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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mice expressing the severe combined immunodeficiency trait (SCID) lack functional T and B lymphocytes and have been widely used for the study of B- cell development and for cancer and HIV research. The purpose of this study was to evaluate the SCID mouse as a potential model for T-cell maturation and transplantation studies. C3H/HEN SCID mice screened by fluorescence-activated cell sorting (FACS) and radial immunodiffusion assay (RID) were verified homozygous recessive if CD3-, CD22-, and serum (IgG) <5 mg/liter. C3H/HEN SCID mice pretreated with 250 R total-body gamma irradiation were reconstituted with 2.5 to 4 x 10(7) donor bone marrow cells derived from [syngeneic (syn): male wild-type C3H/HEN, allogeneic (allo): male BALB/c or C57BL/6) mice by intravenous injection. Four weeks post-transplant, engraftment was determined by FACS; repopulation of blood, thymus, and spleen; RID; and histologic evaluation. Immune function against donor, recipient, and third-party antigen was assayed in vitro by mixed lymphocyte response (MLR) and in vivo by full-thickness skin grafting. Greater than 90% of both syngeneic and allogeneic reconstitutions expressed CD3+, CD4+, CD8+, and CD22+ cells of donor origin in peripheral blood and spleen. FACS analyses of lymphocyte subpopulations in blood and spleen were not significantly different between reconstituted SCID mice and wild-type C3H/HEN or BALB/c controls, with engraftment stable for >4 months. No evidence of graft-versus-host disease was observed in stable, long-term (>4 months postreconstitution) chimeras. White blood cell, total thymocyte, and total splenocyte counts were significantly elevated (P < 0.05: ANOVA, Student's t) following reconstitution of homozygous SCID mice to levels found in wild-type controls. Serum (IgG) for reconstituted allo- and syn-SCID mice was consistently > 150 mg/liter (n = 22), with histologic lymphocyte engraftment of spleen, duodenum, and thymus. Histologic examination of lymphocyte engraftment in spleen, duodenum, and thymus was indistinguishable from normal controls in SCID mice after reconstitution. Prior to reconstitution, scant lymphoid cells were observed at these sites. Allo-SCID splenocyte response against third-party antigen was significantly elevated (P < 0.01: ANOVA, Student's t) when compared with donor and recipient antigen response with a proliferation index (PI) comparable to wild-type controls. Unreconstituted SCID mice were unresponsive. In vivo, allo-SCID mice demonstrated rejection of only third-party skin grafts between postoperative days 9 and 14 (controls: postoperative days 7 and 11). The SCID mouse model demonstrates in vitro and in vivo B- and T-cell immune function comparable to that of wild-type mice and provides a useful model for T-cell maturation and transplantation studies.
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PMID:SCID mouse as a model for transplantation studies. 889 4

In the past year, a number of human gene therapy trials involving the adoptive transfer of genetically modified T lymphocytes have been reported. These include trials of adenosine deaminase gene transfer in children with severe combined immunodeficiency syndrome, a gene-marking study of Epstein-Barr virus-specific cytotoxic T cells, and trials of gene-modified T cells expressing suicide or viral resistance genes in patients infected with HIV. Additional strategies for T-cell gene therapy currently being pursued in the clinic involve the engineering of novel T-cell receptors that impart antigen specificity for virally infected or malignant cells.
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PMID:T-cell gene therapy. 893 44

