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Query: UMLS:C0001175 (AIDS)
 120,706 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There are now rather straightforward methods to create transgenic animals whose genome is altered at the germline level. One method consists in the micro-injection of a gene into the pronucleus of a fertilized egg, the second one involves an homologous recombination event obtained in embryonic stem cells in culture. Only the latter method could eventually lead to an authentic gene therapy since it could actually substitute a normal gene for a mutated one instead of merely introducing a supplementary gene as done by micro-injection. Description of these techniques makes it obvious that germline therapy of human beings would not only be inacceptable on ethical grounds but would also hardly have any medical indications. Quite on the contrary, somatic gene therapy does not suffer from the same reservations and has numerous potential applications to man. As a matter of fact, several protocols have already received approval and have reached the stage of clinical trials: for example SCID (severe combined immunodeficiency due to a mutated adenosine deaminase gene), AIDS as well as some forms of malignant tumors.
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PMID:[Transgenesis and gene therapy]. 130 2

Mice infected with various tumor retroviruses have been used as models for evaluating therapeutic substances for the treatment of some cancers, and more recently, for human immunodeficiency virus (HIV) infection, the causative agent of acquired immune deficiency syndrome (AIDS). Consequently, there is a need to determine the ability of biological response modifiers (BRMs) to specifically reduce virus-infected cells, as compared to their non-specific anti-proliferative effects. To address this need, a BRM, imexon, was evaluated in this study using three strains of mice having different Friend virus (FV)-specific immunological capabilities. The first strain, (B10.A x A/WySn)F1, was genetically capable of producing FV-specific neutralization and cytotoxic antibodies, the second, Balb/c, was not, and the third, SCID mice, lacked functional T and B cell immunity. Imexon treatment reduced virally-induced splenomegaly in all 3 strains; however, the concentration of splenic viral infectious centers (IC) were not affected. Since imexon was efficacious in reducing splenomegaly in SCID mice, the mode of action was concluded to not require functional T or B cell immunity. The observation that imexon did not affect splenic IC titers also suggested that imexon did not specifically eliminate virally infected cells, but may have functioned by other mechanisms. This study also demonstrated the use of various mouse strains as a strategy for delineating the modes of action of BRMs against murine retroviral infections.
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PMID:Elucidation of mode of retroviral-inhibitory effects of imexon through use of immune competent and severe combined immune deficiency (SCID) mice. 131 37

Epstein-Barr virus (EBV) is associated with B-cell malignancy in immunosuppressed humans and SCID mice receiving human peripheral blood leukocyte grafts (hu-PBL-SCID). We have further characterized the process of lymphoma development in hu-PBL-SCID mice. We report that EBV-seropositive donors differ markedly in the capacity of their PBL to give rise to immunoblastic lymphomas in SCID mice; some donors (high incidence) generated tumors rapidly in all hu-PBL-SCID mice, other donors (intermediate-low incidence) gave rise to sporadic tumors after a longer latent period (greater than 10 weeks), and some donors failed to produce tumors. B-cell lymphomas arising from high incidence donors were multiclonal in origin, and EBV replication was detected in all tumors. Tumors derived from intermediate-low incidence donors were monoclonal or oligoclonal and often had no evidence of viral replication. All tumors, regardless of the donor, resembled EBV-transformed lymphoblastoid cell lines in surface phenotype but differed from lymphoblastoid cell lines by having less Epstein-Barr nuclear antigen 2 and CD23 expression. The variable patterns of lymphomagenesis seen among different EBV-sero-positive donors may be explained by lower levels of specific immunity to EBV in high incidence donors, permitting activation of EBV replication and potential transformation of secondary B-cell targets. In addition, there may be differences in the transforming potential of EBV infecting different donors. The use of the hu-PBL-SCID model may help predict patients at high risk for posttransplant or acquired immunodeficiency syndrome-associated lymphomas.
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PMID:Heterogeneity among Epstein-Barr virus-seropositive donors in the generation of immunoblastic B-cell lymphomas in SCID mice receiving human peripheral blood leukocyte grafts. 131 93

