The Experts below are selected from a list of 16620 Experts worldwide ranked by ideXlab platform
Baek Kim - One of the best experts on this subject based on the ideXlab platform.
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efficient pre catalytic conformational change of reverse transcriptases from samhd1 non counteracting primate Lentiviruses during dntp incorporation
Virology, 2019Co-Authors: Siana A Coggins, Jason T. Kimata, Baek Kim, Jessica Holler, Donghyun Kim, Raymond F SchinaziAbstract:Abstract Unlike HIV-1, HIV-2 and some SIV strains replicate at high dNTP concentrations even in macrophages due to their accessory proteins, Vpx or Vpr, that target SAMHD1 dNTPase for proteasomal degradation. We previously reported that HIV-1 reverse transcriptase (RT) efficiently synthesizes DNA even at low dNTP concentrations because HIV-1 RT displays faster pre-steady state kpol values than SAMHD1 counteracting lentiviral RTs. Here, since the kpol step consists of two sequential sub-steps post dNTP binding, conformational change and chemistry, we investigated which of the two sub-steps RTs from SAMHD1 non-counteracting viruses accelerate in order to complete reverse transcription in the limited dNTP pools found in macrophages. Our study demonstrates that RTs of SAMHD1 non-counteracting Lentiviruses have a faster conformational change rate during dNTP incorporation, supporting that these Lentiviruses may have evolved to harbor RTs that can efficiently execute the conformational change step in order to circumvent SAMHD1 restriction and dNTP depletion in macrophages.
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interplay of ancestral non primate Lentiviruses with the virus restricting samhd1 proteins of their hosts
Journal of Biological Chemistry, 2018Co-Authors: Sarah A Mereby, Baek Kim, Tatsuya Maehigashi, Jessica Holler, Donghyun Kim, Raymond F SchinaziAbstract:Lentiviruses infect both dividing CD4+ T cells and nondividing myeloid cells, and the infected myeloid cells serve as long-living viral reservoirs. Host sterile alpha motif- and histidine-aspartate domain-containing protein 1 (SAMHD1) kinetically restricts reverse transcription of primate Lentiviruses, including human immunodeficiency virus, type 1 (HIV-1) and simian immunodeficiency virus (SIV), in nondividing myeloid cells. SAMHD1 enforces this restriction through its dNTP triphosphohydrolase (dNTPase) activity that depletes cellular dNTPs. Some primate Lentiviruses, such as HIV-2, SIVsm, and SIVagm, counteract SAMHD1 restriction by using their viral accessory proteins (Vpx or Vpr) that induce the proteosomal degradation of SAMHD1 and increase dNTP levels. SAMHD1 is conserved among non-primate mammals such as cats, cows, and horses that also carry their own Lentiviruses (feline and bovine immunodeficiency viruses and equine infectious anemia viruses, respectively). However, whether these viruses also target SAMHD1 is unknown. Here, we tested whether these ancestral non-primate Lentiviruses also can counteract their host SAMHD1 proteins by promoting their proteosomal degradation. Using biochemical and various cell-based assays, we observed that SAMHD1 proteins from the non-primate host species display dGTP-dependent dNTPase activity, but that the non-primate Lentiviruses fail to proteosomally degrade the SAMHD1 proteins of their hosts. Our findings suggest that accessory protein-mediated proteosomal degradation of SAMHD1 did not exist among the ancestral non-primate Lentiviruses and was uniquely gained by some primate Lentiviruses after their transmission to primate species.
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p21-mediated RNR2 repression restricts HIV-1 replication in macrophages by inhibiting dNTP biosynthesis pathway
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Awatef Allouch, Sarah M Amie, Baek Kim, Annie David, Hichem Lahouassa, Loic Chartier, Florence Margottin-goguet, Françoise Barré-sinoussi, Asier Saez-cirion, Gianfranco PancinoAbstract:Macrophages are a major target cell for HIV-1, and their infection contributes to HIV pathogenesis. We have previously shown that the cyclin-dependent kinase inhibitor p21 inhibits the replication of HIV-1 and other primate Lentiviruses in human monocyte-derived macrophages by impairing reverse transcription of the viral genome. In the attempt to understand the p21-mediated restriction mechanisms, we found that p21 impairs HIV-1 and simian immunodeficiency virus (SIV)mac reverse transcription in macrophages by reducing the intracellular deoxyribonucleotide (dNTP) pool to levels below those required for viral cDNA synthesis by a SAM domain and HD domain-containing protein 1 (SAMHD1)-independent pathway. We found that p21 blocks dNTP biosynthesis by down-regulating the expression of the RNR2 subunit of ribonucleotide reductase, an enzyme essential for the reduction of ribonucleotides to dNTP. p21 inhibits RNR2 transcription by repressing E2F1 transcription factor, its transcriptional activator. Our findings unravel a cellular pathway that restricts HIV-1 and other primate Lentiviruses by affecting dNTP synthesis, thereby pointing to new potential cellular targets for anti-HIV therapeutic strategies.
