Expression Patterns of the HIV Type 1 Coreceptors CCR5 and CXCR4 on CD4<sup>+</sup>T Cells and Monocytes from Cord and Adult Blood

Mo, Hongmei; Monard, Simon; Pollack, Henry; Ip, James E.; Rochford, Gemma; Wu, Lijun; Hoxie, James A.; Borkowsky, William; Ho, David D.; Moore, John P.

doi:10.1089/aid.1998.14.607

Cited by 81 publications

(57 citation statements)

References 59 publications

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“…CCR5 expression on each subset was measured independently of viral infection, as CCR5 staining was strongly diminished in the presence of virus, presumably due to either virally induced downregulation or masking of the CCR5 receptor. CCR5 expression levels were highest on effector memory cells, intermediate on central memory cells, and lowest on naïve cells, consistent with previously published results (7,16,29,34). CD4 expression levels were similar between all subsets.…”

Section: Resultssupporting

confidence: 91%

“…We developed a multiparametric FACS-based assay to monitor infection of T CM , T EM , naïve, and effector T cells by virus in the presence or absence of aplaviroc. While each of these subsets expresses similar levels of CD4, their CCR5 expression profiles vary greatly, with T EM cells expressing higher levels of CCR5 than T CM cells and with naïve T cells expressing very low CCR5 levels (7,16,29,34). The viruses studied here infected T CM and T EM cells with similar efficiencies.…”

Section: Discussionmentioning

confidence: 93%

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HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 ⁺ T Cells

Pfaff

Wilen

Harrison

et al. 2010

J Virol

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We previously reported on a panel of HIV-1 clade B envelope (Env) proteins isolated from a patient treated with the CCR5 antagonist aplaviroc (APL) that were drug resistant. These Envs used the APL-bound conformation of CCR5, were cross resistant to other small-molecule CCR5 antagonists, and were isolated from the patient's pretreatment viral quasispecies as well as after therapy. We analyzed viral and host determinants of resistance and their effects on viral tropism on primary CD4 ؉ T cells. The V3 loop contained residues essential for viral resistance to APL, while additional mutations in gp120 and gp41 modulated the magnitude of drug resistance. However, these mutations were context dependent, being unable to confer resistance when introduced into a heterologous virus. The resistant virus displayed altered binding between gp120 and CCR5 such that the virus became critically dependent on the N terminus of CCR5 in the presence of APL. In addition, the drug-resistant Envs studied here utilized CCR5 very efficiently: robust virus infection occurred even when very low levels of CCR5 were expressed. However, recognition of drug-bound CCR5 was less efficient, resulting in a Entry of human immunodeficiency virus (HIV) into target cells is a complex, multistep process that is initiated by interactions between the viral envelope (Env) protein gp120 and the host cell receptor CD4, which trigger conformational changes in gp120 that form and orient the coreceptor binding site (9,24). Upon binding to coreceptor, which is either CCR5 or CXCR4 for primary HIV isolates, Env undergoes further conformational changes resulting in insertion of the gp41 fusion peptide into the host cell membrane and gp41-mediated membrane fusion (8,15,26). Targeting stages of the HIV entry process with antiretroviral drugs is a productive method of inhibiting HIV replication, as demonstrated by the potent antiviral effects of small-molecule CCR5 antagonists and fusion inhibitors (23,35,49). As with other antiretroviral drugs, HIV can develop resistance to entry inhibitors, and a detailed understanding of viral and host determinants of resistance will be critical to the optimal clinical use of these agents.The coreceptor binding site that is induced by CD4 engagement consists of noncontiguous regions in the bridging sheet and V3 loop of gp120 (4,18,42,43,50). Interactions between gp120 and CCR5 occur in at least two distinct areas: (i) the bridging sheet and the stem of the V3 loop interact with sul-

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 93%

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 ⁺ T Cells

Pfaff

Wilen

Harrison

et al. 2010

J Virol

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show abstract

“…3) demonstrates that there was no significant difference in CD4, CXCR4, and CCR5 expression in these cell types. Similar results on CD4, CXCR4, and CCR5 expression on cord and adult lymphocytes and M͞M have been reported before (14). These data suggest that differential HIV-1 replication in cord vs. adult mononuclear cells does not depend on the cell surface expression of CD4 and CXCR4 and CCR5.…”

