scholarly journals CXCR-4 Is Expressed by Primary Macrophages and Supports CCR5-Independent Infection by Dual-Tropic but Not T-Tropic Isolates of Human Immunodeficiency Virus Type 1

1998 ◽  
Vol 72 (1) ◽  
pp. 772-777 ◽  
Author(s):  
Yanjie Yi ◽  
Shalini Rana ◽  
Julie D. Turner ◽  
Nathan Gaddis ◽  
Ronald G. Collman
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Chemokine Receptors ◽  
Surface Expression ◽  
Reverse Transcription Pcr ◽  
Immunodeficiency Virus ◽  
Inactivating Mutation ◽  
Hiv 1

ABSTRACT Primary macrophages are infected by macrophage (M)-tropic but not T-cell line (T)-tropic human immunodeficiency virus type 1 (HIV-1) strains, and CCR5 and CXCR-4 are the principal cofactors utilized for CD4-mediated entry by M-tropic and T-tropic isolates, respectively. Macrophages from individuals homozygous for an inactivating mutation of CCR5 are resistant to prototype M-tropic strains that depend on CCR5 but are permissive for a dual-tropic isolate, 89.6, that can use both CCR5 and CXCR-4, as well as CCR2b, CCR3, and CCR8. Here we show that 89.6 entry into CCR5-deficient macrophages is blocked by an anti-CXCR-4 antibody and by the CXCR-4-specific chemokine SDF but not by the ligands to CCR2b or CCR3. Reverse transcription-PCR demonstrated expression of CXCR-4 but not CCR3 or CCR8 in macrophages, while CCR2b was variable. Macrophage surface expression of CXCR-4 was confirmed by immunofluorescence staining and flow cytometry. Thus, CXCR-4 is expressed by primary macrophages and functions as a cofactor for entry by dual-tropic but not T-tropic HIV-1 isolates, and macrophage resistance to T-tropic strains does not result from a lack of the T-tropic entry cofactor CXCR-4. Since CXCR-4 on macrophages can be used by some but not other isolates, these results indicate that HIV-1 strains differ in how they utilize chemokine receptors as cofactors for entry and that the ability of a chemokine receptor to mediate HIV-1 entry differs, depending on the cell type in which it is expressed.

scholarly journals A Strongly Transdominant Mutation in the Human Immunodeficiency Virus Type 1 gag Gene Defines an Achilles Heel in the Virus Life Cycle

2009 ◽  
Vol 83 (17) ◽  
pp. 8536-8543 ◽  
Author(s):  
Sook-Kyung Lee ◽  
Janera Harris ◽  
Ronald Swanstrom
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Wild Type ◽  
Immunodeficiency Virus ◽  
Processing Site ◽  
Phenotypic Mixing ◽  
Inactivating Mutation ◽  
Hiv 1

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) protease (PR) makes five obligatory cleavages in the viral Gag polyprotein precursor. The cleavage events release the virion structural proteins from the precursor and allow the virion to undergo maturation to become infectious. The protease cleavage between the matrix protein (MA) domain and the adjacent capsid protein (CA) domain releases CA from the membrane-anchored MA and allows the N terminus of CA to refold into a structure that facilitates the formation of hexamer arrays that represent the structural unit of the capsid shell. In this study, we analyzed the extent to which each of the HIV-1 Gag processing sites must be cleaved by substituting the P1-position amino acid at each processing site with Ile. A mutation that blocks cleavage at the MA/CA processing site (Y132I) displayed a strong transdominant effect when tested in a phenotypic mixing strategy, inhibiting virion infectivity with a 50% inhibitory concentration of only 4% of the mutant relative to the wild type. This mutation is 10- to 20-fold more potent in phenotypic mixing than an inactivating mutation in the viral protease, the target of many successful inhibitors, and more potent than an inactivating mutation at any of the other Gag cleavage sites. The transdominant effect is manifested as the assembly of an aberrant virion core. Virus containing 20% of the Y132I mutant and 80% of the wild type (to assess the transdominant effect on infectivity) was blocked either before reverse transcription (RT) or at an early RT step. The ability of a small amount of the MA/CA fusion protein to poison the oligomeric assembly of infectious virus identifies an essential step in the complex process of virion formation and maturation. The effect of a small-molecule inhibitor that is able to block MA/CA cleavage even partially would be amplified by this transdominant negative effect on the highly orchestrated process of virion assembly.

