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1.
The reservoir for HIV-1 in human peripheral blood is a T cell that maintains expression of CD4 总被引：116，自引：0，他引：116
S M Schnittman M C Psallidopoulos H C Lane L Thompson M Baseler F Massari C H Fox N P Salzman A S Fauci 《Science (New York, N.Y.)》1989,245(4915):305-308
Human immunodeficiency virus type 1 (HIV-1) selectively infects cells expressing the CD4 molecule, resulting in substantial quantitative and qualitative defects in CD4+ T lymphocyte function in patients with acquired immunodeficiency syndrome (AIDS). However, only a very small number of cells in the peripheral blood of HIV-1-infected individuals are expressing virus at any given time. Previous studies have demonstrated that in vitro infection of CD4+ T cells with HIV-1 results in downregulation of CD4 expression such that CD4 protein is no longer detectable on the surface of the infected cells. In the present study, highly purified subpopulations of peripheral blood mononuclear cells (PBMCs) from AIDS patients were obtained and purified by fluorescence-automated cell sorting. They were examined with the methodologies of virus isolation by limiting dilution analysis, in situ hybridization, immunofluorescence, and gene amplification. Within PBMCs, HIV-1 was expressed in vivo predominantly in the T cell subpopulation which, in contrast to the in vitro observations, continued to express CD4. The precursor frequency of these HIV-1-expressing cells was about 1/1000 CD4+ T cells. The CD4+ T cell population contained HIV-1 DNA in all HIV-1-infected individuals studied and the frequency in AIDS patients was at least 1/100 cells. This high level of infection may be the primary cause for the progressive decline in number and function of CD4+ T cells in patients with AIDS. 相似文献
2.
Prevention of HIV-1 infection and preservation of CD4 function by the binding of CPFs to gp120 总被引：4，自引：0，他引：4
R W Finberg D C Diamond D B Mitchell Y Rosenstein G Soman T C Norman S L Schreiber S J Burakoff 《Science (New York, N.Y.)》1990,249(4966):287-291
Infection by human immunodeficiency virus type-1 (HIV-1) is initiated when its envelope protein, gp120, binds to its receptor, the cell surface glycoprotein CD4. Small molecules, termed N-carbomethoxycarbonyl-prolyl-phenylalanyl benzyl esters (CPFs), blocked this binding. CPFs interacted with gp120 and did not interfere with the binding of CD4 to class II major histocompatibility complex molecules. One CPF isomer, CPF(DD), preserved CD4-dependent T cell function while inhibiting HIV-1 infection of H9 tumor cells and human T cells. Although the production of viral proteins in infected T cells is unaltered by CPF(DD), this compound prevents the spread of infection in an in vitro model system. 相似文献
3.
Human immunodeficiency virus infection of human-PBL-SCID mice 总被引：32，自引：0，他引：32
D E Mosier R J Gulizia S M Baird D B Wilson D H Spector S A Spector 《Science (New York, N.Y.)》1991,251(4995):791-794
Severe combined immunodeficient (SCID) mice reconstituted with human peripheral blood leukocytes (hu-PBL-SCID mice) have inducible human immune function and may be useful as a small animal model for acquired immunodeficiency syndrome (AIDS) research. Hu-PBL-SCID mice infected with human immunodeficiency virus-1 (HIV-1) contained virus that was recoverable by culture from the peritoneal cavity, spleen, peripheral blood, and lymph nodes for up to 16 weeks after infection; viral sequences were also detected by in situ hybridization and by amplification with the polymerase chain reaction (PCR). Mice could be infected with multiple strains of HIV-1, including LAV-1/Bru, IIIB, MN, SF2, and SF13. HIV-1 infection affected the concentration of human immunoglobulin and the number of CD4+ T cells in the mice. These results support the use of the hu-PBL-SCID mouse for studies of the pathogenesis and treatment of AIDS. 相似文献
4.
