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

CD4 is the primary cellular receptor for human immunodeficiency virus type 1 (HIV-1), but is not sufficient for entry of HIV-1 into cells. After a decade-long search, the cellular coreceptors that HIV-1 requires in conjunction with CD4 have been identified as members of the chemokine receptor family of seven-transmembrane G-protein coupled receptors. The discovery of distinct chemokine receptors that support entry of T-cell tropic (CXCR-4) and macrophage tropic HIV-1 strains (CCR-5) explains the differences in cell tropism between viral strains, the inability of HIV-1 to infect most nonprimate cells, and the resistance of a small percentage of the population to HIV-1 infection. Further understanding of the role of chemokine receptors in viral entry may also help explain the evolution of more pathogenic forms of the virus, viral transmission, and HIV-induced pathogenesis. These recent discoveries will aid the development of strategies for combating HIV-1 transmission and spread, the understanding of HIV-1 fusion mechanisms, and the possible development of small animal models for HIV-1 drug and vaccine testing.
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PMID:Chemokine receptors as fusion cofactors for human immunodeficiency virus type 1 (HIV-1). 904 6

Human herpesvirus-8 (HHV-8) has been detected in Kaposi's sarcoma (KS) lesions of all types (AIDS-related, classical and endemic), in body-cavity-based B-cell lymphomas (BCBLs) and in lesions of multicentric Castleman's disease (MCD). We have identified a major gamma-herpesvirus-divergent locus (DL-B) in HHV-8 DNA encoding several HHV-8 unique open reading frames (ORFs), including a homologue of interleukin-6 (IL-6) and two homologues of macrophage inflammatory protein MIP-1. We show that the HHV-8-encoded IL-6 homologue (vIL-6) shares functional properties with endogenous IL-6 proteins and that both vIL-6 and vMIP-1 transcripts are present at high levels following butyrate induction of an HHV-8' BCBL cell line. Low amounts of constitutive vIL-6, but not vMIP-1, mRNA were also detected. The presence of a functional IL-6 homologue encoded by HHV-8 may provide a mechanistic model for the hypothesized role of HHV-8 in KS, MCD and BCBL that involves the mitogenic effects of vIL-6 on surrounding cells. MIP-1 proteins may enhance these effects through the chemotactic recruitment of endogenous cytokine-producing cells into affected tissues and could potentially influence HIV disease progression in coinfected individuals through interactions with the HIV co-receptor CCR-5.
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PMID:Kaposi's sarcoma-associated human herpesvirus-8 encodes homologues of macrophage inflammatory protein-1 and interleukin-6. 905 55

Cellular entry of human immunodeficiency virus type 1 (HIV-1) requires binding to both CD4 (ref, 1, 2) and to one of the chemokine receptors recently discovered to act as coreceptors. Viruses that infect T-cell lines to form syncytia (syncytium-inducing, SI) are frequently found in late-stage HIV disease and utilize the chemokine receptor CXCR-4; macrophage-tropic viruses are non-syncytium-inducing (NSI), found throughout disease and utilize CCR-5 (ref. 3-11). We postulated that CCR-5 gene defects might reduce infection risk in seronegative subjects and prolong AIDS-free survival in seropositive subjects with NSI but not SI virus. Homozygous (delta ccr5/delta ccr5) and heterozygous (CCR5/delta ccr5) CCR-5 deletions (delta ccr5) were found in 7 (2.7%) and 51 (19.5%), respectively, of 261 seronegative subjects from the San Francisco Men's Health Study. CCR-5/delta ccr5 genotype was identified in 33 of 172 (19.2%) nonprogressors and 25 of 234 (10.7%) progressors from the seropositive arm of this cohort. The delta ccr5 allele conferred a significant protective effect against HIV-1 infection (P = 0.001) and a survival advantage against disease progression (P = 0.02). Although both progressing and nonprogressing CCR5/delta ccr5 subjects were identified, a distinct survival advantage was shown for those with NSI virus (P < 0.0001). Thus, the protective effect of delta ccr5 against disease progression is lost when the infecting virus uses CXCR-4 as a coreceptor.
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PMID:The role of viral phenotype and CCR-5 gene defects in HIV-1 transmission and disease progression. 1050 92

