Hypothesis: the pathogenesis of AIDS. Activation of the T- and B-cell cascades

The hypothesis is presented that a human T-cell leukemia virus (HTLV) or a related agent produces a lytic response of T cells manifested by the acquired immune deficiency syndrome (AIDS) and a proliferative response represented by the adult leukemia/lymphoma (ATL) syndromes. The sequence or cascade of T-cell events following loss of T4 helper cells in AIDS includes reactivation of Epstein-Barr virus and a B-cell cascade of cytomegalovirus, resulting in Kaposi sarcoma in genetically susceptible persons, and of other intracellular agents (CNS viruses, M. avium intracellulari, T. gondii); opportunistic infections also occur. A comparison of AIDS and ATL syndromes is presented and the details of the B-cell cascade are outlined. The usefulness of prospective serological/immunological studies is discussed in an effort to determine the temporal sequence of infection by the candidate agents and their relation to the appearance of T4/T8 reversal and of the clinical features of AIDS.     

鼻NK／T细胞淋巴瘤间质清道夫受体A的表达及意义

目的 观察清道夫受体A（scavenger receprorA,SR-A）在鼻NK／T细胞淋巴瘤间质中的表达,探讨其意义。方法 对鼻NK／T细胞淋巴瘤,鼻B细胞淋巴瘤以及鼻部炎症的石蜡标本进行HE染色和SP免疫组织化学染色检测SR-A的表达。结果 SR-A蛋白在鼻NK／T细胞淋巴瘤,鼻B细胞淋巴瘤和鼻部炎症中阳性率分别为92．7％,29．2％和6．25%。统计学分析发现,鼻NK／T细胞淋巴瘤中SR-A的表达与B细胞淋巴瘤和炎症中SR-A的表达均有显著差异（P〈0．001）。结论 SR-A可能在鼻NK／T细胞淋巴瘤的诊断及鉴别诊断中有一定的参考价值。     

Descriptive epidemiology of Kaposi sarcoma in Europe. Report from the RARECARE project

Kaposi sarcoma (KS) is a virus-related malignancy which most frequently arises in skin, though visceral sites can also be involved. Infection with Kaposi sarcoma herpes virus (KSHV or HHV-8) is required for development of KS. Nowadays, most cases worldwide occur in persons who are immunosuppressed, usually because of HIV infection or as a result of therapy to combat rejection of a transplanted organ, but classic Kaposi sarcoma is predominantly a disease of the elderly without apparent immunosuppression. We analyzed 2667 KS incident cases diagnosed during 1995–2002 and registered by 75 population-based European cancer registries contributing to the RARECARE project. Total crude and age-standardized incidence rate was 0.3 per 100,000 per year with an estimated 1642 new cases per year in the EU27 countries. Age-standardized incidence rate was 0.8 per 100,000 in Southern Europe but below 0.3 per 100,000 in all other regions. The elevated rate in southern Europe was attributable to a combination of classic Kaposi sarcoma in some Mediterranean countries and the relatively high incidence of AIDS in several countries. Five-year relative survival for 2000–2002 by the period method was 75%. More than 10,000 persons were estimated to be alive in Europe at the beginning of 2008 with a past diagnosis of KS. The aetiological link with suppressed immunity means that many people alive following diagnosis of KS suffer comorbidity from a pre-existing condition. While KS is a rare cancer, it has a relatively good prognosis and so the number of people affected by it is quite large. Thus it provides a notable example of the importance of networking in diagnosis, therapy and research for rare cancers.     

p53 Reactivation Kills KSHV Lymphomas Efficiently In Vitro and In Vivo: New Hope for Treating Aggressive Viral Lymphomas