Immunodeficiency typically appears many years after initial HIV infection. This long, essentially asymptomatic period contributes to the transmission of HIV in human populations. In rare instances, clearance of HIV-1 infection has been observed, particularly in infants. There are also reports of individuals who have been frequently exposed to HIV-1 but remain seronegative for the virus, and it has been hypothesized that these individuals are resistant to infection by HIV-1. However, little is known about the mechanism of immune clearance or protection against HIV-1 in these high-risk individuals because it is difficult to directly demonstrate in vivo protective immunity. Although most of these high-risk individuals show an HIV-1-specific cell-mediated immune response using in vitro assays, their peripheral blood lymphocytes (PBLs) are still susceptible to HIV infection in tissue culture. To study this further in vivo, we have established a humanized SCID mouse infection model whereby T-, B-, and natural killer-cell defective SCID/beige mice that have been reconstituted with normal human PBLs can be infected with HIV-1. When the SCID/beige mice were reconstituted with PBLs from two different multiply exposed HIV-1 seronegative individuals, the mice showed resistance to infection by two strains of HIV-1 (macrophage tropic and T cell tropic), although the same PBLs were easily infected in vitro. Mice reconstituted with PBLs from non-HIV-exposed controls were readily infected. When the same reconstituted mice were depleted of human CD8 T cells, however, they became susceptible to HIV-1 infection, indicating that the in vivo protection required CD8 T cells. This provides clear experimental evidence that some multiply exposed, HIV-1-negative individuals have in vivo protective immunity that is CD8 T cell-dependent. Understanding the mechanism of such protective immunity is critical to the design and testing of effective prophylactic vaccines and immunotherapeutic regimens.
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PMID:Protective immunity to HIV-1 in SCID/beige mice reconstituted with peripheral blood lymphocytes of exposed but uninfected individuals. 896 21

Human immunodeficiency virus type 1 (HIV-1) was immunohistochemically and ultrastructurally localized in human thymus implants in SCID-hu mice 3 weeks after intravenous (i.v.) inoculation of the virus. A viral antigen (gp120) was predominantly distributed in and around the epithelial cells in Hassall's corpuscles as demonstrated by fluorescence immunohistochemistry. Occasional solitary round cells positive for the viral antigen but negative for cytokeratin were detected in the perivascular areas. Ultrastructural examinations clearly revealed a number of mature viral particles in the intercellular spaces of the Hassall's corpuscles. Thus the present study indicates the possibility that thymic epithelial cells in Hassall's corpuscles act as a target and/or reservoir in an early stage of HIV infection.
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PMID:Localization of HIV-1 in human thymic implant in SCID-hu mice after intravenous inoculation. 897 71

Infection by HIV-1 has been associated with perturbations in the TCR V beta repertoire, suggesting the involvement of a superantigen. Among the hallmarks of superantigens is the capacity to delete T cells bearing specific TCR V beta families in the developing thymus. To verify the presence of a superantigen in HIV-1, we analyzed the SCID-hu Thy/Liv TCR V beta repertoire within CD4+CD8+, CD4+CD8-, or CD4-CD8+ thymocytes subsets by flow cytometry using a panel of Abs recognizing about 60% of the TCR repertoire following injection of SEB or infection by two different HIV-1 isolates. Seven days following SEB injection, thymocyte subsets bearing TCR V beta 3, V beta 12, V beta 17, and V beta 20, but not V beta 5 or V beta 8 , were deleted relative to mock-injected mice. In contrast, no changes were observed in the TCR V beta repertoire in CD4+CD8+, CD4+CD8-, or CD4-CD8+ thymocyte subsets after infection with HIV-1. The T cell depletion caused by HIV-1 infection is most likely not mediated by an HIV-encoded superantigen.
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PMID:Superantigen-mediated deletion of specific T cell receptor V beta subsets in the SCID-hu Thy/Liv mouse is induced by staphylococcal enterotoxin B, but not HIV-1. 899 66

