Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q96DT5 (SIV)
 2,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Coreceptor use of HIV can evolve during infection. We previously examined coreceptor use of related SIVsm inoculum viruses and sequential reisolates from cynomolgus macaques. These viruses exhibited broad coreceptor specificities and, generally, CCR5 use remained efficient and stable, while alternative coreceptor use decreased longitudinally. Here we demonstrate that individual envelopes (Envs) from inoculum and reisolate viruses fuse via a range of coreceptors, including CCR5, CCR8, CXCR6, GPR15, GPR1, and APJ. On the whole, coreceptor use of Envs from sequential reisolates recapitulated that of reisolate viruses, thus CCR5 use remained stable while alternative coreceptor use tended to decrease over time. Rhesus CCR5, GPR15, and CXCR6 supported fusion to a similar extent as their human counterparts. Additionally, a number of Envs mediated CD4-independent fusion via CCR5 and GPR15. Envs from different inoculum viruses exhibited distinct dependencies on CD4 for fusion via CCR5, ranging from strictly CD4-dependent to efficiently CD4-independent. Early reisolates from macaques infected with CD4-independent inoculums maintained or evolved Envs with a broad range of CD4-independence. CD4-independence became less variable/efficient in late reisolates from macaques that developed neutralizing antibodies. Infection with a CD4-dependent virus resulted in evolution of CD4-independent Envs in late reisolates. While CD4 independence can potentially broaden tropism in vivo, CD4-independent viruses are particularly sensitive to neutralizing antibodies. Therefore, interplay between receptor tropism and neutralization may shape viral evolution and SIV pathogenesis.
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PMID:Evolution of coreceptor use and CD4-independence in envelope clones derived from SIVsm-infected macaques. 1459 87

Since the Prehistoric times hunting has been a vital activity for man. However, this may account for the contamination of the hunter, his family and relatives. Infections may occur by direct contact with blood or tissues of infected animal during handling and cutting up preys and when preparing or eating meat, or also when bitten by injured animal. Apes and antelopes hunting in sub-Saharan Africa proves to be particularly important since it has been well established that the recent or previous emergence of some viral zoonosis (Ebola, Aids, T lymphotropic viruses and Monkeypox) resulted from hunting and poaching. Moreover predation among different species of non human primates such as that practised by chimpanzees against monkeys, has led to the construction of recombinant simian Lentiviruses, such as SIV cpz able to infect man and then spread over the entire mankind as it was the case with HIV-1. SARS is another possible example of the zoonotic risks represented by the sale, handling and cutting up Chinese wild animals such as Himalayan civets for culinary purposes.
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PMID:[Bacterial and viral epidemics of zoonotic origin; the role of hunting and cutting up wild animals]. 1546 4

The TRIM5alpha proteins of humans and some Old World monkeys have been shown to block infection of particular retroviruses following virus entry into the host cell. Infection of most New World monkey cells by the simian immunodeficiency virus of macaques (SIVmac) is restricted at a similar point. Here we examine the antiretroviral activity of TRIM5alpha orthologs from humans, apes, Old World monkeys, and New World monkeys. Chimpanzee and orangutan TRIM5alpha proteins functionally resembled human TRIM5alpha, potently restricting infection by N-tropic murine leukemia virus (N-MLV) and moderately restricting human immunodeficiency virus type 1 (HIV-1) infection. Notably, TRIM5alpha proteins from several New World monkey species restricted infection by SIVmac and the SIV of African green monkeys, SIVagm. Spider monkey TRIM5alpha, which has an expanded B30.2 domain v3 region due to a tandem triplication, potently blocked infection by a range of retroviruses, including SIVmac, SIVagm, HIV-1, and N-MLV. Tandem duplications in the TRIM5alpha B30.2 domain v1 region of African green monkeys are also associated with broader antiretroviral activity. Thus, variation in TRIM5alpha proteins among primate species accounts for the observed patterns of postentry restrictions in cells from these animals. The TRIM5alpha proteins of some monkey species exhibit dramatic lengthening of particular B30.2 variable regions and an expanded range of susceptible retroviruses.
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PMID:Retrovirus restriction by TRIM5alpha variants from Old World and New World primates. 1576 95