Infection and replication of HIV-1 in purified progenitor cells of normal human bone marrow 总被引：40，自引：0，他引：40
T M Folks S W Kessler J M Orenstein J S Justement E S Jaffe A S Fauci 《Science (New York, N.Y.)》1988,242(4880):919-922
5.
To better understand the basis for human immunodeficiency virus type 1 (HIV-1) persistence and latency, the form in which viral DNA exists in the peripheral T lymphocyte reservoir of infected individuals was investigated. In asymptomatic individuals, HIV-1 was harbored predominantly as full-length, unintegrated complementary DNA. These extrachromosomal DNA forms retained the ability to integrate upon T cell activation in vitro. In patients with acquired immunodeficiency syndrome (AIDS), there was an increase in integrated relative to extrachromosomal DNA forms. By analysis of DNA from patient lymphocyte subpopulations depleted of human lymphocyte antigen-Dr receptor-positive cells, quiescent T cells were identified as the source of extrachromosomal HIV-1 DNA. Thus quiescent T lymphocytes may be a major and inducible HIV-1 reservoir in infected individuals. 相似文献
6.
B A Watkins H H Dorn W B Kelly R C Armstrong B J Potts F Michaels C V Kufta M Dubois-Dalcq 《Science (New York, N.Y.)》1990,249(4968):549-553
Human immunodeficiency virus (HIV) frequently causes neurological dysfunction and is abundantly expressed in the central nervous system (CNS) of acquired immunodeficiency syndrome (AIDS) patients with HIV encephalitis or myelopathy. The virus is found mostly in cells of the monocyte-macrophage lineage within the CNS, but the possibility of infection of other glial cells has been raised. Therefore, the effects of different HIV-1 and HIV-2 strains were studied in primary cultures of adult human brain containing microglial cells, the resident CNS macrophages, and astrocytes. These cultures could be productively infected with macrophage-adapted HIV-1 isolates but not with T lymphocyte-adapted HIV-1 isolates or two HIV-2 isolates. As determined with a triple-label procedure, primary astrocytes did not express HIV gag antigens and remained normal throughout the 3-week course of infection. In contrast, virus replicated in neighboring microglial cells, often leading to their cell fusion and death. The death of microglial cells, which normally serve immune functions in the CNS, may be a key factor in the pathogenesis of AIDS encephalitis or myelopathy. 相似文献
7.
HIV-1 production from infected peripheral blood T cells after HTLV-I induced mitogenic stimulation 总被引：17，自引：0，他引：17
The human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type I (HTLV-I) are two distinct human retroviruses that infect T cells. Recent epidemiologic studies have identified a cohort of individuals that are coinfected with both viruses. It is reported here that human peripheral blood leukocytes infected with HIV-1 in vitro can be induced to produce large quantities of HIV-1 after mitogenic stimulation by noninfectious HTLV-I virions. It is also shown that HTLV-I virions may exert this effect prior to, immediately following, or well after the cells are infected with HIV-1. These results provide further impetus for epidemiologic studies of dually infected individuals to determine whether HTLV-I may act as a cofactor for acquired immunodeficiency syndrome (AIDS). 相似文献
8.
Harouse JM Gettie A Tan RC Blanchard J Cheng-Mayer C 《Science (New York, N.Y.)》1999,284(5415):816-819
Infection of macaques with chimeric simian-human immunodeficiency virus (SHIV) provides an excellent in vivo model for examining the influence of envelope on HIV-1 pathogenesis. Infection with a pathogenic CCR5 (R5)-specific enveloped virus, SHIVSF162P, was compared with infection with the CXCR4 (X4)-specific SHIVSF33A.2. Despite comparable levels of viral replication, animals infected with the R5 and X4 SHIV had distinct pathogenic outcomes. SHIVSF162P caused a dramatic loss of CD4+ intestinal T cells followed by a gradual depletion in peripheral CD4+ T cells, whereas infection with SHIVSF33A.2 caused a profound loss in peripheral T cells that was not paralleled in the intestine. These results suggest a critical role of co-receptor utilization in viral pathogenesis and provide a reliable in vivo model for preclinical examination of HIV-1 vaccines and therapeutic agents in the context of the HIV-1 envelope protein. 相似文献
9.