KSHV infection is the causative agent in three different tumor types; Kaposi’s sarcoma, a plasmablastic variant of multicentric Castelman’s disease and an AIDS-related form of B cell lymphoproliferative disorder called primary effusion lymphoma (PEL). PEL manifests as an effusion malignancy in Kaposi’s sarcoma patients with advanced AIDS, but also occurs in human immunodeficiency virus-negative individuals. PEL is a very aggressive disease, and currently there are no efficient therapies for treating PEL. In our recent paper we report that p53 reactivation by a small molecule inhibitor of p53-MDM2 interaction, Nutlin-3a, induces selective and massive apoptosis in PEL cells, and has striking anti-tumor activity in a mouse xenograft PEL model 1. In the light of current treatment regimens for PEL, we discuss here the benefits of using reactivation of the p53 pathway as a novel principle for the treatment of this virally induced highly aggressive malignancy.     

NK cell lymphoma, nasal type, with massive lung involvement: a case report

Extranodal NK/T cell lymphoma, nasal type, is an Epstein–Barr virus-associated lymphoma that most commonly involves the nasal cavity and upper respiratory tract. Lung involvement by NK/T cell lymphoma is rare and seldom reported in the literature. We describe the unusual case of a 41-year-old male with NK cell lymphoma, nasal type, who presented with massive secondary lung involvement 2.5 years after the detection of a retroperitoneal mass. The diagnosis was made by open lung biopsy. Despite aggressive treatment, the patient died shortly after the initiation of therapy. Lung involvement by NK/T cell lymphoma occurs most commonly as part of widely disseminated disease and carries a poor prognosis for the patient. Novel agents and innovative therapies need to be developed for this aggressive lymphoma.     

The Biology of Kaposi＇s Sarcoma-Associated Herpesvirus and the Infection of Human Immunodeficiency Virus

Kaposi sarcoma-associated herpesvirus (KSHV),also known as human herpesvirus 8 (HHV-8),is discovered in 1994 from Kaposi's sarcoma (KS) lesion of an acquired immunodeficiency syndrome (AIDS)patient.In addition to its association with KS,KSHV has also been implicated as the causative agent of two other AIDS-associated malignancies:primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD).KSHV is a complex DNA virus that not only has the ability to promote cellular growth and survival for tumor development,but also can provoke deregulated angiogenesis,inflammation,and modulate the patient's immune system in favor of tumor growth.As KSHV is a necessary but not sufficient etiological factor for KS,human immunodeficiency virus (HIV) is a very important cofactor.Here we review the basic information about the biology of KSHV,development of pathogenesis and interaction between KSHV and HIV.     

NKG2C+ NK cells are enriched in AIDS patients with advanced-stage Kaposi's sarcoma

Kaposi's sarcoma (KS) is an AIDS-defining condition in individuals with human immunodeficiency virus type 1 infection. We investigated the phenotype and function of the NKG2C+ NK cell population in individuals with AIDS and Kaposi's sarcoma. The staging of AIDS KS patients according to the AIDS Clinical Trial Group criteria revealed that patients with the S1 disease stage have a significantly higher proportion of NKG2C+ cells than those with the S0 disease stage. NKG2C+ cells from S1-stage patients are highly enriched for the expression of KIR3DL1, are depleted of NKp46, and respond poorly to major histocompatibility complex class I-positive target cells. These data demonstrate a link between NK cell phenotype and function and disease prognosis in AIDS.     

One method to establish Epstein‐Barr virus‐associated NK/T cell lymphoma mouse models

Novel nude mice model of human NK/T cell lymphoma were established by subcutaneously injecting two NK/T cell lymphoma cell lines into the right axillary region of mice and successful passages were completed by injecting cell suspension which was obtained through a 70‐μm cell strainer. These mice models and corresponding cell clones have been successfully developed for more than 8 generations. The survival rates of both resuscitation and transplantation in NKYS and YT models were 90% and 70% correspondingly. Pathologically, the tumour cells in all passages of the lymphoma‐bearing mice and cell lines obtained from tumours were parallel to initial cell lines. Immunologically, the tumour cells expressed the characteristics of the primary and essential NK/T lymphomas. The novel mice models maintained the essential features of human NK/T cell lymphoma, and they would be ideal tools in vivo for further research of human NK/T cell lymphoma.     

