, Akari H, Yoshikawa Y. · Tsukuba Primate Center, National Institute of Infectious Diseases, 1 Hachimandai, Tsukuba, Ibaraki 305-0843, Japan. · Microbes Infect. · Pubmed #10617929 No free full text.

Abstract: We investigated the histological features of lymph nodes, focusing on monocytes/macrophages, in rhesus monkeys (Macaca mulatta) acutely infected with simian immunodeficiency virus (SIV). In monkeys infected with a pathogenic SIV, SIVmac239, MAC387(+) newly blood-derived macrophages markedly increased in number at paracortical areas at 11 to 14 days postinoculation, concomitant with the peak of the primary SIV antigenemia. The MAC387(+) macrophages densely gathered around high endothelial venules and formed cell clusters with CD3(+) T lymphocytes, tingible body macrophages, and plasmacytoid monocytes. In the cell clusters, CD3(+) T lymphocytes which closely adhered to the MAC387(+) macrophages enlarged in size, suggesting a histological manifestation of T-lymphocyte activation by macrophages. By 54 days postinoculation, when SIV antigenemia became undetectable, the MAC387(+) macrophages decreased in number and the cell cluster disappeared from paracortical areas. In contrast, the monkeys infected with a nef-deleted mutant of SIVmac239 showed lower levels of SIV antigenemia and lower numbers of MAC387(+) macrophages in paracortical areas than those infected with SIVmac239. These results indicate that MAC387(+) macrophages accumulate in paracortical areas for the period of the intense primary SIV antigenemia and may play an important role in activating naive T lymphocytes.

Brandful JA, Apeagyei FA, Ampofo WK, Adu-Sarkodie Y, Ansah JE, Nuvor V, Aidoo S, Ishikawa K, Sata T, Yamamoto N, Yamazaki S. · Virology Unit, Noguchi Memorial Institute for Medical Research (NMIMR), University of Ghana, Legon. · Viral Immunol. · Pubmed #10413359 No free full text.

Abstract: In view of the strong association between the acquired immunodeficiency syndrome (AIDS) and sexually transmitted diseases (STDs), we screened 182 human immunodeficiency virus (HIV)-1 infected patients over a 15-month period for serological markers to previously encountered or current STDs, most of viral etiology. The relationship between their immunological and clinical status and the prevalence of STDs was assessed and compared with that of 88 HIV-seronegative patients. Hepatitis B virus and Treponema pallidum were the most frequently occurring pathogens in both HIV-1-infected and HIV-seronegative patients. Hepatitis C virus (HCV) infection was also observed in both groups, but no HIV-seronegative patient was infected with human T-lymphotropic virus type 1 (HTLV-1). The Centers for Disease Control clinical staging of A1 through C3, representing asymptomatic to severe AIDS conditions, was observed in HIV-1 patients with or without STDs. A mean CD4 count of 288 cells per microliter (95% CI of 237-340 cells per microliter) in HIV-1 patients was significantly lower (P < 0.05) than that in HIV-seronegative individuals with 1019 cells per microliter (95% CI of 924-1115 cells per microliter), irrespective of whether subjects in either group had previous or current STDs. The mean CD4 count of patients with a single infection from HIV-1 was not significantly different (P = 0.36) from that of HIV-1 patients with multiple infections. HIV-1 infection alone appears to be responsible for the marked immunodeficiency status of seropositive patients observed in this study.

Kano M, Matano T, Nakamura H, Takeda A, Kato A, Ariyoshi K, Mori K, Sata T, Nagai Y. · No affiliation provided · AIDS. · Pubmed #10894297 No free full text.

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Izumi Y, Ami Y, Matsuo K, Someya K, Sata T, Yamamoto N, Honda M. · AIDS Research Center. Division of Experimental Animal Research. Department of Pathology, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640. Japan. · J Virol. · Pubmed #14645581 links to  free full text

Abstract: To be effective, a vaccine against human immunodeficiency virus type 1 (HIV-1) must induce virus-specific T-cell responses and it must be safe for use in humans. To address these issues, we developed a recombinant vaccinia virus DIs vaccine (rDIsSIVGag), which is nonreplicative in mammalian cells and expresses the full-length gag gene of simian immunodeficiency virus (SIV). Intravenous inoculation of 10(6) PFU of rDIsSIVGag in cynomologus macaques induced significant levels of gamma interferon (IFN-gamma) spot-forming cells (SFC) specific for SIV Gag. Antigen-specific lymphocyte proliferative responses were also induced and were temporally associated with the peak of IFN-gamma SFC activity in each macaque. In contrast, macaques immunized with a vector control (rDIsLacZ) showed no significant induction of antigen-specific immune responses. After challenge with a highly pathogenic simian-human immunodeficiency virus (SHIV), CD4(+) T lymphocytes were maintained in the peripheral blood and lymphoid tissues of the immunized macaques. The viral set point in plasma was also reduced in these animals, which may be related to the enhancement of virus-specific intracellular IFN-gamma(+) CD8(+) cell numbers and increased antibody titers after SHIV challenge. These results demonstrate that recombinant DIs has potential for use as an HIV/AIDS vaccine.