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Frank Kirchhoff - One of the best experts on this subject based on the ideXlab platform.
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Simian Immunodeficiency Virus Utilizes Human and Sooty Mangabey but Not Rhesus Macaque STRL33 for Efficient Entry
Journal of Virology, 2000Co-Authors: Stefan Pöhlmann, Robert W Doms, Mandy Krumbiegel, Silke Meister, George J. Leslie, Frank KirchhoffAbstract:It has been established that many simian immunodeficiency virus (SIV) isolates utilize the orphan receptors GPR15 and STRL33 about as efficiently as the chemokine receptor CCR5 for entry into target cells. Most studies were performed, however, with coreceptors of human origin. We found that SIV from captive rhesus macaques (SIVmac) can utilize both human and simian CCR5 and GPR15 with comparable efficiencies. Strikingly, however, only human STRL33 (huSTRL33), not rhesus macaque STRL33 (rhSTRL33), functioned efficiently as an entry cofactor for a variety of isolates of SIVmac and SIV from sooty mangabeys. A single amino acid substitution of S30R in huSTRL33 impaired coreceptor activity, and the reverse change in rhSTRL33 greatly increased coreceptor activity. In comparison, species-specific sequence variations in N-terminal tyrosines in STRL33 had only moderate effects on SIV entry. These results show that a serine residue located just outside of the cellular membrane in the N terminus of STRL33 is critical for SIV coreceptor function. Interestingly, STRL33 derived from sooty mangabeys, a natural host of SIV, also contained a serine at the corresponding position and was used efficiently as an entry cofactor. These results suggest that STRL33 is not a relevant coreceptor in the SIV/macaque model but may play a role in SIV replication and transmission in naturally infected sooty mangabeys.
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co receptor usage of bob GPR15 in addition to ccr5 has no significant effect on replication of simian immunodeficiency virus in vivo
The Journal of Infectious Diseases, 1999Co-Authors: Stefan Pöhlmann, Nicole Stolte, Jan Munch, Peter Ten Haaft, Jonathan L Heeney, Christiane Stahlhennig, Frank KirchhoffAbstract:: Human immunodeficiency virus type 2 (HIV-2) and the closely related simian immunodeficiency viruses (SIVs) frequently use the orphan receptor BOB/GPR15 in addition to the chemokine receptor CCR5 for efficient entry and replication. However, the role of BOB/GPR15 in replication and pathogenesis of HIV-2 and SIV in vivo is unclear. This study shows that a single amino acid substitution in the V3 loop of the pathogenic SIVmac239 clone, 321P-->S, impaired the ability to use BOB/GPR15 for entry and replication but had little effect on the ability to use CCR5. This envelope variant replicated with an efficiency comparable with the parental SIVmac239 isolate in rhesus macaques. Furthermore, the mutant genotype and phenotype remained stable even after the onset of immunodeficiency. These results suggest that this cofactor plays only a minor role for the pathogenicity of the HIV-2/SIVmac/SIVsm group of primate lentiviruses.
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Co-receptor Usage of BOB/GPR15 in Addition to CCR5 Has No Significant Effect on Replication of Simian Immunodeficiency Virus In Vivo
The Journal of Infectious Diseases, 1999Co-Authors: Stefan Pöhlmann, Nicole Stolte, Jan Munch, Peter Ten Haaft, Jonathan L Heeney, Christiane Stahl-hennig, Frank KirchhoffAbstract:: Human immunodeficiency virus type 2 (HIV-2) and the closely related simian immunodeficiency viruses (SIVs) frequently use the orphan receptor BOB/GPR15 in addition to the chemokine receptor CCR5 for efficient entry and replication. However, the role of BOB/GPR15 in replication and pathogenesis of HIV-2 and SIV in vivo is unclear. This study shows that a single amino acid substitution in the V3 loop of the pathogenic SIVmac239 clone, 321P-->S, impaired the ability to use BOB/GPR15 for entry and replication but had little effect on the ability to use CCR5. This envelope variant replicated with an efficiency comparable with the parental SIVmac239 isolate in rhesus macaques. Furthermore, the mutant genotype and phenotype remained stable even after the onset of immunodeficiency. These results suggest that this cofactor plays only a minor role for the pathogenicity of the HIV-2/SIVmac/SIVsm group of primate lentiviruses.