scholarly journals CCR5 Expression Correlates with Susceptibility of Maturing Monocytes to Human Immunodeficiency Virus Type 1 Infection

1998 ◽  
Vol 72 (1) ◽  
pp. 830-836 ◽  
Author(s):  
Hassan M. Naif ◽  
Shan Li ◽  
Mohammed Alali ◽  
Andrew Sloane ◽  
Lijun Wu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Chemokine Receptors ◽  
Ccr5 Expression ◽  
Hiv Dna ◽  
Immunodeficiency Virus ◽  
P24 Antigen ◽  
Hiv 1

ABSTRACT The chemokine receptor CCR5 and to a lesser extent CCR3 and CCR2b have been shown to serve as coreceptors for human immunodeficiency virus type 1 (HIV-1) entry into blood- or tissue-derived macrophages. Therefore, we examined the expression of the chemokine receptors CCR1, CCR2b, CCR3, CCR5, and CXCR4 as RNAs or as membrane-expressed antigens in monocytes maturing into macrophages and correlated these results with the susceptibility of macrophages to HIV-1 infection, as measured by their concentrations of extracellular p24 antigen and levels of intracellular HIV DNA by quantitative PCR. There was little change in levels of CCR1, CCR2b, and CCR5 RNAs. CCR3 RNA and surface antigen were undetectable throughout maturation of adherent monocytes over 10 days. CXCR4 RNA and membrane antigen were strongly expressed in newly adherent monocytes, but their levels declined at day 7. The amounts of CCR5 RNA remained stable, but the amounts of CCR5 antigen increased from undetectable to peak levels at day 7 and then declined slightly at day 10. Levels of susceptibility to laboratory (HIV-1BaL) and clinical strains of HIV-1 showed parallel kinetics, peaking at day 7 and then decreasing at days 10 to 14. The concordance of levels of HIV DNA and p24 antigen suggested that the changes in susceptibility with monocyte maturation were at or immediately after entry and correlated well with CCR5 expression and inversely with CXCR4 expression.

scholarly journals Costimulation of Naive CD8+ Lymphocytes Induces CD4 Expression and Allows Human Immunodeficiency Virus Type 1 Infection

1998 ◽  
Vol 72 (11) ◽  
pp. 9054-9060 ◽  
Author(s):  
Scott G. Kitchen ◽  
Yael D. Korin ◽  
Michael D. Roth ◽  
Alan Landay ◽  
Jerome A. Zack
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Rapid Disease Progression ◽  
Cd8 Cells ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) infection requires cell surface expression of CD4. Costimulation of CD8+/CD4− T lymphocytes by anti-CD3 and anti-CD28 antibodies or by allogeneic dendritic cells induced expression of CD4 and rendered these CD8 cells susceptible to HIV-1 infection. Naive CD45RA+ cells responded with greater expression of CD4 than did CD45RO+ cells. CD8+lymphocytes derived from fetal or newborn sources exhibited a greater tendency to express CD4, consistent with their naive states. This mechanism of infection suggests HIV-induced perturbation of the CD8 arm of the immune response and could explain the generally rapid disease progression seen in HIV-infected children.

scholarly journals The N-Terminal V3 Loop Glycan Modulates the Interaction of Clade A and B Human Immunodeficiency Virus Type 1 Envelopes with CD4 and Chemokine Receptors

2000 ◽  
Vol 74 (23) ◽  
pp. 11008-11016 ◽  
Author(s):  
Susan E. Malenbaum ◽  
David Yang ◽  
Lisa Cavacini ◽  
Marshall Posner ◽  
James Robinson ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Binding Site ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Chemokine Receptors ◽  
V3 Loop ◽  
Clade B ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT We investigated the underlying mechanism by which the highly conserved N-terminal V3 loop glycan of gp120 conferred resistance to neutralization of human immunodeficiency virus type 1 (HIV-1). We find that the presence or absence of this V3 glycan on clade A and B viruses accorded various degrees of susceptibility to neutralization by antibodies to the CD4 binding site, CD4-induced epitopes, and chemokine receptors. Our data suggest that this carbohydrate moiety on gp120 blocks access to the binding site for CD4 and modulates the chemokine receptor binding site of phenotypically diverse clade A and clade B isolates. Its presence also contributes to the masking of CD4-induced epitopes on clade B envelopes. These findings reveal a common mechanism by which diverse HIV-1 isolates escape immune recognition. Furthermore, the observation that conserved functional epitopes of HIV-1 are more exposed on V3 glycan-deficient envelope glycoproteins provides a basis for exploring the use of these envelopes as vaccine components.