Primate lentiviruses use chemokine coreceptors in addition to the CD4 receptor to initiate virus infection. Simian immunodeficiency virus (SIV) productively infects human cells expressing CD4 and the human allele of the chemokine coreceptor CCR-5 as efficiently as it infects macaque cells expressing human CD4, suggesting that SIV can function with either a simian or a human coreceptor in conjunction with human CD4. In the same macaque cells expressing human CD4, the replication of human immunodeficiency virus type 1 (HIV-1) is blocked at several stages of infection; some isolates are restricted prior to reverse transcription, while others, including some macrophage-tropic and primary isolates, are restricted at a step after reverse transcription but prior to migration of the preintegration complex to the nucleus. Both blocks in HIV-1 replication can be relieved by either expression of the appropriate human coreceptor (CCR-5 or CXCR-4) or expression of SIV gene products in cis with the HIV-1 envelope as a chimera between SIV and HIV-1 (SHIV). Thus, a virus with a SIV core and HIV-1 envelope can efficiently infect macaque cells expressing human CD4, presumably by interacting with the simian coreceptor, whereas a virus with an HIV-1 core and an HIV-1 envelope requires expression of the human allele of the coreceptor for productive infection of these cells. These studies suggest that there are interactions among the coreceptor, the viral envelope, and another viral gene product that govern postentry steps of virus replication. These data are consistent with the hypothesis that such interactions may be required for translocation of the virus core to the nucleus. Moreover, the differential abilities of SIV and HIV-1 to function in these processes with heterologous primate coreceptors may have implications for cross-species transmission.
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PMID:Human immunodeficiency virus type 1 coreceptors participate in postentry stages in the virus replication cycle and function in simian immunodeficiency virus infection. 909 70

We have assayed a variety of 7tm chemokine receptors (CCR-2b, CCR-3, CCR-4, CCR-5, CXCR-1, CXCR-4) and two orphan 7tm receptors (V28 and EBI.1) for their ability to allow infection of CD4-negative feline kidney CCC cells by the HIV-2 strains ROD/A and ROD/B. We found that ROD/B was able to use CXCR-4 transiently expressed in CCC cells, and infection by ROD/A was enhanced 15-fold in the presence of sCD4. Feline CCC cells also became permissive to ROD/B and ROD/A entry when transiently transfected with the chemokine receptor CCR-3 or the orphan 7tm receptor V2B, when cultured in the presence of sCD4. Entry of ROD/A into CCC cells expressing CCR-3 could be blocked by 800 ng/ml eotaxin, the natural ligand for CCR-3.
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PMID:CD4-independent infection by HIV-2 (ROD/B): use of the 7-transmembrane receptors CXCR-4, CCR-3, and V28 for entry. 914 11

The CXCR-4 chemokine receptor and CD4 behave as coreceptors for cell line-adapted human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) and for dual-tropic HIV strains, which also use the CCR-5 coreceptor. The cell line-adapted HIV-1 strains LAI and NDK and the dual-tropic HIV-2 strain ROD were able to infect CD4+ cells expressing human CXCR-4, while only LAI was able to infect cells expressing the rat homolog of CXCR-4. This strain selectivity was addressed by using human-rat CXCR-4 chimeras. All chimeras tested mediated LAI infection, but only those containing the third extracellular domain (e3) of human CXCR-4 mediated NDK and ROD infection. The e3 domain might be required for the functional interaction of NDK and ROD, but not LAI, with CXCR-4. Alternatively, LAI might also interact with e3 but in a different way. Monoclonal antibody 12G5, raised against human CXCR-4, did not stain cells expressing rat CXCR-4. Chimeric human-rat CXCR-4 allowed us to map the 12G5 epitope in the e3 domain. The ability of 12G5 to neutralize infection by certain HIV-1 and HIV-2 strains is also consistent with the role of e3 in the coreceptor activity of CXCR-4. The deletion of most of the amino-terminal extracellular domain (e1) abolished the coreceptor activity of human CXCR-4 for ROD and NDK but not for LAI. These results indicate that HIV strains have different requirements for their interaction with CXCR-4. They also suggest differences in the interaction of dual-tropic HIV with CCR-5 and CXCR-4.
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PMID:Role of the first and third extracellular domains of CXCR-4 in human immunodeficiency virus coreceptor activity. 915 68

