Acquired Immunodeficiency Syndrome: Hoshino Y

Nakata K, Hoshino Y, Honda Y, Tanaka N, Hebisawa A, Weiden M. · Bioscience Medical Research Center, Niigata Medical Dental Hospital, Niigata, Japan. · Kekkaku. · Pubmed #15729891 No free full text.

Abstract: HIV-1 infection is a major cause of worldwide epidemic of tuberculosis. There is increasing clinical evidence that coinfection with M. tuberculosis accelerates progression of AIDS. We found that, in vivo, HIV-1 load and mutation increase in involved lung segments in patients with pulmonary tuberculosis. We also reported that Mycobacterium tuberculosis stimulates HIV-1 replication by enhancing transcription on the 5' LTR in a macrophage cell line, THP-1, in vitro. In contrast, HIV-1 replication is suppressed by M. tuberculosis infection of monocytes derived macrophages (MDM) or differentiated monocytic THP-1 cells. We observed that HIV-1 5' LTR function was repressed in PMA differentiated THP-1 cells after co-infection with M. tuberculosis. Point mutations in C/EBP beta binding domains of the HIV-1 LTR negative regulatory element (NRE) abolished promoter repression. Monocyte-derived macrophages and differentiated THP-1 cells increased expression of the 16kDa inhibitory form of C/EBP after M. tuberculosis co-infection. Bronchoalveolar lavage cells obtained from normal controls and alveolar macrophages from uninflamed lung of tuberculosis patients also expressed the 16kDa inhibitory form of C/EBP. However, alveolar macrophages from lung segments involved with pulmonary tuberculosis had markedly reduced C/EBP expression. These data suggest that 16kDa isoform of C/EBP plays an important role for the control of HIV-1 replication in macrophages. We propose derepression of HIV-1 LTR mediated transcription as one mechanism for enhanced HIV-1 replication observed in pulmonary tuberculosis. Since the cellular immune response in pulmonary tuberculosis requires lymphocyte/macrophage interaction, a model system was developed in which lymphocytes were added to AM. Contact between lymphocytes and AM reduced inhibitory C/EBP beta, activated NF-kappaB and enhanced HIV-1 replication. If contact between lymphocytes and macrophages was prevented, inhibitory C/EBP beta expression was maintained and the HIV-1 long terminal repeat (LTR) was not maximally stimulated although NF-kappaB was activated. Antibodies which cross-linked macrophage expressed B-7, VCAM and CD-40 were used mimic lymphocyte contact. Cross-linking antibodies abolished inhibitory C/EBP beta expression; however, the HIV-1 LTR was not maximally stimulated and NF-kappaB was not activated. Maximal HIV-1 LTR stimulation required both lymphocyte derived soluble factors and cross-linking of macrophage expressed co-stimulatory molecules. These results demonstrate that neither contact nor soluble factor(s) are sufficient to maximally enhance HIV-1 LTR activity in macrophages. Contact between activated lymphocytes and macrophages is necessary to downregulate inhibitory C/EBP beta, thereby derepressing the HIV-1 LTR. Lymphocyte derived soluble factor(s) activate NF-kappaB, further enhancing the HIV-1 LTR.

Hoshino Y, Yamashita N, Nakamura T, Iwamoto A. · Department of Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan. · Endocr J. · Pubmed #12625414 links to  free full text

Abstract: In human immunodeficiency virus infected individuals, human cytomegalovirus (CMV) remains a significant pathogen. The adrenal gland is a preferential site of CMV disease in acquired immunodeficiency syndrome (AIDS) patients. However, glucocorticoid replacement is often not selected because of the risk of exacerbating underlying infection. To evaluate the need for glucocorticoid replacement in these patients, we performed a prospective study to investigate the adrenal function in 60 advanced AIDS patients. Their adrenal function including rapid ACTH test (RAT), basal plasma ACTH level, and daily urinary free cortisol level was evaluated. Approximately 25% of the patients turned out to be abnormal in this evaluation. Almost 60% of the patients could be followed up for one year or until their death. Using the follow-up data, we calculated sensitivity, specificity, positive predictive value and negative predictive value. Excretion of urinary free cortisol with normal RAT was comparable to normal controls, whereas patients with abnormal RAT excreted significantly lower urinary free cortisol. During hospitalization, 14 patients with normal RAT had febrile episode. During the febrile period the concentration of the urinary free cortisol level increased by 2.2 times. This study suggests that glucocorticoid replacement is necessary for AIDS patients suspected as clinically adrenal insufficiency, and that the dose of glucocorticoid replacement might be increased during sick days in AIDS patients with abnormal adrenal function.