HIV-1-infected T cells show a selective signaling defect after perturbation of CD3/antigen receptor 总被引：16，自引：0，他引：16
The binding of antigen or monoclonal antibody to the T cell receptor for antigen or the closely associated CD3 complex causes increases in the concentration of intracellular ionized calcium and subsequent cell proliferation. By measuring second messenger production in primary cultures of human immunodeficiency virus (HIV-1)--infected T cells stimulated with monoclonal antibodies specific for either CD3 or CD2, a specific impairment of membrane signaling was revealed. The HIV-1--infected T cells were unable to mobilize Ca2+ after stimulation with anti-CD3, whereas CD2-induced calcium mobilization remained intact. Furthermore, the HIV-1--infected cells proliferated poorly after CD3 stimulation, although the cells retained normal DNA synthesis in response to interleukin-2 stimulation. These results show that the signals initiated by CD2 and CD3 can be regulated independently within the same T cell; uncoupling of signal transduction after antigen-specific stimulation provides a biochemical mechanism to explain, in part, the profound immunodeficiency of patients with HIV-1 infection. 相似文献
10.
Barouch DH Santra S Schmitz JE Kuroda MJ Fu TM Wagner W Bilska M Craiu A Zheng XX Krivulka GR Beaudry K Lifton MA Nickerson CE Trigona WL Punt K Freed DC Guan L Dubey S Casimiro D Simon A Davies ME Chastain M Strom TB Gelman RS Montefiori DC Lewis MG Emini EA Shiver JW Letvin NL 《Science (New York, N.Y.)》2000,290(5491):486-492
With accumulating evidence indicating the importance of cytotoxic T lymphocytes (CTLs) in containing human immunodeficiency virus-1 (HIV-1) replication in infected individuals, strategies are being pursued to elicit virus-specific CTLs with prototype HIV-1 vaccines. Here, we report the protective efficacy of vaccine-elicited immune responses against a pathogenic SHIV-89.6P challenge in rhesus monkeys. Immune responses were elicited by DNA vaccines expressing SIVmac239 Gag and HIV-1 89.6P Env, augmented by the administration of the purified fusion protein IL-2/Ig, consisting of interleukin-2 (IL-2) and the Fc portion of immunoglobulin G (IgG), or a plasmid encoding IL-2/Ig. After SHIV-89.6P infection, sham-vaccinated monkeys developed weak CTL responses, rapid loss of CD4+ T cells, no virus-specific CD4+ T cell responses, high setpoint viral loads, significant clinical disease progression, and death in half of the animals by day 140 after challenge. In contrast, all monkeys that received the DNA vaccines augmented with IL-2/Ig were infected, but demonstrated potent secondary CTL responses, stable CD4+ T cell counts, preserved virus-specific CD4+ T cell responses, low to undetectable setpoint viral loads, and no evidence of clinical disease or mortality by day 140 after challenge. 相似文献
11.
Expanded HIV-1 cellular tropism by phenotypic mixing with murine endogenous retroviruses 总被引：26，自引：0，他引：26
P Lusso F di Marzo Veronese B Ensoli G Franchini C Jemma S E DeRocco V S Kalyanaraman R C Gallo 《Science (New York, N.Y.)》1990,247(4944):848-852
In view of the current interest in in vivo murine models for acquired immunodeficiency syndrome (AIDS), the interaction between human immunodeficiency virus type 1 (HIV-1) and endogenous murine leukemia virus (MuLV)-related retroviruses was investigated with a human leukemic T cell line (PF-382x) that acquired xenotropic MuLV (X-MuLV) after in vivo passage in immunosuppressed mice. Despite similar levels of membrane CD4 expression and HIV-1 125I-labeled gp 120 binding, a dramatic acceleration in the time course of HIV-1 infection was observed in PF-382x compared to its X-MuLV-negative counterpart (PF-382). Moreover, PF-382 cells coinfected by X-MuLV and HIV-1 generated a progeny of phenotypically mixed viral particles, enabling HIV-1 to productively infect a panel of CD4- human cells, including B lymphoid cells and purified normal peripheral blood CD4-/CD8+ T lymphocytes. Mixed viral phenotypes were also produced by human CD4+ T cells coinfected with an amphotropic MuLV-related retrovirus (A-MuLV) and HIV-1. These data show that endogenous MuLV acquired by human cells transplanted into mice can significantly interact with HIV-1, thereby inducing important alterations of HIV-1 biological properties. 相似文献
12.
