Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001175 (AIDS)
 120,706 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SAIDS-associated lymphoma (SAL) represents a monoclonal expansion of B-cell origin in which simian immunodeficiency virus (SIV) infection is not detected. However, tumor cells are frequently infected with rhesus lymphocryptovirus (RhLCV), a rhesus homologue of Epstein-Barr virus (EBV). In previous studies, the incidence of RhLCV infection in SAL was determined to be 89% as measured by polymerase chain reaction (PCR) and/or in situ hybridization. The main objective of the present study was to ascertain whether the level of RhLCV infection in the SIV-infected macaque is influenced as a function of SAIDS progression, and/or whether increased levels of RhLCV infection may correlate with the development of SAL. To this end, RhLCV infection was evaluated in three independent groups: (1) in lymphomas from SIV-infected rhesus macaques, (2) in peripheral blood mononuclear cells (PBMC) from a cohort of 69 randomly selected healthy animals, and (3) in PBMC collected from 22 SIV-infected animals at various times during progression to SAIDS or SAL. The relative levels of RhLCV infection were evaluated by PCR/Southern blot analysis, visual comparison to a standard dilution series, and assignment of relative signal intensity to a uniform classification scheme. The data show that SIV-infected monkeys have a generally higher RhLCV load in PBMC than do healthy animals, but that the virus load varies widely among animals during disease progression. Increased RhLCV load does not occur uniformly during the progression of SAIDS, although evidence indicates an increased RhLCV viral load in the development of SAL.
AIDS Res Hum Retroviruses 2000 Jan 20
PMID:Rhesus lymphocryptovirus infection during the progression of SAIDS and SAIDS-associated lymphoma in the rhesus macaque. 1065 55

A growing body of literature suggests that the HIV accessory proteins Nef and Vpr could be involved in depletion of CD4(+) and non-CD4(+) cells and tissue atrophy, and in delaying the death of HIV-infected cells. Cell depletion is likely to be predominantly a bystander effect because the number of cells dying far outnumbers HIV-infected cells and is not confined to CD4(+) cells. The myristylated N-terminal region of Nef has severe membrane disordering properties, and when present in the extracellular medium causes rapid lysis in vitro of a wide range of CD4(+) and non-CD4(+) cells, suggesting a role for extracellular Nef in the depletion of bystander cells. A direct role for HIV-1 Nef in cytopathicity is supported by studies in HIV-infected Hu Liv/Thy SCID mice, in transgenic mice expressing nef gene alone, and in rhesus macaques infected with SIV/HIV chimeric virus containing HIV-1 nef. The N-terminal region of Nef has been directly implicated in development of simian AIDS. Extracellular Vpr and C-terminal fragments of Vpr cause membrane permeabilization and apoptosis of a wide range of CD4(+) and non-CD4(+) cells, and could also contribute to depletion of bystander cells. A direct in vivo role for Vpr in thymocyte depletion, thymic atrophy, and nephropathy is suggested in studies with vpr transgenic mice. Intracellular Nef and Vpr could help HIV-infected cells evade cell death by inhibiting apoptosis of infected cells and by avoiding virus-specific CTL response. Nef and Vpr are potential targets for therapeutic intervention and vaccine development, and strategies that prevent the death of bystander cells while promoting the early death of HIV-infected cells could arrest or retard progression to AIDS.
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PMID:Could Nef and Vpr proteins contribute to disease progression by promoting depletion of bystander cells and prolonged survival of HIV-infected cells? 1067 51

Nef is a 27 - 34 kD myristoylated protein unique to primate lentiviruses. A functional Nef gene is important for development of high viremia and simian AIDS in SIV infected rhesus macaques (1). In a transgenic mouse model expression of Nef protein alone when expressed under a CD4-promoter is sufficient to cause an AIDS like disease (2). A critical role for Nef in development of AIDS in humans is suggested by the observation that some individuals with a long-term nonprogressive HIV-1 infection are infected with viruses carrying naturally occurring Nef deletions (3-5). The mechanism of Nef action remains incompletely understood, but multiple lines of evidence point out to a role in modulation of cellular signaling pathways via physical and functional interactions with host cell proteins.
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PMID:Interactions of HIV-1 NEF with cellular signal transducing proteins. 1070 55