scholarly journals Effect of Calcium-Modulating Cyclophilin Ligand on Human Immunodeficiency Virus Type 1 Particle Release and Cell Surface Expression of Tetherin

2009 ◽  
Vol 83 (24) ◽  
pp. 13032-13036 ◽  
Author(s):  
Mariana G. Bego ◽  
Mathieu Dubé ◽  
Johanne Mercier ◽  
Éric A. Cohen
Keyword(s):  
Human Immunodeficiency Virus ◽  
Cell Surface ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Particle Release ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) accessory protein Vpu enhances virus particle release by counteracting a host factor that retains virions at the surfaces of infected cells. It was recently demonstrated that cellular protein BST-2/CD317/Tetherin restricts HIV-1 release in a Vpu-dependent manner. Calcium-modulating cyclophilin ligand (CAML) was also proposed to be involved in this process. We investigated whether CAML is involved in cell surface expression of Tetherin. Here, we show that CAML overexpression in permissive Cos-7 cells or CAML depletion in restrictive HeLa cells has no effect on HIV-1 release or on Tetherin surface expression, indicating that CAML is not required for Tetherin-mediated restriction of HIV-1 release.

scholarly journals Influence of the CCR2-V64I Polymorphism on Human Immunodeficiency Virus Type 1 Coreceptor Activity and on Chemokine Receptor Function of CCR2b, CCR3, CCR5, and CXCR4

1998 ◽  
Vol 72 (9) ◽  
pp. 7450-7458 ◽  
Author(s):  
Benhur Lee ◽  
Benjamin J. Doranz ◽  
Shalini Rana ◽  
Yanji Yi ◽  
Mario Mellado ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Chemokine Receptors ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Immunodeficiency Virus ◽  
Heterologous Desensitization ◽  
Hiv 1

ABSTRACT The chemokine receptors CCR5 and CXCR4 are used by human immunodeficiency virus type 1 (HIV-1) in conjunction with CD4 to infect cells. In addition, some virus strains can use alternative chemokine receptors, including CCR2b and CCR3, for infection. A polymorphism inCCR2 (CCR2-V64I) is associated with a 2- to 4-year delay in the progression to AIDS. To investigate the mechanism of this protective effect, we studied the expression of CCR2b and CCR2b-V64I, their chemokine and HIV-1 coreceptor activities, and their effects on the expression and receptor activities of the major HIV-1 coreceptors. CCR2b and CCR2b-V64I were expressed at similar levels, and neither molecule affected the expression or coreceptor activity of CCR3, CCR5, or CXCR4 in cotransfected cell lines. Peripheral blood mononuclear cells (PBMCs) from CCR2-V64I heterozygotes had normal levels of CCR2b and CCR5 but slightly reduced levels of CXCR4. CCR2b and CCR2b-V64I functioned equally well as HIV-1 coreceptors, and CCR2-V64I PBMCs were permissive for HIV-1 infection regardless of viral tropism. The MCP-1-induced calcium mobilization mediated by CCR2b signaling was unaffected by the polymorphism, but MCP-1 signaling mediated by either CCR2b- or CCR2-V64I-encoded receptors resulted in heterologous desensitization (i.e., limiting the signal response of other receptors) of both CCR5 and CXCR4. The heterologous desensitization of CCR5 and CXCR4 signaling by bothCCR2 allele receptor types provides a mechanistic link that might help explain the in vivo effects of CCR2 gene variants on progression to AIDS as well as the reported antiviral activity of natural CCR2 ligands.

scholarly journals Expression and Function of Chemokine Receptors on Human Thymocytes: Implications for Infection by Human Immunodeficiency Virus Type 1

2001 ◽  
Vol 75 (18) ◽  
pp. 8752-8760 ◽  
Author(s):  
James R. Taylor ◽  
Katherine C. Kimbrell ◽  
Robert Scoggins ◽  
Marie Delaney ◽  
Lijun Wu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Chemokine Receptors ◽  
Cross Reactivity ◽  
Immunodeficiency Virus ◽  
Chemokine Ligands ◽  
And Function ◽  
Hiv 1