Pathogenic organisms are frequently attenuated after long-term culture in vitro. The mechanisms of the attenuation process are not clear, but probably involve mutations of functions required for replication and pathogenicity in vivo. To identify these functions, a direct comparison must be made between attenuated genomes and those that remain pathogenic in vivo. In this study, we used the heterochimeric SCID-hu Thy/Liv mouse as an in vivo model to define human immunodeficiency virus type 1 (HIV-1) determinants which are uniquely required for replication in vivo. The Lai/IIIB isolate and its associated infectious molecular clones (e.g., HXB2) were found to infect T cell lines but failed to replicate in the SCID-hu Thy/Liv model. When a lab worker was accidentally infected by Lai/IIIB, however, HIV-1 was isolated only from infection of primary PBMC, and not from infection of T cell lines. We hypothesized that the lab worker was exposed to a heterogeneous viral stock which had been attenuated by passage in immortalized T cell lines. Either a rare family member from this stock was selected for in vivo replication or, alternatively, an attenuated genotype dominant in vitro may have reverted to become more infectious in vivo. To address this hypothesis, we have used the SCID-hu Thy/Liv model to study the replication of HXB2 and of HXB2 recombinant viruses with HIV-1 fragments isolated from the infected lab worker. HXB2 showed no or very low levels of replication in the Thy/Liv organ. Replacement of its subgenomic fragment encoding the envelope gene with a corresponding fragment from the lab worker isolate generated a recombinant virus (HXB2/LW) which replicated actively in SCID-hu mice. The NEF mutation in the HXB2 genome is still present in HXB2/LW. Thus, the LW sequences encode HIV-1 determinants which enhance HIV replication in vivo in a NEF-independent mechanism. The specific determinants have been mapped to the V1-V3 regions of the HIV-1 genome. Six unique mutations in the V3 loop region of HXB2/LW have been identified which contribute to the increased replication in vivo.
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PMID:Identification of HIV-1 determinants for replication in vivo. 900 57

Late-stage HIV-1 disease in humans has been associated with perturbations of the T cell receptor (TCR) Vbeta repertoire. It is not known if the observed loss of certain Vbeta families is attributable directly to HIV-1 infection or whether this is a consequence of multiple opportunistic infections. Putative HIV-1-associated superantigens have been postulated to be the cause of the perturbed TCR Vbeta repertoire and the subsequent CD4+ T cell depletion in HIV-1-infected humans. In this study, we examined the human TCR Vbeta repertoire in SCID-hu mice, housed in a pathogen-free environment and infected with a molecularly cloned virus strain, to ascertain directly the effect of HIV-1 on the human TCR Vbeta repertoire in the absence of other infectious agents. We demonstrate that mock-infected human thymus/liver (Thy/Liv) implants in SCID-hu mice have complete TCR Vbeta repertoires, reflective of a normal human thymus. However, HIV-1-infected implants in SCID-hu mice had depleted TCR Vbeta repertoires, corresponding with thymocyte depletion. These results indicate that HIV-1-specific mechanisms are the cause of the TCR Vbeta repertoire depletion in infected implants. However, these thymocyte depletions were not restricted to specific TCR Vbeta subsets. These results are not consistent with the hypothesis that HIV-1 acts as a superantigen in vivo. The disruption of the TCR Vbeta repertoire in the human Thy/Liv implants of the SCID-hu mice suggests that HIV-1 infection may be influencing T cell development in the thymus, contributing to both the overall CD4+ T cell depletion in AIDS and limited TCR repertoire diversity.
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PMID:Loss of T cell receptor Vbeta repertoires in HIV type 1-infected SCID-hu mice. 900 98

Gene transfer into haematopoietic stem cells (HSC) has been investigated for treatment of genetic disorders, conferral of chemotherapy resistance and insertion of genes to inhibit HIV-1 replication. Methods have been available for almost a decade to transduce murine HSC using high-titre retroviral vectors and stimulation of HSC proliferation with cytokines such as IL-3 and IL-6. Unfortunately, attempts to replicate the high efficiency of gene transfer using canine or simian gene transfer/bone marrow transplantation models have consistently shown that only a small fraction (0.1-1%) of reconstituting HSC are transduced using protocols similar to those which are successful in murine models. Initial clinical trials using retroviral-mediated gene transfer into human HSC also produced minimal transduction frequencies. The dicotomous results may reflect differences in the cell cycle kinetics of murine HSC versus those of larger mammals or the density of receptors for the retroviral vectors on the cells. Attempts to increase the fraction of HSC which are in active cell cycle, a prerequisite for retroviral-mediated transduction, have used either combinations of recombinant cytokines, culture on marrow stromal layers, or alternative sources for HSC, such as mobilized peripheral blood stem cells or umbilical cord blood. Other efforts have used retroviral vectors packaged with either the Gibbon Ape Leukemia virus envelope or the Vesicular Stomatitis Virus G protein. To date, none of these methods has produced a significantly increased frequency of long-term reconstituting HSC. Results using adeno-associated virus (AAV)-based vectors for HSC transduction have been conflicting, with the stable persistence of non-integrated virus particles making interpretation of results difficult using in vitro assays. Therefore, clinical trials may best be directed toward disorders that may benefit from a small fraction of genetically corrected HSC. These would include disorders where progeny of corrected HSC would be expected to have a selective survival advantage (e.g. SCID, WAS, HIV, chemoresistance) or where a small fraction of corrected cells can have a direct clinical benefit (e.g. CGD, MPS). Further basic research into HSC biology and gene delivery vectors must continue for wider application, such as haemoglobinopathies and some lysosomal storage diseases.
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PMID:Gene therapy for haematopoietic and lymphoid disorders. 902 Sep 37