Michael Emerman - One of the best experts on this subject based on the ideXlab platform.
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the role of the antiviral apobec3 gene family in protecting chimpanzees against Lentiviruses from monkeys
PLOS Pathogens, 2015Co-Authors: Lucie Etienne, Beatrice H Hahn, Frederic Bibolletruche, Peter H Sudmant, Michael EmermanAbstract:Cross-species transmissions of viruses from animals to humans are at the origin of major human pathogenic viruses. While the role of ecological and epidemiological factors in the emergence of new pathogens is well documented, the importance of host factors is often unknown. Chimpanzees are the closest relatives of humans and the animal reservoir at the origin of the human AIDS pandemic. However, despite being regularly exposed to monkey Lentiviruses through hunting, chimpanzees are naturally infected by only a single simian immunodeficiency virus, SIVcpz. Here, we asked why chimpanzees appear to be protected against the successful emergence of other SIVs. In particular, we investigated the role of the chimpanzee APOBEC3 genes in providing a barrier to infection by most monkey Lentiviruses. We found that most SIV Vifs, including Vif from SIVwrc infecting western-red colobus, the chimpanzee’s main monkey prey in West Africa, could not antagonize chimpanzee APOBEC3G. Moreover, chimpanzee APOBEC3D, as well as APOBEC3F and APOBEC3H, provided additional protection against SIV Vif antagonism. Consequently, lentiviral replication in primary chimpanzee CD4+ T cells was dependent on the presence of a lentiviral vif gene that could antagonize chimpanzee APOBEC3s. Finally, by identifying and functionally characterizing several APOBEC3 gene polymorphisms in both common chimpanzees and bonobos, we found that these ape populations encode APOBEC3 proteins that are uniformly resistant to antagonism by monkey Lentiviruses.
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host gene evolution traces the evolutionary history of ancient primate Lentiviruses
Philosophical Transactions of the Royal Society B, 2013Co-Authors: Alex A Compton, Harmit S. Malik, Michael EmermanAbstract:Simian immunodeficiency viruses (SIVs) have infected primate species long before human immunodeficiency virus has infected humans. Dozens of species-specific Lentiviruses are found in African primate species, including two strains that have repeatedly jumped into human populations within the past century. Traditional phylogenetic approaches have grossly underestimated the age of these primate Lentiviruses. Instead, here we review how selective pressures imposed by these viruses have fundamentally altered the evolutionary trajectory of hosts genes and, even in cases where there now remains no trace of the viruses themselves, these evolutionary signatures can reveal the types of viruses that were once present. Examination of selection by ancient viruses on the adaptive evolution of host genes has been used to derive minimum age estimates for modern primate Lentiviruses. This type of data suggests that ancestors of modern SIV existed in simian primates more than 10 Ma. Moreover, examples of host resistance and viral adaptation have implications not only for estimating the age and host range of ancient primate Lentiviruses, but also the pathogenic potential of their modern counterparts.
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the ability of primate Lentiviruses to degrade the monocyte restriction factor samhd1 preceded the birth of the viral accessory protein vpx
Cell Host & Microbe, 2012Co-Authors: Oliver I Fregoso, Connor O Mccoy, Frederick A Matsen, Harmit S. Malik, Michael EmermanAbstract:The human SAMHD1 protein potently restricts lentiviral infection in dendritic cells and monocyte/macrophages but is antagonized by the primate lentiviral protein Vpx, which targets SAMHD1 for degradation. However, only two of eight primate lentivirus lineages encode Vpx, whereas its paralog, Vpr, is conserved across all extant primate Lentiviruses. We find that not only multiple Vpx but also some Vpr proteins are able to degrade SAMHD1, and such antagonism led to dramatic positive selection of SAMHD1 in the primate subfamily Cercopithecinae. Residues that have evolved under positive selection precisely determine sensitivity to Vpx/Vpr degradation and alter binding specificity. By overlaying these functional analyses on a phylogenetic framework of Vpr and Vpx evolution, we can decipher the chronology of acquisition of SAMHD1-degrading abilities in Lentiviruses. We conclude that vpr neofunctionalized to degrade SAMHD1 even prior to the birth of a separate vpx gene, thereby initiating an evolutionary arms race with SAMHD1.