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coreceptor usage of bob GPR15 and bonzo strl33 by primary isolates of human immunodeficiency virus type 1
Journal of General Virology, 1999Co-Authors: Stefan Pöhlmann, Mandy Krumbiegel, Frank KirchhoffAbstract:Primary isolates of human and simian immunodeficiency viruses (HIV and SIV) use the chemokine receptor CCR5, in association with CD4, as coreceptor. During AIDS progression, HIV-1 and HIV-2 often adapt to use additional cofactors, particularly CXCR4. In contrast, SIV isolates do not use CXCR4, but other coreceptors such as BOB/GPR15 and Bonzo/STRL33. Only limited information is currently available on usage of BOB/GPR15 and Bonzo/STRL33 by HIV-1. Therefore, we investigated a panel of gp160 clones from 15 primary isolates, representing 5 different subtypes, for utilization of these cofactors. The majority of HIV-1 envelopes mediated entry into BOB/GPR15-expressing cells, albeit often with low efficiency. Usage of Bonzo/STRL33 was less common and usually inefficient. To investigate if HIV-1 entry via these orphan receptors is sufficient to allow virus replication, 15 uncloned primary HIV-1 isolates and 7 molecular clones were used to infect target cells expressing CD4 and Bonzo/STRL33 or BOB/GPR15. Three primary isolates and two molecular clones replicated efficiently in cells expressing BOB/GPR15. Two of these isolates were X4-tropic, two were R5X4-tropic and one was R5-tropic. In contrast, none of the HIV-1 variants showed significant levels of replication in Bonzo/STRL33-expressing cells. Our data show that some HIV-1 isolates of different genetic subtype and of different biological phenotype use BOB/GPR15 for productive infection and suggest that this cofactor may play a role in HIV-1 pathogenesis and transmission.
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Coreceptor usage of BOB/GPR15 and Bonzo/STRL33 by primary isolates of human immunodeficiency virus type 1.
Journal of General Virology, 1999Co-Authors: Stefan Pöhlmann, Mandy Krumbiegel, Frank KirchhoffAbstract:Primary isolates of human and simian immunodeficiency viruses (HIV and SIV) use the chemokine receptor CCR5, in association with CD4, as coreceptor. During AIDS progression, HIV-1 and HIV-2 often adapt to use additional cofactors, particularly CXCR4. In contrast, SIV isolates do not use CXCR4, but other coreceptors such as BOB/GPR15 and Bonzo/STRL33. Only limited information is currently available on usage of BOB/GPR15 and Bonzo/STRL33 by HIV-1. Therefore, we investigated a panel of gp160 clones from 15 primary isolates, representing 5 different subtypes, for utilization of these cofactors. The majority of HIV-1 envelopes mediated entry into BOB/GPR15-expressing cells, albeit often with low efficiency. Usage of Bonzo/STRL33 was less common and usually inefficient. To investigate if HIV-1 entry via these orphan receptors is sufficient to allow virus replication, 15 uncloned primary HIV-1 isolates and 7 molecular clones were used to infect target cells expressing CD4 and Bonzo/STRL33 or BOB/GPR15. Three primary isolates and two molecular clones replicated efficiently in cells expressing BOB/GPR15. Two of these isolates were X4-tropic, two were R5X4-tropic and one was R5-tropic. In contrast, none of the HIV-1 variants showed significant levels of replication in Bonzo/STRL33-expressing cells. Our data show that some HIV-1 isolates of different genetic subtype and of different biological phenotype use BOB/GPR15 for productive infection and suggest that this cofactor may play a role in HIV-1 pathogenesis and transmission.
Stefan Pöhlmann - One of the best experts on this subject based on the ideXlab platform.
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Toll-like receptor 3 signalling up-regulates expression of the HIV co-receptor G-protein coupled receptor 15 on human CD4+ T cells.
PLOS ONE, 2014Co-Authors: Miriam Kiene, Bence Rethi, Marianne Jansson, Stephanie M. Dillon, Rebecka Lantto, Cara C. Wilson, Stefan Pöhlmann, Francesca ChiodiAbstract:Many HIV-2 and SIV isolates, as well as some HIV-1 strains, can use the orphan 7-transmembrane receptor GPR15 as co-receptor for efficient entry into host cells. GPR15 is expressed on central memory and effector memory CD4(+) T cells in healthy individuals and a subset of these cells is susceptible to HIV-1 and SIV infection. However, it has not been determined whether GPR15 expression is altered in the context of HIV-1 infection.
