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

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

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

Aspartate 368 on human immunodeficiency virus type 1 (HIV-1) gp120 forms multiple contacts with CD4; in mutagenesis studies, its replacement by asparagine and corresponding changes in simian immunodeficiency virus SIVmac (D385N) reduced binding with CD4. Nevertheless, simian immunodeficiency virus envelopes with D385N were prevalent in several studies. Extending these observations, we also found D385N to be dominant among env clones from two rhesus macaques that progressed rapidly to simian AIDS. These envelopes showed a CD4-independent phenotype as well as reduced affinity to CD4. Moreover, an adjacent change, G383R, which was frequently coselected with D385N, further decreased binding. An optical biosensor study demonstrated that the SIVmac239 gp120 bound to CD4 with kinetics similar to those of HIV-1. However, the gp120s with D385N and G383R showed a 40-fold reduction in affinity, with a drastic increase in dissociation rate, indicating an inherently unstable complex. This finding showed that rapid progression to simian AIDS may be accompanied by the selection of CD4-independent gp120 variants with impaired CD4 binding ability.
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PMID:Rapid progression to simian AIDS can be accompanied by selection of CD4-independent gp120 variants with impaired ability to bind CD4. 1209 5

The objective of this study was to determine whether simian immunodeficiency virus (SIV) infection of macaques could be used as a model system to assess the role of selenium in AIDS. Plasma and serum selenium levels were determined by standard assays in monkeys before and after inoculation of SIV. SIV-infected cells or cells expressing the HIV Tat protein were labeled with 75Se, and protein extracts were prepared and electrophoresed to analyze selenoprotein expression. Total tRNA was isolated from CEMx174 cells infected with SIV or from KK1 cells infected with HIV, and selenocysteine tRNA isoforms were characterized by reverse phase chromatography. SIV-infected monkeys show a decrease in blood selenium levels similar to that observed in AIDS with development of SAIDS. Cells infected with SIV in vitro exhibit reduced selenoprotein levels and an accumulation of small molecular weight selenium compounds relative to uninfected cells. Examination of the selenocysteine tRNA isoforms in HIV-infected KK1 cells or SIV-infected CEMx174 cells reveals an isoform distribution characteristic of selenium-deficient cells. Furthermore, transfection of Jurkat E6 cells with the Tat gene selectively altered selenoprotein synthesis, with GPX4 and Sep15 being the most inhibited and TR1 the most enhanced. Taken together, the data show that monkeys infected with SIV in vivo and cells infected with SIV in vitro will provide appropriate models for investigating the mechanism(s) responsible for reduced selenium levels that accompany the progression of AIDS in HIV disease.
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PMID:Rhesus monkey simian immunodeficiency virus infection as a model for assessing the role of selenium in AIDS. 1247 32

Elevated levels of interleukin 7 (IL-7) have been correlated with various T-cell depletion conditions, including HIV infection, and suggested as an indicator of HIV disease progression (AIDS and death). Here, the assessment of pathogenic simian immunodeficiency virus (SIVmac239) infection in rhesus macaques demonstrated a clear association between a significant elevation in IL-7 levels and disease progression. In 5 macaques that progressed to simian AIDS and death, elevated IL-7 levels were unable to restore T-cell homeostasis. In contrast, increased IL-7 levels were followed by relatively high and stable T-cell numbers in the SIV-infected macaques with a slow-progressing phenotype. Further, studies in sooty mangabeys that do not progress to simian AIDS and that maintain stable T-cell numbers despite high levels of viral replication support the importance of IL-7 and T-cell homeostasis in disease progression. These data suggest that during pathogenic SIV infection with high viral replication, elevated IL-7 levels are unable to recover T-cell homeostasis, thereby leading to disease progression. The utility of IL-7 as a potential immunotherapeutic agent to improve HIV/SIV-related T-cell depletion may therefore depend on controlling the pathogenic effects of viral replication prior to the administration of IL-7.
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PMID:Elevated interleukin-7 levels not sufficient to maintain T-cell homeostasis during simian immunodeficiency virus-induced disease progression. 1452 80