Adenoviruses are among the many pathogens and opportunistic agents that cause serious infection in the congenitally immunocompromised, in patients undergoing immunosuppressive treatment for organ and tissue transplants and for cancers, and in human immunodeficiency virus-infected patients. Adenovirus infections in these patients tend to become disseminated and severe, and the serotypes involved are clustered according to the age of the patient and the nature of the immunosuppression. Over 300 adenovirus infections in immunocompromised patients, with an overall case fatality rate of 48%, are reviewed in this paper. Children with severe combined immunodeficiency syndrome and other primary immunodeficiencies are exposed to the serotypes of subgroups B and C that commonly infect young children, and thus their infections are due to types 1 to 7 and 31 of subgenus A. Children with bone marrow and liver transplants often have lung and liver adenovirus infections that are due to an expanded set of subgenus A, B, C, and E serotypes. Adults with kidney transplants have viruses of subgenus B, mostly types 11, 34, and 35, which cause cystitis. This review indicates that 11% of transplant recipients become infected with adenoviruses, with case fatality rates from 60% for bone marrow transplant patients to 18% for renal transplant patients. Patients with AIDS become infected with a diversity of serotypes of all subgenera because their adult age and life-style expose them to many adenoviruses, possibly resulting in antigenically intermediate strains that are not found elsewhere. Interestingly, isolates from the urine of AIDS patients are generally of subgenus B and comprise types 11, 21, 34, 35, and intermediate strains of these types, whereas isolates from stool are of subgenus D and comprise many rare, new, and intermediate strains that are untypeable for practical purposes. It has been estimated that adenoviruses cause active infection in 12% of AIDS patients and that 45% of these infections terminate in death within 2 months. In all immunocompromised patients, generalized illness involving the central nervous system, respiratory system, hepatitis, and gastroenteritis usually have a fulminant course and result in death. Treatments for adenovirus infections are of little proven value, although certain purine and pyrimidine analogs have shown beneficial effects in vitro and may be promising drugs.
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PMID:Adenoviruses in the immunocompromised host. 132 83

Murine models with type C murine leukemia viruses have been used to develop major new prophylactic and therapeutic strategies in vaccination, drug therapy of acute virus exposure and chronic viremia, combination therapy, prevention of maternal transmission, and therapy targeted to the central nervous system. Transgenic mice expressing either the whole human immunodeficiency virus type 1 (HIV-1) provirus or subgenomic sequences allow the in vivo analysis of selected HIV-1 functions. The full replicative cycle of HIV-1 can be studied in human/mouse chimerae which were created by transplanting human hematolymphoid cells into SCID mice. The chimeric SCID mouse models have been used successfully to evaluate anti-HIV-1 drugs. The role of the various murine retrovirus systems in the development of anti-HIV-1 and anti-AIDS therapies is summarized.
AIDS Res Hum Retroviruses 1992 Jun
PMID:Development of antiviral treatment strategies in murine models. 132 85

Epstein-Barr virus (EBV) infection is associated with Burkitt's lymphoma (BL) in normal individuals and immunoblastic B cell lymphomas in immunosuppressed or HIV-infected individuals. SCID mice reconstituted with human peripheral blood leukocytes (hu-PBL-SCID) from EBV-seropositive donors also may develop spontaneous B cell lymphomas which histologically and phenotypically resemble post-transplant tumors, and are distinct from BL. These tumors always contain EBV DNA. We have noted three different reproducible outcomes depending upon the EBV-seropositive donor used for generation of hu-PBL-SCID mice: (i) no tumors appear; (ii) tumors appear in a fraction of hu-PBL-SCID mice with a 10-20 wk. latent period; or (iii) tumors appear in all hu-PBL-SCID mice within 6-10 wk. Southern blot analysis of late versus early tumors using a probe specific for the EBV terminal repeat sequences (BamNJ), which allows distinction between circular latent and linear replicating genomes, shows that late tumors do not involve active EBV replication but that early tumors do show replicating genomes. In addition, EBV genomes were monoclonal in late tumors but polyclonal in early tumors. These data suggest two mechanisms for EBV lymphomagenesis, slow outgrowth of rare latently-infected B cells, and more rapid transformation of uninfected bystander B cells by replicating virus. The latter process may be highly amenable to therapy in patients at risk for EBV-related lymphomas. In addition, prospective screening of EBV-seropositive transplant recipients in the hu-PBL-SCID model may predict the risk of post-transplant lymphoma development.
AIDS Res Hum Retroviruses 1992 May
PMID:EBV-induced human B cell lymphomas in hu-PBL-SCID mice. 132 70