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Amino acid 324 in the simian immunodeficiency virus SIVmac V3 loop can confer CD4 independence and modulate the interaction with CCR5 and alternative coreceptors.
Journal of Virology, 2004Co-Authors: Stefan Pöhlmann, Jacqueline D. Reeves, Mandy Krumbiegel, Carl W. Davis, Silke Meister, George J. Leslie, Claas Otto, Bridget A. Puffer, Armin Papkalla, Andrea MarziAbstract:The V3 loop of the simian immunodeficiency virus (SIV) envelope protein (Env) largely determines interactions with viral coreceptors. To define amino acids in V3 that are critical for coreceptor engagement, we functionally characterized Env variants with amino acid substitutions at position 324 in V3, which has previously been shown to impact SIV cell tropism. These changes modulated CCR5 engagement and, in some cases, allowed the efficient usage of CCR5 in the absence of CD4. The tested amino acid substitutions had highly differential effects on viral infectivity. Eleven of sixteen substitutions disrupted entry via CCR5 or the alternative coreceptor GPR15. Nevertheless, most of these variants replicated in the macaque T-cell line 221-89 and some also replicated in rhesus macaque peripheral blood monocytes, suggesting that efficient usage of CCR5 and GPR15 on cell lines is not a prerequisite for SIV replication in primary cells. Four variants showed enhanced entry into the macaque sMagi reporter cell line. However, sMagi cells did not express appreciable amounts of CCR5 and GPR15 mRNA, and entry into these cells was not efficiently blocked by a small-molecule CCR5 antagonist, suggesting that sMagi cells express as-yet-unidentified entry cofactors. In summary, we found that a single amino acid at position 324 in the SIV Env V3 loop can modulate both the efficiency and the types of coreceptors engaged by Env and allow for CD4-independent fusion in some cases.
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Simian Immunodeficiency Virus Utilizes Human and Sooty Mangabey but Not Rhesus Macaque STRL33 for Efficient Entry
Journal of Virology, 2000Co-Authors: Stefan Pöhlmann, Robert W Doms, Mandy Krumbiegel, Silke Meister, George J. Leslie, Frank KirchhoffAbstract:It has been established that many simian immunodeficiency virus (SIV) isolates utilize the orphan receptors GPR15 and STRL33 about as efficiently as the chemokine receptor CCR5 for entry into target cells. Most studies were performed, however, with coreceptors of human origin. We found that SIV from captive rhesus macaques (SIVmac) can utilize both human and simian CCR5 and GPR15 with comparable efficiencies. Strikingly, however, only human STRL33 (huSTRL33), not rhesus macaque STRL33 (rhSTRL33), functioned efficiently as an entry cofactor for a variety of isolates of SIVmac and SIV from sooty mangabeys. A single amino acid substitution of S30R in huSTRL33 impaired coreceptor activity, and the reverse change in rhSTRL33 greatly increased coreceptor activity. In comparison, species-specific sequence variations in N-terminal tyrosines in STRL33 had only moderate effects on SIV entry. These results show that a serine residue located just outside of the cellular membrane in the N terminus of STRL33 is critical for SIV coreceptor function. Interestingly, STRL33 derived from sooty mangabeys, a natural host of SIV, also contained a serine at the corresponding position and was used efficiently as an entry cofactor. These results suggest that STRL33 is not a relevant coreceptor in the SIV/macaque model but may play a role in SIV replication and transmission in naturally infected sooty mangabeys.
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co receptor usage of bob GPR15 in addition to ccr5 has no significant effect on replication of simian immunodeficiency virus in vivo
The Journal of Infectious Diseases, 1999Co-Authors: Stefan Pöhlmann, Nicole Stolte, Jan Munch, Peter Ten Haaft, Jonathan L Heeney, Christiane Stahlhennig, Frank KirchhoffAbstract:: Human immunodeficiency virus type 2 (HIV-2) and the closely related simian immunodeficiency viruses (SIVs) frequently use the orphan receptor BOB/GPR15 in addition to the chemokine receptor CCR5 for efficient entry and replication. However, the role of BOB/GPR15 in replication and pathogenesis of HIV-2 and SIV in vivo is unclear. This study shows that a single amino acid substitution in the V3 loop of the pathogenic SIVmac239 clone, 321P-->S, impaired the ability to use BOB/GPR15 for entry and replication but had little effect on the ability to use CCR5. This envelope variant replicated with an efficiency comparable with the parental SIVmac239 isolate in rhesus macaques. Furthermore, the mutant genotype and phenotype remained stable even after the onset of immunodeficiency. These results suggest that this cofactor plays only a minor role for the pathogenicity of the HIV-2/SIVmac/SIVsm group of primate lentiviruses.