AIDS-associated malignancies: research perspectives

The appearance in 1981 of a usually rare malignancy, Kaposi’s sarcoma, in homosexual men [1] was one of the first harbingers of an epidemic caused by a retrovirus, human immunodeficiency virus (HIV), which causes the acquired immunodeficiency syndrome (AIDS). Lymphoid and other malignancies were also increased, most strikingly non-Hodgkin’s lymphoma and primary central nervous system (CNS) lymphoma. Advances in molecular biology, immunology, virology, and anti-viral therapy have combined to create unique research opportunities. One developing theme is the role of viral co-infection and malignancy. Human herpes virus 8 (HHV8), Epstein-Barr virus (EBV) and papilloma virus each may have a causal role in the development of HIV-associated malignancy. New antiretroviral therapies are able to substantially reverse or delay the profound immunosuppression of HIV infection. The changes in the epidemiology of malignancies, and understanding the mechanism of action of these new therapeutics provide research opportunities to understand the pathogenesis of these malignancies. The opportunities to discover the consequences of T-cell based immunodeficiency and the interactions with specific viral pathogens will likely lead to progress in HIV treatment and new strategies for other malignancies.     

Viruses, cancer and AIDS

Patients with AIDS are at risk of lymphoma and Kaposi's sarcoma. These tumours are associated with the gamma herpesviruses, Epstein-Barr virus (EBV) and human herpesvirus 8 (HHV-8), although a proportion of AIDS lymphomas lacks both viruses. EBV and HHV-8 are latent in the tumour cells, with genes that play a direct role in driving cell proliferation. Human immunodeficiency virus, in contrast, while being the greatest risk factor for lymphoma and Kaposi's sarcoma, acts indirectly, mainly by causing immune suppression, as immunosuppressed transplant patients are at risk for the same types of tumour.     

KSHV Latency Locus Cooperates with Myc to Drive Lymphoma in Mice

Kaposi sarcoma-associated herpesvirus (KSHV) has been linked to Kaposi sarcoma and B-cell malignancies. Mechanisms of KSHV-induced oncogenesis remain elusive, however, in part due to lack of reliable in vivo models. Recently, we showed that transgenic mice expressing the KSHV latent genes, including all viral microRNAs, developed splenic B cell hyperplasia with 100% penetrance, but only a fraction converted to B cell lymphomas, suggesting that cooperative oncogenic events were missing. Myc was chosen as a possible candidate, because Myc is deregulated in many B cell lymphomas. We crossed KSHV latency locus transgenic (latency) mice to Cα Myc transgenic (Myc) mice. By itself these Myc transgenic mice develop lymphomas only rarely. In the double transgenic mice (Myc/latency) we observed plasmacytosis, severe extramedullary hematopoiesis in spleen and liver, and increased proliferation of splenocytes. Myc/latency mice developed frank lymphoma at a higher rate than single transgenic latency or Myc mice. These data indicate that the KSHV latency locus cooperates with the deregulated Myc pathways to further lymphoma progression.     

Biological response of endothelial cells and its modulation by cytokines: prospects for therapy and bioprocesses

Endothelial cells are involved in important pathological situations. They could be the target for infectious processes as for example in Cowdriosis, an important disease in cattle due to the rickettsia Cowdria ruminantium prevalent in the south of the Sahara. They are also connected to angiogenic processes related to tumor invasion. Our results indicate that AIDS related Kaposi sarcoma cells may be of endothelial origin. We conclude from our data the mobility of those cells, related to the expression of the metalloproteinases (especially the 92 kD form of the enzyme), is an important factor in Kaposi saroma dissemination and is the main factor limiting the scale up of Cowdriosis vaccine production in Bovine Umbilical Endothelial Cell line. We showed that PMA and TNF increased the 92 kD Metallaproteinase and that TGFβ, produced in an inactive form in cultures of Human Umbilical Vein Endothelial Cells, is a potential inhibitor of Kaposi sarcoma spreading, and could also be useful in improving our process for Cowdria ruminantium vaccine production, since it reduces the sensitivity of the cells to mechanical stress without affecting significantly the overall infectious process. This revised version was published online in June 2006 with corrections to the Cover Date.     