Infection by the lentivirus, human immunodeficiency virus type 1 (HIV-1), results in a variety of syndromes involving both the central (CNS) and the peripheral (PNS) nervous systems. Productive HIV-1 infection of the CNS is chiefly detectable in perivascular macrophages and microglia. HIV-1 encoded transcripts and proteins have also been detected in the PNS; however, productive viral replication appears to be sparse and restricted to the macrophage cell population. Despite the absence of productive infection of neurons, HIV-1 infection has been associated with neuronal loss in distinct regions of the brain. Neuronal cell loss may occur through both necrosis and apoptosis, although neuronal apoptosis appears to be a feature of AIDS, as only rare apoptotic neurons have been demonstrated in a few pre-AIDS cases. Although there is no clear consensus as to the underlying mechanism of HIV-induced neuropathogenesis, two complementary concepts predominate. Firstly, HIV-1 encoded proteins injure neurons directly without requiring the intermediary functions of nonneuronal cells. Alternatively, neuronal apoptosis may result indirectly from the secretion of neurotoxic host molecules by resident brain macrophages or microglia in response to HIV-1 infection, stimulation by viral proteins or immune activation. Herein, we review the neurological disorders and their underlying mechanisms associated with HIV infection, focusing on HIV-associated dementia (HAD) and HIV sensory neuropathy (HIV-SN). The evidence that neuronal loss in HIV-1-infected individuals may be due to neuronal apoptosis is then discussed. This review also summarizes the current data supporting both the direct and indirect mechanisms by which neuronal death may occur during infection with HIV-1 or the closely related lentiviruses SIV and FIV. Lastly, strategies are examined for treating or preventing HAD by targeting specific neurotoxic mechanisms.
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PMID:Regulation of neural cell survival by HIV-1 infection. 1629 36

The global impact of HIV/AIDS intensifies the need for a preventive vaccine and nonhuman primate models can help provide critical insights into effective immunity. Pigtail macaques (Macaca nemestrina) are increasingly studied as a nonhuman primate model for AIDS. We compared the virologic and immunologic characteristics of HIV-1, SIV, and SHIV infection of naive pigtail macaques across a series of preclinical HIV vaccine studies. SIVmac251 and SIVmac239 infection of naive pigtail macaques resulted in a gradual decline in peripheral CD4+ T cells in the setting of high levels of viremia, approximating most closely human infection of HIV-1. In contrast, the CXCR4-utilizing SHIVmn229 virus resulted in rapid depletion of CD4+ T cells and minimal generation of humoral or cellular immune responses, similar to that observed with SHIV89.6P infection of rhesus macaques. Infection with the CCR5-utilizing, rhesus macaque passaged, SHIVSF162P3 resulted in some overall CD4+ T cell decline, however, three of eight macaques naturally control SHIVSF162P3 viremia to very low levels in the setting of robust adaptive immunity. Despite attempts at infecting pigtail macaques with HIV-1 strains passaged in juvenile pigtail macaques in vivo or in PBMC isolated from pigtail macaques in vitro, only lower nonsustained levels of viral replication were observed. Our results provide a series of virologic models with which to evaluate potential AIDS vaccines in pigtail macaques.
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PMID:Comparative evaluation of simian, simian-human, and human immunodeficiency virus infections in the pigtail macaque (Macaca nemestrina) model. 1679 33