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Co-receptor Usage of BOB/GPR15 in Addition to CCR5 Has No Significant Effect on Replication of Simian Immunodeficiency Virus In Vivo
The Journal of Infectious Diseases, 1999Co-Authors: Stefan Pöhlmann, Nicole Stolte, Jan Munch, Peter Ten Haaft, Jonathan L Heeney, Christiane Stahl-hennig, Frank KirchhoffAbstract:: Human immunodeficiency virus type 2 (HIV-2) and the closely related simian immunodeficiency viruses (SIVs) frequently use the orphan receptor BOB/GPR15 in addition to the chemokine receptor CCR5 for efficient entry and replication. However, the role of BOB/GPR15 in replication and pathogenesis of HIV-2 and SIV in vivo is unclear. This study shows that a single amino acid substitution in the V3 loop of the pathogenic SIVmac239 clone, 321P-->S, impaired the ability to use BOB/GPR15 for entry and replication but had little effect on the ability to use CCR5. This envelope variant replicated with an efficiency comparable with the parental SIVmac239 isolate in rhesus macaques. Furthermore, the mutant genotype and phenotype remained stable even after the onset of immunodeficiency. These results suggest that this cofactor plays only a minor role for the pathogenicity of the HIV-2/SIVmac/SIVsm group of primate lentiviruses.
Eugene C Butcher - One of the best experts on this subject based on the ideXlab platform.
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a mucosal and cutaneous chemokine ligand for the lymphocyte chemoattractant receptor GPR15
Frontiers in Immunology, 2017Co-Authors: Borja Ocon, Theresa T Dinh, Wei Chen, Romain Ballet, Michael Bscheider, Aida Habtezion, Hua Tu, Brian A Zabel, Eugene C ButcherAbstract:Chemoattractants control lymphocyte recruitment from the blood, contributing to the systemic organization of the immune system. The G protein-linked receptor GPR15 mediates lymphocyte homing to the large intestines and skin. Here we show that the 9 kDa CC-motif containing cationic polypeptide AP57/colon-derived SUSD2 binding factor (CSBF), encoded by C10orf99 in the human and 2610528A11Rik in the mouse, functions as a chemokine ligand for GPR15 (GPR15L). GPR15L binds GPR15 and attracts GPR15-expressing T cells including lymphocytes in colon draining lymph nodes and Vγ3+ thymic precursors of dermal epithelial T cells. Patterns of GPR15L expression by epithelial cells in adult mice and humans suggest a homeostatic role for the chemokine in lymphocyte localization to the large intestines, as well as a role in homing to the epidermis during wound healing or inflammation. GPR15L is also significantly expressed in squamous mucosa of the oral cavity and esophagus with still poorly defined regulation. Identification of the chemotactic activity of GPR15 adds to its reported anti-bacterial and tumor cell growth regulatory functions, and suggests the potential of targeting GPR15L-GPR15 interactions for modulation of mucosal and cutaneous inflammation.
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Role and species-specific expression of colon T cell homing receptor GPR15 in colitis
Nature Immunology, 2015Co-Authors: Linh P Nguyen, Thanh Theresa Dinh, Husein Hadeiba, Edward O'hara, Ahmad Ebtikar, Arnulf Hertweck, M Refik Gökmen, Graham M Lord, Richard G Jenner, Eugene C ButcherAbstract:Lymphocyte recruitment maintains intestinal immune homeostasis but also contributes to inflammation. The orphan chemoattractant receptor GPR15 mediates regulatory T cell homing and immunosuppression in the mouse colon. We show that GPR15 is also expressed by mouse T_H17 and T_H1 effector cells and is required for colitis in a model that depends on the trafficking of these cells to the colon. In humans GPR15 is expressed by effector cells, including pathogenic T_H2 cells in ulcerative colitis, but is expressed poorly or not at all by colon regulatory T (T_reg) cells. The T_H2 transcriptional activator GATA-3 and the T_reg-associated transcriptional repressor FOXP3 robustly bind human, but not mouse, GPR15 enhancer sequences, correlating with receptor expression. Our results highlight species differences in GPR15 regulation and suggest it as a potential therapeutic target for colitis. The chemoattractant receptor GPR15 can direct CD4^+ T cells to the colon. Habtezion and colleagues show that GATA-3 and Foxp3 exhibit species-specific differences in promoting GPR15 expression and thereby influences homing of CD4^+ effector and regulatory T cells.