Antibody-enhanced infection by HIV-1 via Fc receptor-mediated entry 总被引：49，自引：0，他引：49
Monocytes and macrophages, which may play a central role in the pathogenesis of infection with human immunodeficiency virus type 1 (HIV-1), express the CD4 molecule and Fc receptors (FcR) for immunoglobulin G (IgG). To explore the possibility that FcR mediate HIV-1 infection of monocytes, studies were conducted with the human monocytic cell line U937. These cells were exposed to HIV-1 complexed with various concentrations of serum from HIV-1 antibody-positive individuals and monitored for HIV-1 replication. Serum samples from antibody-negative normal individuals did not affect virus yields. High concentrations of antibody-positive sera showed virus-neutralizing activity; however, cells infected with HIV-1 in the presence of antibody-positive sera at subneutralizing concentrations significantly enhanced virus replication. This infection enhancement was blocked by heat-aggregated gamma-globulin. Moreover, the IgG fraction from an HIV-1 antibody-positive serum enhanced HIV-1 infection at the same serum dilution equivalents. In contrast, IgG-F(ab')2 did not enhance HIV-1 infection but showed neutralizing activity with HIV-1. These results are compatible with the concept of FcR-mediated infection enhancement and suggest that this immunological response to HIV-1, instead of protecting the host, potentially facilitates the infection. 相似文献
13.
Enhancement of SIV infection with soluble receptor molecules 总被引：27，自引：0，他引：27
The CD4 receptor on human T cells has been shown to play an integral part in the human immunodeficiency virus type 1 (HIV-1) infection process. Recombinant soluble human CD4 (rCD4) was tested for its ability to inhibit SIVagm, an HIV-like virus that naturally infects African green monkeys, in order to define T cell surface receptors critical for SIVagm infection. The rCD4 was found to enhance SIVagm infection of a human T cell line by as much as 18-fold, whereas HIV-1 infection was blocked by rCD4. Induction of syncytium formation and de novo protein synthesis were observed within the first 24 hours after SIVagm infection, whereas this process took 4 to 6 days in the absence of rCD4. This enhancing effect could be inhibited by monoclonal antibodies directed to rCD4. The enhancing effect could be abrogated with antibodies from naturally infected African green monkeys with inhibitory titers of from 1:2,000 to 1:10,000; these antibodies did not neutralize SIVagm infection in the absence of rCD4. Viral enhancement of SIVagm infection by rCD4 may result from the modulation of the viral membrane through gp120-CD4 binding, thus facilitating secondary events involved in viral fusion and penetration. 相似文献
14.
Lalani AS Masters J Zeng W Barrett J Pannu R Everett H Arendt CW McFadden G 《Science (New York, N.Y.)》1999,286(5446):1968-1971
Chemokine receptors serve as portals of entry for certain intracellular pathogens, most notably human immunodeficiency virus (HIV). Myxoma virus is a member of the poxvirus family that induces a lethal systemic disease in rabbits, but no poxvirus receptor has ever been defined. Rodent fibroblasts (3T3) that cannot be infected with myxoma virus could be made fully permissive for myxoma virus infection by expression of any one of several human chemokine receptors, including CCR1, CCR5, and CXCR4. Conversely, infection of 3T3-CCR5 cells can be inhibited by RANTES, anti-CCR5 polyclonal antibody, or herbimycin A but not by monoclonal antibodies that block HIV-1 infection or by pertussis toxin. These findings suggest that poxviruses, like HIV, are able to use chemokine receptors to infect specific cell subtypes, notably migratory leukocytes, but that their mechanisms of receptor interactions are distinct. 相似文献
15.