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the host restriction factor apobec3g and retroviral vif protein coevolve due to ongoing genetic conflict
Cell Host & Microbe, 2012Co-Authors: Alex A Compton, Vanessa M Hirsch, Michael EmermanAbstract:Summary APOBEC3G (A3G) is a host cytidine deaminase that inhibits retroviruses. HIV and related primate Lentiviruses encode Vif, which counteracts A3G by inducing its degradation. This Vif-mediated A3G inhibition is species specific, suggesting that the A3G-Vif interaction has evolved as primate Lentiviruses have adapted to their hosts. We examined the evolutionary dynamics of the A3G-Vif interaction within four African green monkey (AGM) subspecies, which are each naturally infected with a distinct simian immunodeficiency virus (SIV). We identified single amino acid changes within A3G in two AGM subspecies that render it resistant to Vif proteins, except for Vif from the viruses that naturally infect these subspecies. Moreover, experimental infection of AGMs shows that Vif can rapidly adapt to these arising Vif-resistant A3G genotypes. These data suggest that despite being generally nonpathogenic in its natural host, SIV infection selects for Vif-resistant forms of A3G in AGM populations, driving Vif counterevolution and functional divergence.
Barbara Blacklaws - One of the best experts on this subject based on the ideXlab platform.
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small ruminant Lentiviruses immunopathogenesis of visna maedi and caprine arthritis and encephalitis virus
Comparative Immunology Microbiology and Infectious Diseases, 2012Co-Authors: Barbara BlacklawsAbstract:The small ruminant Lentiviruses include the prototype for the genus, visna-maedi virus (VMV) as well as caprine arthritis encephalitis virus (CAEV). Infection of sheep or goats with these viruses causes slow, progressive, inflammatory pathology in many tissues, but the most common clinical signs result from pathology in the lung, mammary gland, central nervous system and joints. This review examines replication, immunity to and pathogenesis of these viruses and highlights major differences from and similarities to some of the other Lentiviruses.
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diagnostic tests for small ruminant Lentiviruses
Veterinary Microbiology, 2005Co-Authors: D De Andres, Barbara Blacklaws, E Berriatua, Sigurbjorg Torsteinsdottir, N J Watt, Dieter Klein, Gordon D HarkissAbstract:Maedi visna virus and caprine arthritis encephalitis virus are closely related retroviruses that cause chronic inflammatory disease in small ruminants. The infections are characterised by insidious onset and slow progression. Diagnosis of infection is usually by serological testing. A variety of assays are available for this purpose, though the relative sensitivity and specificity of these assays has not been compared systematically. Here we review recent developments in laboratory diagnostic methods and their use in field diagnosis. The results suggest that a combination of ELISA and PCR might afford optimal detection of SRLV infection.
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transmission of small ruminant Lentiviruses
Veterinary Microbiology, 2004Co-Authors: Barbara Blacklaws, E Berriatua, Sigurbjorg Torsteinsdottir, N J Watt, D De Andres, Dieter Klein, Gordon D HarkissAbstract:Small ruminant Lentiviruses (SRLV) are classical slow retroviruses causing chronic inflammatory disease in a variety of target organs. The routes of transmission have been investigated and a large body of evidence has accumulated over many years. The main routes are through ingestion of infected colostrum and/or milk, or through inhalation of respiratory secretions. However, many studies also provide evidence that intrauterine infection may occur, though the extent and significance of this route is controversial. Embryos treated to IETS standards appear to pose very little risk of infection. SRLV have been detected in semen suggesting a potential source of transmission. However, such transmission has not been demonstrated to date. The application of control measures based on this information allows more efficient strategies to be developed which will reduce the rate of transmission.
Gordon D Harkiss - One of the best experts on this subject based on the ideXlab platform.
