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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The simian immunodeficiency virus (SIV) Mne envelope undergoes genetic changes that alter tropism, syncytium-inducing capacity, and antigenic properties of the emerging variant virus population during the course of an infection. Here we investigated whether the mutations in envelope of SIVMne also influence coreceptor usage. The data demonstrate that the infecting macrophage-tropic SIVMne clone as well as the envelope variants that are selected during the course of disease progression all recognize both CCR5 and Bob (GPR15) but not Bonzo (STRL33), CXCR4, or CCR3. Although it remains to be determined if there are other coreceptors specific for dualtropic or T-cell-tropic variants of SIVMne that emerge during late stages of infection, these data suggest that such SIV variants that evolve in pathogenic infections do not lose the ability to recognize CCR5 or Bob/GPR15.
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PMID:Coreceptor specificity of temporal variants of simian immunodeficiency virus Mne. 988 75

Binding of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp120 to both CD4 and one of several chemokine receptors (coreceptors) permits entry of virus into target cells. Infection of tissues may establish latent viral reservoirs as well as cause direct pathologic effects that manifest as clinical disease such as HIV-associated dementia. We sought to identify the critical coreceptors recognized by HIV-1 tissue-derived strains as well as to correlate these coreceptor preferences with site of infection and dementia diagnosis. To reconstitute coreceptor use, we cloned HIV-1 envelope V3 sequences encoding the primary determinants of coreceptor specificity from 13 brain-derived and 6 colon-derived viruses into an isogenic (NL4-3) viral background. All V3 recombinants utilized the chemokine receptor CCR5 uniformly and efficiently as a coreceptor but not CXCR4, BOB/GPR15, or Bonzo/STRL33. Other receptors such as CCR3, CCR8, and US28 were inefficiently and variably used as coreceptors by various envelopes. CCR5 without CD4 present did not allow for detectable infection by any of the tested recombinants. In contrast to the pathogenic switch in coreceptor specificity frequently observed in comparisons of blood-derived viruses early after HIV-1 seroconversion and after onset of AIDS, the characteristics of these V3 recombinants suggest that CCR5 is a primary coreceptor for brain- and colon-derived viruses regardless of tissue source or diagnosis of dementia. Therefore, tissue infection may not depend significantly on viral envelope quasispeciation to broaden coreceptor range but rather selects for CCR5 use throughout disease progression.
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PMID:V3 recombinants indicate a central role for CCR5 as a coreceptor in tissue infection by human immunodeficiency virus type 1. 997 18

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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PMID:Coreceptor usage of BOB/GPR15 and Bonzo/STRL33 by primary isolates of human immunodeficiency virus type 1. 1035 71

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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PMID:Effects of soluble CD4 on simian immunodeficiency virus infection of CD4-positive and CD4-negative cells. 1036 84

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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PMID:Simian immunodeficiency virus utilizes human and sooty mangabey but not rhesus macaque STRL33 for efficient entry. 1079 81

Primary simian immunodeficiency virus (SIV) isolated from sooty mangabey (SIVsm [n = 6]), stumptail (SIVstm [n = 1]), mandrill (SIVmnd [n = 1]), and African green (SIVagm [n = 1]) primates were examined for their ability to infect human cells and for their coreceptor requirements. All isolates infected human peripheral blood mononuclear cells (PBMCs) from a CCR5(+/+) donor, and seven of eight isolates tested also infected CCR5(-/-) PBMCs. Analysis of coreceptor utilization using GHOST and U87 cell lines revealed that all of the isolates tested used CCR5 and the orphan receptors STRL33 and GPR15. Coreceptors such as CCR2b, CCR3, CCR8, and CX3CR1 were also utilized by some primary SIV isolates. More importantly, we found that CXCR4 was used as a coreceptor by the SIVstm, the SIVagm, and four of the SIVsm isolates in GHOST and U87 cells. These data suggest that primary SIV isolates from diverse primate species can utilize CXCR4 for viral entry, similar to what has been described for human immunodeficiency viruses.
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PMID:Simian immunodeficiency viruses of diverse origin can use CXCR4 as a coreceptor for entry into human cells. 1082 78

CCR5 and CXCR4 are the major coreceptors that mediate human immunodeficiency virus 1 (HIV-1) infection, while most simian immunodeficiency virus (SIV) isolates use CCR5. A number of alternative coreceptors can also mediate infection of some virus strains in vitro, although little is known about their in vivo relevance. Therefore, we characterized the expression pattern and coreceptor activity of one of these alternative coreceptors, STRL33/Bonzo, using a newly developed monoclonal antibody. In addition to being highly expressed (approximately 1000-7000 STRL33 ABS [antibody binding sites]) on specific subsets of natural killer cells (CD3(-)/CD16(-/low)/CD56(+) and CD3(-)/CD16(low)/CD56(-)) and CD19(+) B lymphocytes (approximately 300-5000 STRL33 ABS), STRL33 was expressed at levels sufficient to support virus infection on freshly isolated, truly naive CD4(+)/CD45RA(+)/CD62L(+) cells (6000-11 000 ABS). STRL33 expression on peripheral blood mononuclear cells (PBMCs) was increased by mitogenic stimulation (OKT3/IL-2 [interleukin-2] had a greater effect than phytohemaglutinin (PHA)/IL-2), but it was dramatically decreased upon Ficoll purification. Infection of CCR5(-) human peripheral blood lymphocytes (PBLs) showed that 2 different SIV envelope (Env) proteins mediated entry into STRL33(+) cells. More importantly, the preferential infection of STRL33(+) cells in CCR5(-) PBLs by an R5/X4/STRL33 HIV-1 maternal isolate in the presence of a potent CXCR4 antagonist (AMD3100) suggests that STRL33 can be used as a coreceptor by HIV-1 on primary cells. Rhesus macaque (rh) STRL33 was used less efficiently than human STRL33 by the majority of SIV Env proteins tested despite similar levels of expression, thereby making it less likely that STRL33 is a relevant coreceptor in the rhesus macaque system. In summary, the expression pattern and coreceptor activity of STRL33 suggest its involvement in trafficking of tumor-infiltrating lymphocytes and indicate that STRL33 may be a relevant coreceptor in vivo.
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PMID:Expression and coreceptor activity of STRL33/Bonzo on primary peripheral blood lymphocytes. 1089 28