The opportunistic pathogen Pneumocystis carinii (Pc) is considered to be the leading cause of morbidity in patients with AIDS. It is important, therefore, to determine the immunological mechanisms of resistance to Pc. We have taken advantage of the lack of both T and B lymphocytes in severe combined immunodeficiency (scid) mice to determine the critical factors in resistance to spontaneously acquired Pc pneumonia. Using adoptive transfer of unfractionated or fractionated lymphocyte subsets or hyperimmune serum from congenic normal donors, we have demonstrated that effective immunity to Pc results from the action of CD4+ but not CD8+ T cells (in the absence of antibody) or from humoral immunity (in the absence of T cells). However, responses of CD4+ T cells (but not antibody) to already well-established burdens of Pc are often accompanied by a fatal hyperinflammatory reaction. The activity of CD4+ T cells against Pc thus illustrates a broadly applicable principle that T cell immunity represents a critical balance between consequences beneficial and harmful to the host.
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PMID:Both immunity and hyperresponsiveness to Pneumocystis carinii result from transfer of CD4+ but not CD8+ T cells into severe combined immunodeficiency mice. 135 67

Primate and non-primate species have been used to study the pathobiology of the simian immunodeficiency virus (SIV) and of the human immunodeficiency virus type 1 (HIV-1), respectively, and to develop new therapeutic regimes. Transgenic mice which express either the entire HIV-1 provirus or subgenomic fragments have been used to analyze viral gene products in vivo and may serve as models for the development of agents targeted to select viral functions. Chimeric mice which were created by transplanting human hematolymphoid cells into mice suffering from congenital severe combined immunodeficiency (scid/scid or so called SCID mice), can be infected with HIV-1 and allow one to study the entire HIV-1 replicative cycle. Type C murine leukemia virus models have been used to develop new prophylactic and therapeutic strategies but their use is restricted to the evaluation of select antiviral drug inhibition, targeted to retroviral genes common to both Lentivirinae and Oncovirinae. The role of various animal model systems in the development of anti-HIV-1 and anti-AIDS therapies is summarized.
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PMID:Animal models for anti-AIDS therapy. 144 26

Aggressive B-cell lymphomas are occurring with increasing incidence among individuals infected with human immunodeficiency virus (HIV). Several lines of evidence implicate both Epstein-Barr virus (EBV) and c-myc activation in the pathogenesis of a major subset of these tumors. These observations prompted our investigation of interactions among EBV, c-myc, and HIV in primary B cells. We show that nonimmortalized peripheral B lymphocytes from EBV-seropositive, HIV-seronegative donors can be infected by HIV and that a subset of these lymphocytes become transformed. Malignant transformation was documented by several criteria. These cells displayed altered growth properties, propagating in 1% serum and cloning in soft agar, and formed invasive tumors of Burkitt lymphoma phenotype after subcutaneous injection into severe combined immunodeficiency mice. Such cells revealed marked enhancement of EBV DNA and RNA and of endogenous c-myc transcripts and protein. HIV-1 infection of already immortalized B-cell lines led to a similar upregulation of EBV and c-myc transcripts. These data indicate that HIV has properties of a transforming retrovirus, as it mediates two events linked to B-cell neoplasia: deregulation of c-myc and activation of EBV. They also raise the possibility of a role for HIV, apart from induction of immune suppression, in the pathogenesis of B-cell lymphoma in the acquired immune deficiency syndrome.
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PMID:Human immunodeficiency virus induction of malignant transformation in human B lymphocytes. 165 56

Epstein--Barr virus (EBV) is a latent human herpes virus that growth-transforms EBV receptor/CD21+ B cells and is associated with several high-frequency malignancies. Reactivation of latent EBV occurs in approximately 1/3 of organ graft recipients and a majority of AIDS patients; EBV-positive B lymphoproliferative lesions represent often fatal complications in organ transplantation and late-stage AIDS. Although such lymphomas can arise from endogenous virus, the high tumor risk in EBV-seronegative transplant recipients implies de novo infection, in particular virus transmission with intra-graft B lymphocytes. Since SCID mice engrafted with human lymphocytes (SCIDhum) typically develop endogenous EBV+ (human) tumors in their graft it is difficult to study exogenous virus transmission in this model. We here demonstrate that beige/nude/xid mice engrafted with human lymphoid cells (BNXhum) selectively accept human B but not T cell grafts. Unexpectedly these mice fail to develop endogenous lymphomas observed in SCIDhum mice engrafted in parallel. However, injection of as few as less than 500 EBV particles produces rapidly fatal, polyclonal lymphomas in BNXhum animals. This virus sensitivity of BNXhum approaches conditions for EBV transmission with organ grafts.
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PMID:Exogenous but not endogenous EBV induces lymphomas in beige/nude/xid mice carrying human lymphoid xenografts. 165 5


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