Secretion of neurotoxins by mononuclear phagocytes infected with HIV-1 总被引：50，自引：0，他引：50
Mononuclear phagocytes (microglia, macrophages, and macrophage-like giant cells) are the principal cellular targets for human immunodeficiency virus-1 (HIV-1) in the central nervous system (CNS). Since HIV-1 does not directly infect neurons, the causes for CNS dysfunction in acquired immunodeficiency syndrome (AIDS) remain uncertain. HIV-1-infected human monocytoid cells, but not infected human lymphoid cells, released toxic agents that destroy chick and rat neurons in culture. These neurotoxins were small, heat-stable, protease-resistant molecules that act by way of N-methyl-D-aspartate receptors. Macrophages and microglia infected with HIV-1 may produce neurologic disease through chronic secretion of neurotoxic factors. 相似文献
16.
Biologic features of HIV-1 that correlate with virulence in the host 总被引：120，自引：0，他引：120
Individuals infected with the human immunodeficiency virus type 1 (HIV-1) may be asymptomatic or have AIDS-related complex or the acquired immuno deficiency syndrome (AIDS). Little is known about the factors that influence progression of infection to AIDS. In this study of isolates of HIV-1 obtained at intervals during the infection of four individuals, the development of disease was found to be correlated with the emergence of HIV-1 variants that were more cytopathic in vitro as the disease progressed and that replicated more efficiently in a wide variety of different human cells. The biologic properties of HIV-1 in vitro thus appear to reflect its virulence in the host. Further studies of such sequentially isolated viruses may lead to the identification of viral genes that govern pathogenesis. 相似文献
17.
The murine acquired immunodeficiency syndrome (MAIDS) is associated with proliferation of target cells that have been infected by a defective retrovirus. To control the growth of this primary neoplasia, virus-inoculated mice were treated with anti-neoplastic drugs. Paradoxically, cyclophosphamide, which is also immunosuppressive, was very effective in preventing the appearance and progression of the disease, in restoring a normal T cell function, and in depleting the number of infected target cells. This result suggests that the proliferating infected target cells were responsible for the immunodeficiency. 相似文献
18.
Infection of the SCID-hu mouse by HIV-1 总被引：44，自引：0，他引：44
R Namikawa H Kaneshima M Lieberman I L Weissman J M McCune 《Science (New York, N.Y.)》1988,242(4886):1684-1686
19.
20.
Activation of the HIV-1 LTR by T cell mitogens and the trans-activator protein of HTLV-I 总被引：102，自引：0，他引：102
M Siekevitz S F Josephs M Dukovich N Peffer F Wong-Staal W C Greene 《Science (New York, N.Y.)》1987,238(4833):1575-1578
To investigate the mechanism by which immune activation augments replication of the human immunodeficiency virus type 1 (HIV-1) in infected T cells, four different classes of T cell mitogens were evaluated for their effects on the HIV-1 long terminal repeat (LTR). Phytohemagglutinin (PHA), a mitogenic lectin; phorbol 12-myristic 13-acetate, a tumor promoter; ionomycin, a calcium ionophore; and tat-1, the trans-activator protein from the human T cell leukemia/lymphoma virus type I (HTLV-I) each stimulated the HIV-1 LTR. Studies of deleted forms of the LTR supported a central role in these responses for the HIV-1 enhancer, which alone was sufficient for mitogen inducibility, but also suggested that other 5' positive and negative regulatory elements contribute to the overall magnitude of the response. Synergistic activation of the HIV-1 LTR (up to several thousandfold) was observed with combinations of these mitogens and the HIV-1--derived tat-III protein. Cyclosporin A, an immunosuppressive agent, inhibited PHA-mediated activation of the HIV-1 LTR but was without effect in the presence of other mitogens. Thus, HIV-1 gene expression and replication appear to be regulated, via the HIV-1 LTR, by the same mitogenic signals that induce T cell activation. 相似文献