An increasing body of evidence suggests that a vaccine that elicits anti-HIV-1 cellular immunity could provide the basis for an effective AIDS vaccine. Comparative immunization experiments testing a variety of vaccine approaches have demonstrated that replication-incompetent adenovirus vectors are an effective means for eliciting cytotoxic T-lymphocyte (CTL) immune responses against HIV-1 antigens. These immune responses effectively control viremia in nonhuman primates following challenge with simian AIDS viruses. Such data, coupled with epidemiology studies that identify HIV-1 gag, pol, and nef as the best antigens for broadly directed cellular immune responses, provide guidance for the development of a potential AIDS vaccine.
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PMID:Recent advances in the development of HIV-1 vaccines using replication-incompetent adenovirus vectors. 1474 26

Newborn rhesus macaques were infected with two chimeric simian-human immunodeficiency virus (SHIV) strains which contain unique human immunodeficiency virus type 1 (HIV-1) env genes and exhibit distinct phenotypes. Infection with either the CCR5-specific SHIV(SF162P3) or the CXCR4-utilizing SHIV(SF33A) resulted in clinical manifestations consistent with simian AIDS. Most prominent in this study was the detection of severe thymic involution in all SHIV(SF33A)-infected infants, which is very similar to HIV-1-induced thymic dysfunction in children who exhibit a rapid pattern of disease progression. In contrast, SHIV(SF162P3) induced only a minor disruption in thymic morphology. Consistent with the distribution of the coreceptors CXCR4 and CCR5 within the thymus, the expression of SHIV(SF162P3) was restricted to the thymic medulla, whereas SHIV(SF33A) was preferentially detected in the cortex. This dichotomy of tissue tropism is similar to the differential tropism of HIV-1 isolates observed in the reconstituted human thymus in SCID-hu mice. Accordingly, our results show that the SHIV-monkey model can be used for the molecular dissection of cell and tissue tropisms controlled by the HIV-1 env gene and for the analysis of mechanisms of viral immunopathogenesis in AIDS. Furthermore, these findings could help explain the rapid progression of disease observed in some HIV-1-infected children.
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PMID:Induction of simian AIDS in infant rhesus macaques infected with CCR5- or CXCR4-utilizing simian-human immunodeficiency viruses is associated with distinct lesions of the thymus. 1474 77

Of the 40 million people living with HIV/AIDS worldwide in 2003, only 7% received highly active antiretroviral treatment (HAART). Without treatment, approximately half of AIDS patients will suffer from NeuroAIDS including neurological dysfunction, peripheral neuropathies, motor impairment, cognitive difficulties and frank dementia. HAART has reduced mortality from AIDS in the developed world, but CNS/neurological complications continue to be a leading cause of death or disability in AIDS patients on HAART. Despite years of use in developed countries, it is still not clear what the long-term impact of HAART will be on NeuroAIDS. The mechanisms of AIDS-related CNS pathology, in the presence or absence of HAART, are not completely understood. Infection with simian immunodeficiency virus (SIV) in macaques provides an excellent research model of AIDS, including AIDS-related CNS pathology and cognitive/behavioral impairments. A major goal of research with the SIV/macaque model has been to characterize behavioral and cognitive impairments in NeuroAIDS and elucidate the CNS pathology behind these impairments. Review of the studies assessing cognitive impairment in SIV infected macaques demonstrates the high concordance between neuropsychological impairment in human and simian AIDS. Consistent with results in human AIDS patients, SIV-infected monkeys tend to be impaired most often on tasks dependent upon intact frontal cortical and/or subcortical functioning. Building on the strengths of the SIV/macaque model of AIDS, directions for future research are discussed including further mechanistic studies of the neuropathology leading to cognitive impairment as well as assessment of the impact of antiretroviral therapy or drugs of abuse on NeuroAIDS.
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PMID:Neuropsychopathology in the SIV/macaque model of AIDS. 1556 12


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