ABSTRACT The presence or absence of the receptor CD4 and the coreceptors CCR5 and CXCR4 restrict the cell tropism of human immunodeficiency virus type 1 (HIV-1). Despite the importance of thymic infection by HIV-1, conflicting reports regarding the expression of HIV-1 coreceptors on human thymocytes have not been resolved. We assayed the expression and function of the major HIV-1 coreceptors, CCR5 and CXCR4, as well as CCR4 and CCR7 as controls, on human thymocytes. We detected CCR5 on 2.5% of thymocytes, CXCR4 on 53% of the cells, and CCR4 on 16% and CCR7 on 11% of human thymocytes. Moreover, infection by R5 HIV-1 did not significantly induce expression of CCR5. We found that two widely used anti-CCR5 monoclonal antibodies cross-reacted with CCR8, which may account for discrepancies among published reports of CCR5 expression on primary cells. This cross-reactivity could be eliminated by deletion of amino acids 2 through 4 of CCR8. Chemotaxis assays showed that SDF-1, which binds CXCR4; MDC, which binds CCR4; and ELC, which binds CCR7, mediated significant chemotaxis of thymocytes. In contrast, MIP-1β, whose receptor is CCR5, did not induce significant chemotaxis. Our results indicate that CXCR4, CCR4, CCR7, and their chemokine ligands may be involved in thymocyte migration during development in the thymus. CCR5 and its ligands, however, are likely not involved in these processes. Furthermore, the pattern of CCR5 and CXCR4 expression that we found may explain the greater susceptibility of human thymocytes to infection by HIV-1 isolates capable of using CXCR4 in cell entry compared to those that use only CCR5.

scholarly journals V3 Recombinants Indicate a Central Role for CCR5 as a Coreceptor in Tissue Infection by Human Immunodeficiency Virus Type 1

1999 ◽  
Vol 73 (3) ◽  
pp. 2350-2358 ◽  
Author(s):  
Stephen Y. Chan ◽  
Roberto F. Speck ◽  
Christopher Power ◽  
Sarah L. Gaffen ◽  
Bruce Chesebro ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Chemokine Receptors ◽  
Viral Envelope ◽  
Tissue Infection ◽  
Target Cells ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT 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.

scholarly journals Identification of Determinants on a Dualtropic Human Immunodeficiency Virus Type 1 Envelope Glycoprotein That Confer Usage of CXCR4

1998 ◽  
Vol 72 (3) ◽  
pp. 2509-2515 ◽  
Author(s):  
Michael W. Cho ◽  
Myung K. Lee ◽  
Michelle C. Carney ◽  
Joanne F. Berson ◽  
Robert W. Doms ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Cell Fusion ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Chemokine Receptors ◽  
Mononuclear Cells ◽  
Virus Infectivity ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The chemokine receptors CCR5 and CXCR4, in combination with CD4, mediate cellular entry of macrophage-tropic (M-tropic) and T-cell-tropic strains of human immunodeficiency virus type 1 (HIV-1), respectively, while dualtropic viruses can use either receptor. We have constructed a panel of chimeric viruses and envelope glycoproteins in which various domains of the dualtropic HIV-1DH12 gp160 were introduced into the genetic background of an M-tropic HIV-1 isolate, HIV-1AD8. These constructs were employed in cell fusion and virus infectivity assays using peripheral blood mononuclear cells, MT4 T cells, primary monocyte-derived macrophages, or HOS-CD4 cell lines, expressing various chemokine receptors, to assess the contributions of different gp120 subdomains in coreceptor usage and cellular tropism. As expected, the dualtropic HIV-1DH12gp120 utilized either CCR3, CCR5, or CXCR4, whereas HIV-1AD8 gp120 was able to use only CCR3 or CCR5. We found that either the V1/V2 or the V3 region of HIV-1DH12 gp120 individually conferred on HIV-1AD8 the ability to use CXCR4, while the combination of both the V1/V2 and V3 regions increased the efficiency of CXCR4 use. In addition, while the V4 or the V5 region of HIV-1DH12 gp120 failed to confer the capacity to utilize CXCR4 on HIV-1AD8, these regions were required in conjunction with regions V1 to V3 of HIV-1DH12 gp120 for efficient utilization of CXCR4. Comparison of virus infectivity analyses with various cell types and cell fusion assays revealed assay-dependent discrepancies and indicated that events occurring at the cell surface during infection are complex and cannot always be predicted by any one assay.

Sign in / Sign up

Export Citation Format

Share Document