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diagnostic tests for small ruminant Lentiviruses
Veterinary Microbiology, 2005Co-Authors: D De Andres, Barbara Blacklaws, E Berriatua, Sigurbjorg Torsteinsdottir, N J Watt, Dieter Klein, Gordon D HarkissAbstract:Maedi visna virus and caprine arthritis encephalitis virus are closely related retroviruses that cause chronic inflammatory disease in small ruminants. The infections are characterised by insidious onset and slow progression. Diagnosis of infection is usually by serological testing. A variety of assays are available for this purpose, though the relative sensitivity and specificity of these assays has not been compared systematically. Here we review recent developments in laboratory diagnostic methods and their use in field diagnosis. The results suggest that a combination of ELISA and PCR might afford optimal detection of SRLV infection.
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transmission of small ruminant Lentiviruses
Veterinary Microbiology, 2004Co-Authors: Barbara Blacklaws, E Berriatua, Sigurbjorg Torsteinsdottir, N J Watt, D De Andres, Dieter Klein, Gordon D HarkissAbstract:Small ruminant Lentiviruses (SRLV) are classical slow retroviruses causing chronic inflammatory disease in a variety of target organs. The routes of transmission have been investigated and a large body of evidence has accumulated over many years. The main routes are through ingestion of infected colostrum and/or milk, or through inhalation of respiratory secretions. However, many studies also provide evidence that intrauterine infection may occur, though the extent and significance of this route is controversial. Embryos treated to IETS standards appear to pose very little risk of infection. SRLV have been detected in semen suggesting a potential source of transmission. However, such transmission has not been demonstrated to date. The application of control measures based on this information allows more efficient strategies to be developed which will reduce the rate of transmission.
P Moroni - One of the best experts on this subject based on the ideXlab platform.
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genetic analysis of small ruminant Lentiviruses following lactogenic transmission
Virology, 2010Co-Authors: G Pisoni, Giuseppe Bertoni, G Manarolla, Hansrudolf Vogt, L Scaccabarozzi, Clara Locatelli, P MoroniAbstract:Lactogenic transmission plays an important role in the biology of Lentiviruses such as HIV and SIV or the small ruminant Lentiviruses (SRLV). In this work we analyzed the characteristics of viruses that goats, naturally infected with two strains of SRLV, transmitted to their kids. The spectrum of viral genotypes transmitted was broader and the efficiency of transmission greater compared to their human and simian counterparts. The newly described A10 subgroup of SRLV was more efficiently transmitted than the B1 genotype. The analysis of a particular stretch of the envelope glycoprotein encompassing a potential neutralizing epitope revealed that, as in SIV, the transmitted viruses were positively charged in this region, but, in contrast to SIV, they tended to lack a glycosylation site that might protect against antibody neutralization. We conclude that the physiology of the ruminant neonatal intestine, which permits the adsorption of infected maternal cells, shaped the evolution of these particular Lentiviruses that represent a valid model of lactogenic lentivirus transmission.
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phylogenetic analysis of the gag region encoding the matrix protein of small ruminant Lentiviruses comparative analysis and molecular epidemiological applications
Virus Research, 2006Co-Authors: G Pisoni, Giuseppe Bertoni, P J Boettcher, W Ponti, P MoroniAbstract:Little sequence information exists on the matrix-protein (MA) encoding region of small ruminant Lentiviruses (SRLV). Fifty-two novel sequences were established and permitted a first phylogenetic analysis of this region of the SRLV genome. The variability of the MA encoding region is higher compared to the gag region encoding the capsid protein and surprisingly close to that reported for the env gene. In contrast to primate Lentiviruses, the deduced amino acid sequences of the N- and C-terminal domains of MA are variable. This permitted to pinpoint a basic domain in the N-terminal domain that is conserved in all Lentiviruses and likely to play an important functional role. Additionally, a seven amino acid insertion was detected in all MVV strains, which may be used to differentiate CAEV and MVV isolates. A molecular epidemiology analysis based on these sequences indicates that the Italian lentivirus strains are closely related to each other and to the CAEV-CO strain, a prototypic strain isolated three decades ago in the US. This suggests a common origin of the SRLV circulating in the monitored flocks, possibly related to the introduction of infected goats in a negative population. Finally, this study shows that the MA region is suitable for phylogenetic studies and may be applied to monitor SRLV eradication programs.