CD34+ hematopoietic progenitor cells were assessed for mRNA expression of the human immunodeficiency virus type-1 (HIV-1) coreceptors CXCR-4, also termed fusin or LESTR, and CKR-5, also called CC-CKR-5 or CCR-5. The CD34+ cells were obtained from leukapheresis products of 17 patients after granulocyte colony-stimulating factor-supported cytotoxic chemotherapy. Using a two-step enrichment procedure including immunomagnetic bead separation and fluorescence-activated cell sorting, the CD34+ cells had a median purity of 99.8%. Assessing 9 CD34+ cell samples by polymerase chain reaction after reverse transcription (RT-PCR), CXCR-4 mRNA was found in all samples, whereas CKR-5 mRNA was only present in 3 samples, even though a nested PCR was used. Eight additional CD34+ cell samples were sorted according to CD4 expression. Based on a three-color immunofluorescence analysis, the mean relative fluorescence intensity of HLA-DR was smaller on CD34+/CD4+ cells in comparison with CD34+/ CD4- cells. CXCR-4 mRNA was found in 5 of 8 CD34+/CD4+ samples and in 7 of 8 CD34+/CD4- samples, whereas CKR-5 mRNA was detected in 2 CD34+/CD4+ samples and in 1 CD34+/CD4- cell sample. Looking at the total number of CD34+ cell samples examined, the proportion of specimens containing CXCR-4 mRNA was 84% in comparison with 24% of specimens positive for CKR-5 mRNA. These data suggest that CD34+/CD4+ hematopoietic progenitor cells, including true stem cell candidates, could be susceptible to HIV-1 infection. Considering the relatively low incidence of CD34+ cell samples containing CKR-5 mRNA, CD34+/CD4+ cells appear to be particularly prone for HIV-1 infection via the CXCR-4 coreceptor. Because this chemokine receptor allows T-cell-tropic HIV-1 strains to infect cells, CD34+ cells expressing CD4 and CXCR-4 might be infected by HIV-1 during later stages of the disease, following a viral phenotype switch from macrophage- to T-cell-tropic HIV-1 strains.
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PMID:Expression of the human immunodeficiency virus type-1 coreceptors CXCR-4 (fusin, LESTR) and CKR-5 in CD34+ hematopoietic progenitor cells. 916 Jun 56