HIV-1 Tat protein activates resting cells, rendering them permissive for viral replication. Replication of HIV-1 in vitro is enhanced by intercellular passage of Tat protein and inhibited by anti-Tat antibodies. Tat dependence of HIV-1 replication in vivo during acute, chronic asymptomatic and AIDS stages of infection was assessed by comparisons of plasma viremia in Tat-immunized or control monkeys challenged with SHIV(33) or SHIV(33A). Chronic plasma viremia became undetectable or minimized in Tat-immunized asymptomatic SHIV(33)-infected monkeys (p<0.008) while the high viral loads of acute infection or SHIV(33A)-induced simian AIDS were unaffected by Tat immunization. Active or passive immunotherapies targeting Tat provide potential approaches to controlling chronic HIV-1 viremia and preventing AIDS.
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PMID:Minimization of chronic plasma viremia in rhesus macaques immunized with synthetic HIV-1 Tat peptides and infected with a chimeric simian/human immunodeficiency virus (SHIV33). 1081 20

Increasing interest has been devoted to the role that monocyte-macrophages play in the pathogenesis of AIDS. The hypothesis of an involvement in AIDS pathogenesis of human/simian immunodeficiency virus (HIV/SIV) Nef also is currently under evaluation by many investigators. The original basis of this hypothesis came from evidence that monkeys infected with a nef-deleted SIV strain failed to develop simian AIDS. Here, we show that treatment of human monocyte-derived macrophages (MDM) with recombinant HIV-1 Nef protein (rNef) induces a strong inhibition of the replication of either macrophage (M-) or dual-tropic HIV-1 strains. Through cytofluorimetric analyses, we detected internalization of FITC-conjugated rNef in MDM as early as 6 h after treatment. Confocal microscope observations demonstrated that the intracellular distribution of internalized rNef was identical to that of endogenously produced Nef. Down-regulation of the CD4 HIV receptor detected upon rNef treatment of MDM suggested that the rNef-induced HIV inhibition occurred at the virus entry step. This deduction was strengthened by the observation that CD4-independent infection was totally insensitive to rNef treatment. The specificity of all observed effects was demonstrated by immunodepletion of rNef. Finally, we showed that the resistance to HIV replication induced by rNef treatment in MDM favours the spread of T-tropic over M-tropic HIV strains in doubly infected CD4(+) lymphocyte-MDM co-cultures. We propose that extracellular Nef contributes to AIDS pathogenesis by inducing resistance to M-tropic HIV replication in MDM, thereby facilitating the switching from M- to T-tropic HIV prevalence that correlates frequently with AIDS progression.
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PMID:T-tropic human immunodeficiency virus (HIV) type 1 Nef protein enters human monocyte-macrophages and induces resistance to HIV replication: a possible mechanism of HIV T-tropic emergence in AIDS. 1108 22

To address the subtle interactions between antiviral cytotoxic T-cell (CTL) immune responses and the evolution of viral quasispecies variants in vivo, we performed a longitudinal study in a simian immunodeficiency virus (SIV)-infected rhesus macaque that had a long experimental SIV infection before developing simian AIDS. Before being infected with SIV, this animal was immunized with a mixture of seven lipopeptides derived from SIV Nef and Gag proteins and showed a bispecific antiviral CTL response directed toward Nef 169-178 and 211-225 peptides. After SIV infection, CTL activity against the Nef 169-178 epitope was no longer detectable, as assessed from peripheral blood mononuclear cells stimulated by autologous SIV. CTL activity against the 211-225 epitope was lost after 3 months, and an additional CTL response to the amino acids 112-119 Nef epitope emerged. Analysis of the Nef proviral sequence revealed the presence of immune escape variants first in the 211-225 epitope and much later in the 112-119 epitope. In contrast, epitope 169-178 showed only two mutations among all viral sequencing performed. We conclude that in this macaque, bispecific CTL exerted a strong selective pressure and escape virus mutants finally emerged. We identified CTL recognizing a conserved Nef epitope 112-119 (SYKLAIDM), essential for viral replication, which could be associated with a prolonged AIDS-free period. These results stress the importance of the induction of broader multispecific CTLs directed against highly conserved and functional T-cell epitopes by vaccination, with the aim of keeping HIV infection in check.
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PMID:Temporal loss of Nef-epitope CTL recognition following macaque lipopeptide immunization and SIV challenge. 1111 77

Nonhuman primate models are increasingly used in the screening of candidate AIDS vaccine and immunization strategies for advancement to large-scale human trials. The predictive value of such macaque studies is largely dependent upon the fidelity of the model system in mimicking human immunodeficiency virus (HIV) type 1 infection in terms of viral transmission, replication, and pathogenesis. Herein, we describe the efficient mucosal transmission of a CCR5-specific chimeric simian/human immunodeficiency virus, SHIV(SF162P3). Female rhesus macaques were infected with SHIV(SF162P3) after a single atraumatic application to the cervicovaginal mucosa. The disease course of SHIV(SF162P3)-infected monkeys is similar and as varied as natural HIV infection in terms of viral replication, gradual loss of CD4(+) peripheral blood mononuclear cells, and the development of simian AIDS-defining opportunistic infections. The SHIV(SF162P3)/macaque model should facilitate direct preclinical assessment of HIV vaccine strategies in addition to antiviral compounds directed towards envelope target cell interactions. Furthermore, this controlled model provides the setting to investigate immunologic responses and putative host-specific susceptibility factors that alter viral transmission and subsequent disease progression.
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PMID:Mucosal transmission and induction of simian AIDS by CCR5-specific simian/human immunodeficiency virus SHIV(SF162P3). 1116 Jun 99