Exposure to the anti-TNF-alpha drug thalidomide induces apoptotic cell death in human T leukemic cells.

TNF-alpha is a pro-inflammatory cytokine that plays a key role in disorders due to HIV-1 infection and replication such as Kaposi sarcoma, wasting, aphthous ulcerations and progression to AIDS. The controversial drug thalidomide is anti-inflammatory, anti-angiogenic and a selective inhibitor of TNF-alpha that is being studied as a treatment for HIV-1-related disorders, immune disorders and cancer. The cellular and molecular mechanism of thalidomide is unclear despite renewed clinical interest in the drug. Previous data from this laboratory indicate that thalidomide decreases cell growth and cell-cell interactions of human T leukemic cells. The specific aim of the present study is to determine whether thalidomide administration induces cell death via apoptosis. Low dose thalidomide treatment of human T leukemic cells exhibited rapid increases in caspase-3 activity, annexin V-FITC binding and DNA disintegration that is characteristic of apoptosis. These data indicate that low doses of thalidomide signal human T leukemic cells to die by apoptosis, which is a possible method of altering inflammatory cells and inflammatory activities.     

Prevention and treatment of KSHV-associated diseases with antiviral drugs

s Kaposi's sarcoma-associated herpesvirus (KSHV) was first identified as the etiologic agent of Kaposi's sarcoma (KS) in 1994.KSHV infection is necessary,but not sufficient for the development of Kaposi sarcoma (KS),primary effusion lymphoma (PEL),and multicentric Castleman disease (MCD).Advances in the prevention and treatment of KSHV-associated Diseases have been achieved,even though current treatment options are ineffective,or toxic to many affected persons.The identification of new targets for potential future therapies and the randomized trial to evaluate the efficacy of new antivirals are required.     

Depression of murine natural killer cell cytotoxicity by isobutyl nitrite

Summary We have investigated the effect of isobutyl nitrite on murine NK-cell antitumor-directed cytotoxicity. This agent has been suggested as one of the factors underlying immunodeficiency syndrome (AIDS) in man. We demonstrated that two injections, each of 0.25 ml isobutyl nitrite, resulted in significant depression of endogenous splenic and peripheral blood natural killer (NK) cell cytotoxicity against T-cell lymphoma, YAC-1. In addition to endogenous NK cells, activity of pyrimidinol-activated NK cells was also substantially depressed by this agent. The latter observation is of the utmost importance, since it suggests that the attempt to augment NK-cell activity (to promote resistance to infections and malignancies) could fail in patients with AIDS who are isobutyl nitrite users. Isobutyl nitrite was NK-cell-suppressive not only after in vivo administration but, most importantly, also after inhalation. This indicates that isobutyl nitrite, via its NK-cell suppressive effect, could contribute to immunodeficiency in AIDS. Studies on the mechanism of NK-cell depression by isobutyl nitrite demonstrated that the NK-cell tumor-binding properties as well as NK-cell cytotoxic potential were substantially depressed. Mixing experiments failed to reveal any regulation by suppressor cell activities. The results of these studies clearly indicate that isobutyl nitrite is an immunosuppressive agent and that its use should be avoided. Abbreviations used: NK, natural killer; S-RPMI 1640, supplemented tissue culture medium 1640; HEPES, N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid; TBC, tumor-binding cells; C-TBC, cytotoxic tumor-binding cells; AIPP, 2-amino-5-iodo-6-phenyl-4 pyrimidinol; LU, lytic units; T:E, target-to-effector; AIDS, acquired immunodeficiency syndrome     