Infection with HIV-1, SIV, or simian HIV is associated with abnormalities in the number, size, and structure of germinal centers (GCs). To determine whether these histopathologic abnormalities are associated with abnormalities in Ab development, we analyzed nucleotide sequences of Igs from splenic GCs of simian HIV-infected macaques. Virus-specific GCs were identified in frozen splenic tissue sections by inverse immunohistochemistry using rHIV-1 gp120 as a probe. B cells from envelope-specific GCs were isolated from these sections using laser capture microdissection. Their Igs were amplified from cDNA using nested PCR, then cloned and sequenced. Nucleotide sequences were recovered from nine multimember clonal lineages. Within each lineage, sequences had similar V-D-J or V-J junctions but differed by somatic mutations distributed throughout the variable domain. The clones were highly mutated, similar to that previously reported for HIV-1-specific human IgG Abs. The average clone had 37 mutations in the V region, for a frequency of 0.11 mutations/base. The mutational pattern was strikingly nonrandom, with somatic mutations occurring preferentially at RGYW/WRCY hotspots. Transition mutations were favored over transversions, with C-->T and G-->A replacements together accounting for almost one-third of all mutations. Analysis of replacement and silent mutations in the framework and CDRs suggests that the Igs were subjected to affinity selection. These data demonstrate that the process of Ab maturation is not seriously disrupted in GCs during the early stages of immunodeficiency virus infection, and that Env-specific Igs developing in GCs are subject to extensive somatic mutation and profound selection pressures.
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PMID:Germinal center function in the spleen during simian HIV infection in rhesus monkeys. 1681 68

Vif is a primate lentiviral accessory protein that is crucial for viral infectivity. Vif counteracts the antiviral activity of host deaminases such as APOBEC3G and APOBEC3F. We now report a novel function of African green monkey simian immunodeficiency virus (SIVagm) Vif that promotes replication of SIVagm in human cells lacking detectable deaminase activity. We found that cyclophilin A (CypA) was excluded from wild-type SIV particles but was efficiently packaged into vif-deficient SIVagm virions. The presence of CypA in vif-defective SIVagm was correlated with reduced viral replication. Infection of CypA knockout Jurkat cells or treatment of Jurkat cells with cyclosporine A eliminated the Vif-sensitive inhibition and resulted in replication profiles that were similar for wild-type and vif-deficient SIVagm. Importantly, the inhibitory effect of CypA was restricted to virus-producing cells and was TRIM5alpha independent. The abilities of SIVagm Vif to inhibit encapsidation of CypA and to increase viral infectivity were shared by rhesus macaque SIV Vif and thus seem to be general properties of SIV Vif proteins. Exclusion of CypA from SIVagm particles was not associated with intracellular degradation, suggesting a mode of Vif action distinct from that proposed for APOBEC3G. This is the first report of a novel vif-sensitive antiviral activity of human CypA that may limit zoonotic transmission of SIV and the first demonstration of CypA encapsidation into a virus other than human immunodeficiency virus type 1.
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PMID:Vif counteracts a cyclophilin A-imposed inhibition of simian immunodeficiency viruses in human cells. 1752 32

Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically significant viral diseases in the swine industry. Infection with PRRSV following vaccination is common, since protection is incomplete. Persistent infection may be one of the biggest obstacles to control of the disease. "Glycan shielding" was postulated to be a primary mechanism to explain evasion from neutralizing immune response, ensuring in vivo persistence of virus, such as HIV, SIV, and HBV. The objective of this study was to construct recombinant adenoviruses expressing single or multiple N-linked glycosylation site (NGS) mutant GP5 of PRRSV, and evaluate the expression in cell culture, and potential to induce immune responses in BALB/c mice. Six recombinant adenoviruses were constructed each expressing wild-type GP5 and 1-4 NGS mutants: N44S, N44/51S, N30/44/51S, N30/33/44/51S and N30/33S. Inoculation of BALB/c mice with all five recombinants expressing NGS mutant GP5 resulted in a significant neutralizing antibody responses which were significantly higher than that of recombinant adenovirus expressing wild-type GP5. But there were no significant difference in lymphocyte proliferation responses induced by wild type and NGS mutant GP5. It indicated that glycosylations of GP5 at residues N30, N33, N44 and N51 are critical for induction of neutralizing antibodies. These NGS mutant PRRSV GP5 will be useful to characterize the effects of glycosylation on immunogenicity in the natural host, and may lead to a new approach for the generation of PRRSV vaccines.
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PMID:Influence of porcine reproductive and respiratory syndrome virus GP5 glycoprotein N-linked glycans on immune responses in mice. 1767 39