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role and species specific expression of colon t cell homing receptor GPR15 in colitis
Nature Immunology, 2015Co-Authors: Linh P Nguyen, Thanh Theresa Dinh, Husein Hadeiba, Ahmad Ebtikar, Arnulf Hertweck, Graham M Lord, Richard G Jenner, Edward Ohara, Refik M Gokmen, Eugene C ButcherAbstract:The chemoattractant receptor GPR15 can direct CD4+ T cells to the colon. Habtezion and colleagues show that GATA-3 and Foxp3 exhibit species-specific differences in promoting GPR15 expression and thereby influences homing of CD4+ effector and regulatory T cells.
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orphan chemoattractant receptor GPR15 mediates dendritic epidermal t cell recruitment to the skin
European Journal of Immunology, 2014Co-Authors: Katharina Lahl, Johanna M Sweere, Eugene C ButcherAbstract:Homing of murine dendritic epidermal T cells (DETCs) from the thymus to the skin is regulated by specific trafficking receptors during late embryogenesis. Once in the epidermis, Vγ3δ1 TCR DETCs are maintained through self-renewal and participate in wound healing. GPR15 is an orphan G protein-linked chemoattractant receptor involved in the recruitment of regulatory T cells to the colon. Here we show that GPR15 is highly expressed on fetal thymic DETC precursors and on recently recruited DETCs, and mediates the earliest seeding of the epidermis, which occurs at the time of establishment of skin barrier function. DETCs in GPR15−/− mice remain low at birth, but later participation of CCR10 and CCR4 in DETC homing allows DETCs to reach near normal levels in adult skin. Our findings establish a role for GPR15 in skin lymphocyte homing and suggest that it may contribute to lymphocyte subset targeting to diverse epithelial sites.
Norma P Gerard - One of the best experts on this subject based on the ideXlab platform.
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Effects of Soluble CD4 on Simian Immunodeficiency Virus Infection of CD4-Positive and CD4-Negative Cells
Journal of Virology, 1999Co-Authors: Dominik Schenten, Luisa Marcon, Gunilla B Karlsson, Norma P Gerard, Cristina Parolin, Toshiaki Kodama, Joseph SodroskiAbstract:A soluble form of the CD4 receptor (sCD4) can either enhance or inhibit the infection of cells by simian immunodeficiency virus (SIV) and human immunodeficiency virus. We investigated the basis for these varying effects by studying the entry of three SIV isolates into CD4-positive and CD4-negative cells expressing different chemokine receptors. Infection of CD4-negative cells depended upon the viral envelope glycoproteins and upon the chemokine receptor, with CCR5 and GPR15 being more efficient than STRL33. Likewise, enhancement of infection by sCD4 was observed when CCR5- and GPR15-expressing target cells were used but not when those expressing STRL33 were used. The sCD4-mediated enhancement of virus infection of CD4-negative, CCR5-positive cells was related to the sCD4-induced increase in binding of the viral gp120 envelope glycoprotein to CCR5. Inhibitory effects of sCD4 could largely be explained by competition for virus attachment to cellular CD4 rather than other detrimental effects on virus infectivity (e.g., disruption of the envelope glycoprotein spike). Consistent with this, the sCD4-activated SIV envelope glycoprotein intermediate on the virus was long-lived. Thus, the net effect of sCD4 on SIV infectivity appears to depend upon the degree of enhancement of chemokine receptor binding and upon the efficiency of competition for cellular CD4.