Epstein-Barr virus (EBV) type and strain variations were examined using both lymphoblastoid cell lines (LCLs), spontaneously derived in vitro from peripheral blood mononuclear cells (PBMC) of 15 HIV-1-seropositive individuals; and SCID mouse tumours induced by inoculation of PBMC from 11 healthy human donors (Hu-SCID tumours). Polymerase chain reaction (PCR) analysis disclosed that all but one of the 26 EBV + samples harboured EBV nuclear antigen (EBNA) 2 and 3C type A virus. On the other hand, single strand conformation polymorphism (SSCP) analysis using Epstein-Barr encoded RNA (EBER) specific primers detected an AG876-like (type B) band pattern in 21 of the 26 EBV + samples. Three Hu-SCID tumours scored as B95.8-like (type A), and two showed neither a type A nor a type B SSCP migration pattern. Sequence analysis of the amplified EBER fragments confirmed the PCR-SSCP findings; moreover, additional mutations were present not only in the two EBV + samples with anomalous SSCP pattern, but also in two other samples with a standard SSCP profile. Thus, EBER analysis did not correlate with EBNA typing, and appeared to be unsuitable for EBV type assessment. Latent membrane protein (LMP) analysis disclosed, on the whole, sever size variants: as expected, the differences were due to the variable numbers of a 33-bp repeat in the amplified fragment, as assessed by direct sequencing. The broader variability detected by LMP analysis should prove more useful than typing for assessing the presence of single and/or mixed variants resulting from EBV reactivation and/or reinfection.
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PMID:Analysis of Epstein-Barr virus (EBV) type and variant in spontaneous lymphoblastoid cells and Hu-SCID mouse tumours. 902 83

The identification of fusin and other chemokine receptors as coreceptors for HIV-1 has renewed the interest in agents that may prevent viral entry. Polyanionic compounds such as dextran sulfate, curdian sulfate, and suramin act on the V3 loop of the viral envelope and may prevent its interaction with fusin. These agents show activity against a wide range of HIV-1 strains, but have undesirable circulating half-life, bioavailability, and toxicity. We have developed a small molecule inhibitor of HIV-1 that has several advantages over these other agents. FP-21399 is a novel compound of the bis(disulfonaphthalene) dimethoxybenzene class that blocks entry of HIV into CD4+ cells and blocks fusion of infected and noninfected CD4+ cells. This compound only weakly inhibits binding of CD4 and gp120, at concentrations much greater than are required to block viral entry. Furthermore, FP-21399 can block the interaction between gp120 and antibodies directed against the V3 loop, but does not block binding of antibodies directed against the V4 loop. Animal studies demonstrate that FP-21399 is concentrated in lymph nodes, making it a promising compound for anti-HIV therapy. In SCID mice reconstituted with human immune cells, maintenance of HIV-1 infection was blocked by a 5-day treatment with low doses of FP-21399, suggesting that lymph node accumulation may contribute to antiviral activity. Finally, attempts to generate drug-resistant virus in cell culture resulted in only weakly resistant variants with IC90 values that are much lower than concentrations of FP-21399 found in lymph nodes.
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PMID:FP-21399 blocks HIV envelope protein-mediated membrane fusion and concentrates in lymph nodes. 909 35


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