The emergence of T cell-tropic, syncytium-inducing (T-tropic/SI) HIV-1 variants from the background of macrophage-tropic, non-syncytium-inducing (M-tropic/NSI) strains is associated with disease progression in infected individuals. HIV89.6 is a primary isolate with a transitional phenotype: like M-tropic strains it replicates in primary macrophages and lymphocytes but not in most transformed cells, yet it is also syncytium inducing. We have shown that HIV89.6 can utilize both the M-tropic and T-tropic cofactors CCR-5 and CXCR-4, respectively, in conjunction with CD4 for fusion and entry into otherwise nonpermissive nonhuman cells. To better understand the nature of restricted HIV89.6 infection of transformed cells, we analyzed its interaction with CD4-expressing transformed human HeLaCD4-LTR/beta-Gal cells, which contain the beta-galactosidase gene linked to the HIV-1 LTR. Here we show that HIV89.6 enters these cells and undergoes reverse transcription and integration. Furthermore, HIV89.6 induces LTR-driven beta-galactosidase expression, indicating Tat-dependent trans-activation, in a similar number of cells as the permissive T-tropic/SI isolate HIV(HXB). Acute infection with HIV89.6, however, produces markedly lower levels of p24 antigen and infectious virus per trans-activation-positive cell than HIV(HXB). In contrast, transfection results in high levels of expression for both viruses but HIV89.6 still fails to establish spreading infection. HIV89.6 is also blocked after entry in two other nonpermissive cell lines, SUP-T1 and U937. HIV89.6 arrest in HeLaCD4-LTR/beta-Gal cells at a stage subsequent to entry, reverse transcription, integration, and Tat expression is a novel level at which HIV-1 strain- and cell-specific restrictions define host cell tropism. These studies emphasize that complex patterns of tropism are determined by the interplay of permissive or restricted virus-cell interactions at multiple steps in the replication cycle.
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PMID:Abortive infection in HeLaCD4 cells by a primary HIV type 1 isolate: implications for differential host cell tropism. 917 Dec 20

Although the human hCCR-5 chemokine receptor can serve as a co-receptor for both M-tropic (ADA and BaL) and dual-tropic (89.6) strains of human immunodeficiency virus type 1 (HIV-1), the closely related mouse mCCR-5 homolog is inactive. We used chimeric hCCR-5-mCCR-5 receptor molecules to examine the functional importance of the three extracellular domains of hCCR-5 that differ in sequence from their mCCR-5 equivalents. While this analysis revealed that all three of these extracellular domains could participate in the functional interaction with HIV-1 envelope, clear differences were observed when different HIV-1 strains were analyzed. Thus, while the ADA HIV-1 isolate could effectively utilize chimeric human-mouse CCR-5 chimeras containing any single human extracellular domain, the BaL isolate required any two human extracellular sequences while the 89.6 isolate would only interact effectively with chimeras containing all three human extracellular sequences. Further analysis using hybrid HIV-1 envelope proteins showed that the difference in co-receptor specificity displayed by the ADA and BaL isolates was due partly to a single amino acid change in the V3 loop, although this interaction was clearly also modulated by other envelope domains. Overall, these data indicate that the interaction between HIV-1 envelope and CCR-5 is not only complex but also subject to marked, HIV-1 isolate-dependent variation.
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PMID:HIV-1-induced cell fusion is mediated by multiple regions within both the viral envelope and the CCR-5 co-receptor. 918 7

Human immunodeficiency virus type 1 (HIV-1) entry is governed by the interaction of the viral envelope glycoprotein (Env) with its receptor. The HIV-1 receptor is composed of two molecules, the CD4 binding receptor and a coreceptor. The seven-membrane-spanning chemokine receptor CCR-5 is one of the coreceptors used by primary isolates of HIV-1. We demonstrate that the mouse homolog of CCR-5 (mCCR-5) does not function as an HIV-1 coreceptor. A set of chimeras of human CCR-5 and mCCR-5 was studied for Env-induced cell fusion and HIV-1 infection. Using the HIV-1ADA envelope glycoprotein in a syncytium formation assay, we show that replacement of any fragment containing extracellular domains of mCCR-5 by its human counterparts is sufficient to allow Env-induced fusion. Conversely, replacement of any fragment containing human extracellular domains by its murine counterpart did not lead to coreceptor function loss. These results show that several domains of CCR-5 participate in coreceptor function. In addition, using a panel of primary nonsyncytium-inducing and syncytium-inducing isolates that use CCR-5 or both CXCR-4 and CCR-5 as coreceptors, we show that the latter dual-tropic isolates are less tolerant to changes in CCR-5 than strains with a more restricted coreceptor use. Thus, different strains are likely to have different ways of interacting with the CCR-5 coreceptor.
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PMID:Multiple extracellular domains of CCR-5 contribute to human immunodeficiency virus type 1 entry and fusion. 918 65


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