γ-Herpesvirus Load as Surrogate Marker of Early Death in HIV-1 Lymphoma Patients Submitted to High Dose Chemotherapy and Autologous Peripheral Blood Stem Cell Transplantation

Autologous stem cell transplantation (ASCT) is a feasible procedure for human immunodeficiency virus-1 (HIV-1) lymphoma patients, whose underlying disease and intrinsic HIV-1- and ASCT-associated immunodeficiency might increase the risk for γ-herpesvirus load persistence and/or reactivation. We evaluated this hypothesis by investigating the levels of Epstein-Barr virus (EBV)- and Kaposi sarcoma-associated herpesvirus (KSHV)-DNA levels in the peripheral blood of 22 HIV-1-associated lymphoma patients during ASCT, highlighting their relationship with γ-herpesvirus lymphoma status, immunological parameters, and clinical events. EBV-DNA was detected in the pre-treatment plasma and peripheral blood mononuclear cells (PBMCs) of 12 (median 12135 copies/mL) and 18 patients (median 417 copies/10⁶ PBMCs), respectively; the values in the two compartments were correlated (r = 0.77, p = 0.0001). Only EBV-positive lymphomas showed detectable levels of plasma EBV-DNA. After debulking chemotherapy, plasma EBV-DNA was associated with lymphoma chemosensitivity (p = 0.03) and a significant higher mortality risk by multivariate Cox analysis adjusted for EBV-lymphoma status (HR, 10.46, 95% CI, 1.11–98.32, p = 0.04). After infusion, EBV-DNA was detectable in five EBV-positive lymphoma patients who died within six months. KSHV-DNA load was positive in only one patient, who died from primary effusion lymphoma. Fluctuations in levels of KSHV-DNA reflected the patient’s therapy and evolution of his underlying lymphoma. Other γ-herpesvirus-associated malignancies, such as multicentric Castleman disease and Kaposi sarcoma, or end-organ complications after salvage treatment were not found. Overall, these findings suggest a prognostic and predictive value of EBV-DNA and KSHV-DNA, the monitoring of which could be a simple, complementary tool for the management of γ-herpesvirus-positive lymphomas in HIV-1 patients submitted to ASCT.     

Racial and other characteristics of human T cell leukemia/lymphoma (HTLV-I) and AIDS (HTLV-III) in Trinidad.

Adult T cell leukaemia/lymphoma was first recognised as a clinical entity in southwest Japan. Subsequently the Caribbean has been found to be another area where the disease is endemic, and sporadic cases have been identified in different parts of the world. The human T cell leukaemia/lymphoma virus (HTLV-I) is causally related to adult T cell leukaemia/lymphoma. A subgroup of HTLV, designated HTLV-III, has recently been isolated from many patients with the acquired immunodeficiency syndrome (AIDS) and preAIDS, and there is now evidence that this variant is the primary cause of AIDS. This is the first report from Trinidad to describe 12 cases of adult T cell leukaemia/lymphoma and 14 of AIDS. All were in patients of African descent. No cases were seen in subjects of East Indian descent, who, like those of African descent, comprise as much as 40% of the population. West Indians of African descent may have increased susceptibility to infection with both HTLV-I and HTLV-III.     