Dendritic cells (DCs) have been shown to be important in the replication of human and simian immunodeficiency viruses (HIV and SIV, respectively) in vivo and in vitro. DCs express CD4 and several chemokine receptors, such as CCR5 and CXCR4, which are important for viral entry. In vivo, DCs are abundant at body surfaces, where they might be one of the first cells that encounter naturally transmitted virus. Furthermore, DCs pulsed with HIV or SIV in vitro can efficiently transmit virus to T cells, thereby propagating vigorous viral replication. Reports have implicated Bonzo/STRL33/TYMSTR to be an additional alternative coreceptor for HIV and especially SIV infection. However, at present there are no reports regarding the expression of Bonzo/STRL33/TYMSTR by human or macaque DCs. Here we demonstrate the presence of Bonzo/STRL33/TYMSTR transcripts in rhesus macaque and human skin-derived DCs, in immature and mature blood monocyte-derived DCs, and in T cells from both skin and blood. Therefore, Bonzo/STRL33/TYMSTR is expressed in DCs and T cells that can play a role in the transmission of immunodeficiency viruses.
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PMID:The immunodeficiency virus coreceptor, Bonzo/STRL33/TYMSTR, is expressed by macaque and human skin- and blood-derived dendritic cells. 1093 20

In an attempt to generate broadly cross-reactive, neutralizing monoclonal antibodies (MAbs) to simian immunodeficiency virus (SIV), we compared two immunization protocols using different preparations of oligomeric SIV envelope (Env) glycoproteins. In the first protocol, mice were immunized with soluble gp140 (sgp140) from CP-MAC, a laboratory-adapted variant of SIVmacBK28. Hybridomas were screened by enzyme-linked immunosorbent assay, and a panel of 65 MAbs that recognized epitopes throughout the Env protein was generated. In general, these MAbs detected Env by Western blotting, were at least weakly positive in fluorescence-activated cell sorting (FACS) analysis of Env-expressing cells, and preferentially recognized monomeric Env protein. A subset of these antibodies directed toward the V1/V2 loop, the V3 loop, or nonlinear epitopes were capable of neutralizing CP-MAC, a closely related isolate (SIVmac1A11), and/or two more divergent strains (SIVsmDeltaB670 CL3 and SIVsm543-3E). In the second protocol, mice were immunized with unfixed CP-MAC-infected cells and MAbs were screened for the ability to inhibit cell-cell fusion. In contrast to MAbs generated against sgp140, the seven MAbs produced using this protocol did not react with Env by Western blotting and were strongly positive by FACS analysis, and several reacted preferentially with oligomeric Env. All seven MAbs potently neutralized SIVmac1A11, and several neutralized SIVsmDeltaB670 CL3 and/or SIVsm543-3E. MAbs that inhibited gp120 binding to CD4, CCR5, or both were identified in both groups. MAbs to the V3 loop and one MAb reactive with the V1/V2 loop interfered with CCR5 binding, indicating that these regions of Env play similar roles for SIV and human immunodeficiency virus. Remarkably, several of the MAbs generated against infected cells blocked CCR5 binding in a V3-independent manner, suggesting that they may recognize a region analogous to the conserved coreceptor binding site in gp120. Finally, all neutralizing MAbs blocked infection through the alternate coreceptor STRL33 much more efficiently than infection through CCR5, a finding that has important implications for SIV neutralization assays using CCR5-negative human T-cell lines.
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PMID:Characterization and epitope mapping of neutralizing monoclonal antibodies produced by immunization with oligomeric simian immunodeficiency virus envelope protein. 1093

Chemokines play necessary and important roles in regulating the trafficking of lymphocytes to intra- or interlymphoid tissues as well as to sites of inflammation. The complex migratory patterns of lymphoid lineage cells is governed by subset-specific expression of chemokine receptors and their access to specific ligands. Several chemokine receptors and chemokine receptor-like orphan receptors also serve, in conjunction with CD4, as coreceptors for infection by human and simian immunodeficiency viruses (HIV and SIV). Here we show that the expression pattern of Bonzo/STRL33, an orphan SIV/HIV coreceptor, is highly restricted to the memory subset of T cells and is up-regulated upon stimulation of these cells with IL-2 or IL-15. Both the pattern and the regulation of Bonzo expression closely paralleled that of CC family chemokine receptors CCR5 or CCR6 and inversely correlated with CXCR4 expression. However, in striking contrast to CCR5, Bonzo expression was not down-modulated by PMA or mitogen stimulation of T cells. Targeted replacement of the Bonzo gene with a gene encoding green fluorescent protein in mice revealed that the expression and cytokine regulation of mouse Bonzo are comparable to those of its human counterpart. The similar expression and regulation patterns of Bonzo and the HIV coreceptor CCR5 may have implications for understanding the role of HIV/SIV receptors in viral evolution and pathogenesis.
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PMID:The primate lentiviral receptor Bonzo/STRL33 is coordinately regulated with CCR5 and its expression pattern is conserved between human and mouse. 1097 45


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