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.

Hoshino Y, Hoshino S, Gold JA, Raju B, Prabhakar S, Pine R, Rom WN, Nakata K, Weiden M. · Division of Pulmonary and Critical Care Medicine, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA. · J Infect Dis. · Pubmed #17396999 No free full text.

Abstract: BACKGROUND: Pulmonary tuberculosis (TB) can present with polymorphonuclear neutrophil (PMN)-predominant alveolitis. TB accelerates acquired immunodeficiency syndrome by increasing human immunodeficiency virus type 1 (HIV-1) replication and mutation in alveolar macrophages. A 16-kDa CCAAAT/enhancer-binding protein beta (C/EBP beta ) isoform is a strong transcriptional repressor of the HIV long terminal repeat (LTR) in resting alveolar macrophages, leading to latent viral infection; its expression is lost during TB, derepressing the HIV LTR. METHODS: Lung segments were sampled from HIV/Mycobacterium tuberculosis-coinfected patients by means of bronchoalveolar lavage. In vitro coculture experiments defined the mechanism of induction of HIV-1 infection in macrophages by PMNs. RESULTS: Lung segments from patients with PMN-predominant TB had a markedly elevated viral load. Direct contact between activated PMNs and macrophages stimulated HIV-1 replication and LTR transcription and down-regulated inhibitory C/EBP beta . Isolated PMN membranes substituted for PMN contact, derepressing the HIV-1 LTR. The lipid raft fraction of PMN membranes expressed CD40 ligand (CD40L), CD28, and leukocyte function-associated antigen 1 (LFA-1 [i.e., CD11a and CD18]), and PMN activation increased lipid raft expression of CD40L and CD28. Blocking antibodies to CD40L, CD28, and LFA-1 inhibited PMN membrane-mediated HIV-1 LTR derepression. Alternately, cross-linking of macrophage receptors for CD40L, CD28, and LFA-1 (CD40, CD80/86, and intercellular adhesion molecule 1) abolished inhibitory C/EBP beta expression. CONCLUSION: PMN-macrophage contact derepresses the HIV-1 LTR and enhances HIV-1 replication in alveolar macrophages during pulmonary TB. Derepression is mediated through costimulatory molecule signaling.

Tachikawa N, Goto M, Hoshino Y, Gatanaga H, Yasuoka A, Wakabayashi T, Katano H, Kimura S, Oka S, Iwamoto A. · AIDS Clinical Center, International Medical Center of Japan, Tokyo. · Intern Med. · Pubmed #10435361 links to  free full text

Abstract: OBJECT: Toxoplasmic encephalitis (TE), primary central nervous system lymphoma (PCNSL) and progressive multifocal leukoencephalopathy (PML) are major central nervous system (CNS) diseases in patients with acquired immunodeficiency syndrome (AIDS). We assessed the diagnostic value of polymerase chain reaction (PCR) in the detection of DNAs of Toxoplasma gondii (T. gondii), Epstein-Barr virus (EBV) and JC virus (JCV) in the cerebrospinal fluid (CSF). METHODS: We compared the PCR results with those of pathological findings at autopsy. PATIENTS OR MATERIALS: The present study included 23 autopsies representing those in whom CSF samples were obtained before death while the patient was hospitalized or at autopsy. RESULTS: The threshold levels for PCR detection were 4 tachyzoites of T. gondii, 5-15 genomes of EBV and 10 genomes of JCV. We identified T. gondii DNA in 4 out of 5 autopsy-defined cases of TE, EBV DNA in 5 out of 5 cases with PCNSL, and JCV DNA in 2 out of 2 cases with PML. The specificity of PCR was 100% in TE, 78% in PCNSL, and 100% in PML. CONCLUSION: Although the number of cases was relatively small in this study, PCR correctly identified T. gondii DNA in those cases in which PML or PCNSL was the sole clinical diagnosis. Our results indicate that PCR examination of CSF is a clinically useful tool for the diagnosis of focal brain lesions in patients with AIDS.