Serous fluid cytology of multicentric Castleman’s disease and other lymphoproliferative disorders associated with Kaposi sarcoma‐associated herpes virus: a review with case reports

C. Lobo, S. Amin, A. Ramsay, T. Diss and G. Kocjan Serous fluid cytology of multicentric Castleman’s disease and other lymphoproliferative disorders associated with Kaposi sarcoma‐associated herpes virus: a review with case reports Objective: The aim of this study is to describe and review the cytological features of Kaposi sarcoma‐associated herpes virus (KSHV) related entities, such as multicentric Castleman’s disease (MCD), plasmablastic‐lymphoma (PBL) and primary effusion lymphoma (PEL), which all may present as body cavity effusions. Serous fluid cytology of MCD and PBL has not, to our knowledge, thus far been described. Although different in nature, MCD, PBL and PEL are characterized by similar morphological features. Materials and methods: Body cavity effusions from four different patients with previously known or unknown KSHV‐related lymphoproliferations have been examined by routine cytology, immunocytochemistry (IC) and polymerase chain reaction (PCR). Results: MCD, PBL and PEL are all characterized by increased cellularity, comprising mainly lymphoid and plasmacytoid cells with variable proportions of immunoblasts. Immunocytochemistry and PCR results show the MCD to be CD138 and KSHV positive, CD30 negative, IgM, IgH and lambda restricted but IgH polyclonal. PBL was CD138 positive, kappa restricted, weakly positive with VS38 and over 80% positive with MIB 1. PEL was CD45, EMA, CD138, KSHV, p53 and CD3 positive, CD20, EBV, CD30, CD2, CD4, ALK1, epithelial and mesothelial markers negative, and PCR monoclonal B‐cell expanded (Ig‐kappa bands). Conclusion: Cytological examination of effusions in KSHV‐related lymphoproliferative disorders may show similar morphological features but clonality studies and immunocytochemistry are very helpful in distinguishing between these rare benign and malignant lymphoproliferative diseases.     

Selective killing of Kaposi's sarcoma-associated herpesvirus lytically infected cells with a recombinant immunotoxin targeting the viral gpK8.1A envelope glycoprotein

Kaposi sarcoma-associated herpesvirus (KSHV, human herpesvirus 8) is etiologically associated with three neoplastic syndromes: Kaposi sarcoma and the uncommon HIV-associated B-cell lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman disease. The incidence of the latter B-cell pathology has been increasing in spite of antiretroviral therapy; its association with lytic virus replication has prompted interest in therapeutic strategies aimed at this phase of the virus life cycle. We designed and expressed a recombinant immunotoxin (2014-PE38) targeting the gpK8.1A viral glycoprotein expressed on the surface of the virion and infected cells. We show that this immunotoxin selectively kills KSHV-infected cells in dose-dependent fashion, resulting in major reductions of infectious virus release. The immunotoxin and ganciclovir, an inhibitor of viral DNA replication, showed marked reciprocal potentiation of antiviral activities. These results suggest that the immunotoxin, alone or in combination, may represent a new approach to treat diseases associated with KSHV lytic replication.     

Gamma-interferon-induced monocyte major histocompatibility complex class II antigen expression individuals with acquired immune deficiency syndrome

Twelve patients with the acquired immune deficiency syndrome (AIDS) and Kaposi's sarcoma were treated with recombinant human gamma-interferon (rIFN-gamma). A rapid, substantial increase in the fraction of HLA-DQ-positive monocytes was noted after treatment with rIFN-gamma. The rIFN-gamma-induced increase in monocyte HLA-DQ was seen throughout the course of treatment, with the percentage of HLA-DQ-positive monocytes dropping slightly following each week's treatment with rIFN-gamma and then rapidly increasing following the next course of treatment. Although the percentage of HLA-DR-positive monocytes was unchanged (HLA-DR was expressed on greater than 80% of monocytes prior to treatment), the density of HLA-DR on monocytes also increased following rIFN-gamma treatment. Following rIFN-gamma treatment, no changes were seen in CD3, CD4, CD8 T cell numbers, in T cell subset ratio (CD4/CD8), in Leu 7 or CD16 (Leu 11) cell number, in spontaneous Ig secretion, in PHA-induced in vitro proliferation, or in NK activity. These results indicate that exposure to rIFN-gamma in vivo led to the increased expression of class II antigens on monocytes in patients with AIDS.