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two orphan seven transmembrane segment receptors which are expressed in cd4 positive cells support simian immunodeficiency virus infection
Journal of Experimental Medicine, 1997Co-Authors: Michael Farzan, Hyeryun Choe, Kathleen A Martin, Luisa Marcon, Wolfgang Hofmann, Gunilla B Karlsson, Peter L Barrett, Nathalie Marchand, Nancy Sullivan, Norma P GerardAbstract:Clinical isolates of primate immunodeficiency viruses, including human immunodeficiency virus type 1 (HIV-1), enter target cells by sequential binding to CD4 and the chemokine receptor CCR5, a member of the seven-transmembrane receptor family. HIV-1 variants which use additional chemokine receptors are present in the central nervous system or emerge during the course of infection. Simian immunodeficiency viruses (SIV) have been shown to use CCR5 as a coreceptor, but no other receptors for these viruses have been identified. Here we show that two orphan seven-transmembrane segment receptors, gpr1 and GPR15, serve as coreceptors for SIV, and are expressed in human alveolar macrophages. The more efficient of these, GPR15, is also expressed in human CD4+ T lymphocytes and activated rhesus macaque peripheral blood mononuclear cells. The GPR15 and gpr1 proteins lack several hallmarks of chemokine receptors, but share with CCR5 an amino-terminal motif rich in tyrosine residues. These results underscore the potential diversity of seven-transmembrane segment receptors used as entry cofactors by primate immunodeficiency viruses, and may contribute to an understanding of viral variation and pathogenesis.
Robert W Doms - One of the best experts on this subject based on the ideXlab platform.
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Evolution of coreceptor use and CD4-independence in envelope clones derived from SIVsm-infected macaques.
Virology, 2003Co-Authors: Dalma Vödrös, Robert W Doms, Rigmor Thorstensson, Eva Maria Fenyö, Jacqueline D. ReevesAbstract: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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Simian Immunodeficiency Virus Utilizes Human and Sooty Mangabey but Not Rhesus Macaque STRL33 for Efficient Entry
Journal of Virology, 2000Co-Authors: Stefan Pöhlmann, Robert W Doms, Mandy Krumbiegel, Silke Meister, George J. Leslie, Frank KirchhoffAbstract:It has been established that many simian immunodeficiency virus (SIV) isolates utilize the orphan receptors GPR15 and STRL33 about as efficiently as the chemokine receptor CCR5 for entry into target cells. Most studies were performed, however, with coreceptors of human origin. We found that SIV from captive rhesus macaques (SIVmac) can utilize both human and simian CCR5 and GPR15 with comparable efficiencies. Strikingly, however, only human STRL33 (huSTRL33), not rhesus macaque STRL33 (rhSTRL33), functioned efficiently as an entry cofactor for a variety of isolates of SIVmac and SIV from sooty mangabeys. A single amino acid substitution of S30R in huSTRL33 impaired coreceptor activity, and the reverse change in rhSTRL33 greatly increased coreceptor activity. In comparison, species-specific sequence variations in N-terminal tyrosines in STRL33 had only moderate effects on SIV entry. These results show that a serine residue located just outside of the cellular membrane in the N terminus of STRL33 is critical for SIV coreceptor function. Interestingly, STRL33 derived from sooty mangabeys, a natural host of SIV, also contained a serine at the corresponding position and was used efficiently as an entry cofactor. These results suggest that STRL33 is not a relevant coreceptor in the SIV/macaque model but may play a role in SIV replication and transmission in naturally infected sooty mangabeys.
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Microglia Express CCR5, CXCR4, and CCR3, but of These, CCR5 Is the Principal Coreceptor for Human Immunodeficiency Virus Type 1 Dementia Isolates
Journal of Virology, 1999Co-Authors: Andrew V. Albright, Robert W Doms, Joseph T.c. Shieh, Takayuki Itoh, David E Pleasure, Michael J. O'connor, Francisco Gonzalez-scaranoAbstract:Human immunodeficiency virus (HIV) dementia (HIVD) is a central nervous system (CNS) complication that affects 20 to 30% of individuals infected with HIV and is a defining condition for AIDS (24). The underlying cause of HIVD is unknown, but since productive HIV infection in the CNS occurs mostly in microglia, or brain macrophages, it is generally thought that these cells play a key role in the development of neurological abnormalities. HIVD might then be caused by neuronal damage or dysfunction resulting from the release of putative neurotoxic products by infected microglia or, alternatively, by neuronal interaction with viral proteins released or expressed by the infected cells. The propensity for certain viral isolates to infect the CNS and mediate neuronal damage is one of the major unanswered questions of HIVD. A proportion of HIV isolates replicate in cultured microglia (44), resulting in prominent syncytial formation, which is an important