Studies on HIV-1 mucosal transmission to evaluate early events in pathogenesis and the development of effective preventive/prophylactic methods have thus far been hampered by the lack of a suitable animal model susceptible to HIV-1 infection by either vaginal and/or rectal routes. In this regard, while primate-SIV/SHIV and cat-FIV models provided useful surrogate platforms to derive comparative data, these viruses are distinct and different from that of HIV-1. Therefore an optimal model that permits direct study of HIV-1 transmission via mucosal routes is highly desirable. The new generation of humanized NOD/SCID BLT, NOD/SCIDgammac(-/-), and Rag2(-/-)gammac(-/-) mouse models show great promise to achieve this goal. Here, we show that humanized Rag2(-/-)gammac(-/-) mice (RAG-hu) engrafted with CD34 hematopoietic progenitor cells harbor HIV-1-susceptible human cells in the rectal and vaginal mucosa and are susceptible to HIV-1 infection when exposed to cell-free HIV-1 either via vagina or rectum. Infection could be established without any prior hormonal conditioning or mucosal abrasion. Both R5 and X4 tropic viruses were capable of mucosal infection resulting in viremia and associated helper T cell depletion. There was systemic spread of the virus with infected cells detected in different organs including the intestinal mucosa. R5 virus was highly efficient in mucosal transmission by both routes whereas X4 virus was relatively less efficient in causing infection. HIV-1 infection of RAG-hu mice by vaginal and rectal routes as shown here represents the first in vivo model of HIV-1 transmission across intact mucosal barriers and as such may prove very useful for studying early events in HIV-1 pathogenesis in vivo, as well as the testing of microbicides, anti-HIV vaccines/therapeutics, and other novel strategies to prevent HIV-1 transmission.
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PMID:Mucosal transmission of R5 and X4 tropic HIV-1 via vaginal and rectal routes in humanized Rag2-/- gammac -/- (RAG-hu) mice. 1820 84

Infection of primates by HIV-1 and SIV induces multiple hematological abnormalities of central hematopoietic origin. Although these defects greatly contribute to the pathophysiology of HIV-1 infection, the molecular basis for altered BM function remains unknown. Here we show that when cynomolgus macaques were infected with SIV, the multipotent potential of their hematopoietic progenitor cells was lost, and this correlated with downregulation of STAT5A and STAT5B expression. However, forced expression of STAT5B entirely rescued the multipotent potential of the hematopoietic progenitor cells. In addition, an accessory viral protein required for efficient SIV and HIV replication and pathogenicity, "Negative factor" (Nef), was essential for SIV-mediated impairment of the multipotent potential of hematopoietic progenitors ex vivo and in vivo. This newly uncovered property of Nef was both conserved between HIV-1 and SIV strains and entirely dependent upon the presence of PPARgamma in targeted cells. Further, PPARgamma agonists mimicked Nef activity by inhibiting STAT5A and STAT5B expression and hampering the functionality of hematopoietic progenitors both ex vivo and in vivo. These findings have extended the role of Nef in the pathogenicity of HIV-1 and SIV and reveal a pivotal role for the PPARgamma/STAT5 pathway in the regulation of early hematopoiesis. This study may provide a basis for investigating the potential therapeutic benefits of PPARgamma antagonists in both patients with AIDS and individuals with hematopoietic disorders.
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PMID:Human and simian immunodeficiency viruses deregulate early hematopoiesis through a Nef/PPARgamma/STAT5 signaling pathway in macaques. 1843 12


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