Genetic variation of SIV env during the course of infection provides a large population pool that is continually shaped by selective forces in vivo and may influence the development of clinical disease. SAIDS-associated lymphoma (SAL) in the SIV-infected macaque is typically a clonal or oligoclonal mass of B cell origin, extranodal in anatomic distribution, in which SIV is restricted largely to infiltrating macrophages. To explore the degree of genetic variation in SIV env represented in SAL, a 480-bp DNA fragment containing the V1 region was PCR amplified from seven cases of SAL and from a nonneoplastic lymph node of an SIV-infected macaque. The nucleotide sequence of the V1 region was determined from at least 10 clones from multiple independent amplification reactions of each tissue. Overall, the degree of V1 variability within lymphomas was found not to be restricted but to resemble the heterogeneity reported in SIV-infected lymphoid and other tissues. V1 variation in the nonneoplastic lymph node was unexpectedly limited, perhaps related to the unusual disease condition associated with SAIDS in that animal. Unlike observations from SIV-infected tissues of animals without neoplastic disease, no increase was detected in the number of O- or N-linked glycosylation sites in the V1 regions isolated from lymphomas as compared with the original inoculum. These findings suggest that, within the microenvironment of the lymphoma, the immune evasion conferred by increased glycosylation may offer little selective advantage.
AIDS Res Hum Retroviruses 2001 Mar 20
PMID:Variation in simian immunodeficiency virus env V1 region in simian AIDS-associated lymphoma. 1128 15

An effective vaccine against AIDS is unlikely to be available for many years. As we approach two decades since the first identification of human immunodeficiency virus, type 1 (HIV-1), currently, only one subunit vaccine candidate has reached phase 3 of clinical trials. The subunit approach has been criticized for its inability to elicit effectively cytotoxic T-lymphocyte (CTL) response, which is felt by many to be needed for protection against HIV-1 infection. In subhuman primates, a live attenuated simian immunodeficiency virus (SIV) vaccine candidate, capable of inducing CTL, has been found to confer prophylactic immunity sufficient to prevent simian AIDS. Because replication competent (live) attenuated viruses could over time revert to virulence, such a live attenuated approach has largely been dismissed for HIV-1. Here, we describe the creation of constitutively dead conditionally live (CDCL) HIV-1 genomes. These genomes are constitutively defective for the Tat/TAR axis and are conditionally dependent on tetracycline for attenuated replication with robust expression of viral antigens. Our results suggest that CDCL genomes merit consideration as safer "live" attenuated HIV-1 vaccine candidates.
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PMID:Constitutively dead, conditionally live HIV-1 genomes. Ex vivo implications for a live virus vaccine. 1139 95

Infection of rhesus macaques with chimeric simian-human immunodeficiency viruses (SHIV) is an established method to study AIDS pathogenesis and is increasingly used to assess the efficacy of vaccine and antiviral candidates. For these reasons, a detailed understanding of those molecular determinants, which confer pathogenic potential to SHIV viruses, should assist in both rational experimental design and interpretation of results. In this report, we describe the development and in vivo characterization of a pathogenic molecular clone, SHIVSF33A2, which contains an envelope sequence derived from the CXCR4-dependent isolate, HIV-1SF33. Proviral DNA, amplified from a rhesus macaque infected with the pathogenic isolate SHIVSF33A, was substituted into the corresponding region of the parental, nonpathogenic SHIVSF33 genome creating the molecular clone SHIVSF33A2. Coreceptor specificity of SHIVSF33A2 was determined to be CXCR4 specific. Naive rhesus macaques were productively infected after a single exposure to cell-free SHIVSF33A2 by either the intravenous (IV) or intravaginal (IVAG) routes. Animals infected with SHIVSF33A2 suffered a severe loss of peripheral CD4+ T cells and high acute plasma viremia with development of simian AIDS 9 months after inoculation. Sequence analysis identified 25 discreet amino acid changes within the V1-V5 regions of the envelope protein when compared with the nonpathogenic parental virus. These data indicate that domains within the HIV-1 envelope protein are sufficient to define pathogenic potential in the context of the SIVmac239 genome.
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PMID:Pathogenic determinants of the mucosally transmissible CXCR4-specific SHIV(SF33A2) map to env region. 1146 40


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