signature of HIV replication in the CNS (39). This cytopathology is presumably the result of membrane fusion between microglia mediated by HIVD envelope proteins. Cellular entry by HIV is now known to require at least two cell membrane proteins, CD4, and one of several seven-transmembrane domain G-protein-coupled receptors (GPCRs), principally CXCR4, an α-chemokine receptor, and CCR5, whose natural ligands are β-chemokines (7). CXCR4 mediates infection of T-tropic HIV strains, i.e., those, that replicate in T-cell lines, whereas CCR5 is the most important coreceptor for M-tropic strains, which replicate both in monocyte-derived macrophages (MDM) and in microglia. Studies with cultured fetal and adult microglia have shown that CCR5 is sufficient for HIV entry (19, 43). The role of CCR3, another β-chemokine receptor, is more controversial. Several HIVD isolates isolated from the CNS can use CCR3 to enter cells dually transfected with CCR3 and CD4 and to enter fetal microglia, which express CCR3 on their cell surface. However, studies that examined the inhibition of microglial infection by anti-CCR3 antibodies or the CCR3 ligand eotaxin have yielded conflicting results (16, 19). Microglia also express CXCR4 in vivo and in vitro (27), but in general T-tropic strains do not replicate very well in microglia or MDM (42, 48). Whether microglial GPCRs can respond to their natural chemokine ligands, and what role signal transduction may play in HIV infection of microglia or CNS pathogenesis, is thus far unknown. Recent studies have demonstrated that HIV and simian immunodeficiency virus (SIV) envelopes can also use other GPCRs, besides CCR5, CCR3, and CXCR4, for viral entry and fusion. Among these are CCR8 (21, 40), the receptor for I309, and the orphan receptors GPR1 (8, 12), GPR15 (6, 8, 12), STRL33 (6, 8, 29), and APJ (3, 10). The mRNAs for GPR1 (31) and APJ (3, 32, 36) are expressed in the brain, but their cellular localization is unknown. Choe and colleagues have recently demonstrated that APJ is not utilized by the HIVD isolates JrFL and YU-2 (3), although JrFL has been reported to use STRL33 (29) and YU-2 utilizes GPR15 (6, 12). Little else is known regarding the ability of HIVD envelopes to use CCR8 or orphan receptors as HIV coreceptors. However, it is quite conceivable that preferential replication in the brain is a consequence of the utilization of one or more of these alternate coreceptors by HIV isolates. To begin to develop a more detailed understanding of the role of each of the established coreceptors (CCR5, CCR3, and CXCR4) in HIV entry into adult microglia, we have assayed their surface expression by flow cytometry. We have also addressed the functionality of these GPCRs by determining the microglial response to α- and β-chemokines. To determine whether viruses obtained from the brain can use CCR5, CCR3, or CXCR4 as a coreceptor, we have looked at infection with pseudotyped viruses expressing the luciferase reporter gene, as well as with wild-type viruses.
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use of gpr1 GPR15 and strl33 as coreceptors by diverse human immunodeficiency virus type 1 and simian immunodeficiency virus envelope proteins
Virology, 1998Co-Authors: Aimee L Edinger, Brian F Odowd, Trevor L Hoffman, Matthew Sharron, Robert W DomsAbstract:Abstract Human and simian immunodeficiency viruses (HIV and SIV, respectively) use chemokine receptors as coreceptors along with CD4 to mediate viral entry. Several orphan receptors, including GPR1, GPR15, and STRL33, can also serve as coreceptors for a more limited number of HIV and SIV isolates. We investigated whether these orphan receptors could function as efficient coreceptors for a diverse group of HIV and SIV envelopes (Envs) in comparison with the principal coreceptors CCR5 and CXCR4. We found that a limited number of HIV-1 isolates could mediate inefficient cell–cell fusion with the orphan receptors relative to CCR5 and CXCR4; however, none of the orphan receptors tested could support pseudotype virus infection despite robust infection via CCR5 or CXCR4. All except one of the SIV Envs tested mediated some degree of cell–cell fusion and pseudotype infection, with target cells expressing at least one of these orphan receptors, although CCR5 proved to be the most efficient coreceptor for infection. Only one SIV Env protein, BK28, could mediate infection using GPR1 as a coreceptor, albeit much less efficiently than with CCR5. In addition, use of these coreceptors did not correlate with the published tropism of the SIV clones and was strictly CD4 dependent for both SIV and HIV. We also examined the expression of these molecules in cell lines and primary cells widely used for virus propagation and as targets for infection. All cells examined expressed STRL33, a more limited number expressed GPR15, and GPR1 was much more restricted in its expression pattern. Taken together, our results indicate that GPR15 and STRL33 are rarely used by HIV-1 but are more frequently used by SIV strains, although not in a manner that correlates with SIV tropism.