Section: Discussionsupporting

confidence: 89%

“…These data suggest that differential HIV-1 replication in cord vs. adult mononuclear cells does not depend on the cell surface expression of CD4 and CXCR4 and CCR5. The differential HIV-1 replication in these cell types also is not due to differences in cellular phenotypes (naïve-CD45RA high and memory-CD45RA low ) and cell activation, because T cell activation markers' (CD25 and HLA-DR) expression are not significantly different between cord and PBMCs (14).…”

Section: Discussionmentioning

confidence: 94%

“…Therefore, we sought to compare HIV-1 replication kinetics between neonatal and adult blood mononuclear cells (PBMCs) and determine the mechanisms of HIV-1 replication in these cell types. We have used cord blood in place of neonatal blood because, like neonatal blood, it has more CD45RA ϩ T cells and less CD45RO ϩ T cells, is immature compared with adult blood (14), and is available in a larger volume than neonatal blood.…”

mentioning

confidence: 99%

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Differential HIV-1 replication in neonatal and adult blood mononuclear cells is influenced at the level of HIV-1 gene expression

Sundaravaradan

Saxena

Ramakrishnan

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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The majority of HIV-1-infected neonates and infants have a higher level of viremia and develop AIDS more rapidly than infected adults, including differences seen in clinical manifestations. To determine the mechanisms of HIV-1 infection in neonates vs. adults, we compared the replication kinetics of HIV-1 in neonatal (cord) and adult blood T lymphocytes and monocyte-derived macrophages (MDM) from seven different donors. We found that HIV-1 replicated 3-fold better in cord blood T lymphocytes compared with adult blood T lymphocytes and 9-fold better in cord MDM than adult MDM. We also show that this differential HIV-1 replication did not depend on differences in cell proliferative capabilities, cell surface expression of CD4, CXCR4, and CCR5, or in the amount of PCR products of reverse transcription, DNA synthesis, and translocation of preintegration complex into the nucleus in cord and adult T lymphocytes and MDM. Furthermore, using a single-cycle replication competent HIV-1-NL4 -3-Env ؊ luciferase amphotropic virus, which measures HIV-1 transcriptional activity independent of receptor and coreceptor expression, we found there was a 3-fold increase of HIV-1 LTR-driven luciferase expression in cord T lymphocytes compared with adult T lymphocytes and 10-fold in cord MDM than in adult MDM. The HIV-1 LTR-driven luciferase expression correlated with HIV-1 LTR transcription, as measured by ribonuclease protection assay. These data suggest that the increased replication of HIV-1 in cord blood compared with adult blood mononuclear cells is regulated at the level of HIV-1 gene expression, resulting in a higher level of viremia and faster disease progression in neonates than adults.

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Activation of blood T lymphocytes down-regulates CXCR4 expression and interferes with propagation of X4 HIV strains

et al. 1998

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The chemokine receptor CXCR4 serves as a coreceptor for HIV-1 entry into CD4+ cells, in particular for strains emerging late in the infection. Cell surface expression of CXCR4 has, therefore, important implications for HIV-1 pathogenesis. Using blood lymphocytes cultured under various conditions, we studied the expression and regulation of CXCR4. Flow cytometry showed that only about 20% of freshly isolated lymphocytes expressed CXCR4 on the cell surface whereas in 80% of resting blood lymphocytes CXCR4 was located intracellularly. Within a few hours in culture, the intracellular CXCR4 was translocated to the surface and was expressed in the large majority of both naive and memory lymphocytes. A decrease in surface expression of CXCR4 was found when lymphocytes cultured overnight for maximal receptor expression were stimulated with phytohemagglutinin, anti-CD3 antibodies, phorbol 12-myristate 13-acetate and stromal cell-derived factor-1. The superantigen staphylococcal enterotoxin A, a more selective stimulus, induced a marked decrease in CXCR4 expression preferentially in cells positive for the CD25 activation marker. Confocal laser scanning microscopy demonstrated the presence of CXCR4 in the cytosol and on the surface of resting lymphocytes and also showed CXCR4 redistribution after activation. The number of cells infected by the X4 HIV strain NL4.3 paralleled the expression of CXCR4 in CD4+ T lymphocytes. Sustained reduction of CXCR4 cell surface expression upon activation with phytohemagglutinin correlated with a low number of CD4+ T lymphocytes expressing HIV p24 gag antigen. Our results indicate that activation of CD4+ T lymphocytes reduces surface expression of CXCR4 in part by receptor internalization and that cell activation-dependent CXCR4 down-regulation limits spread of infection by X4 viruses.

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Expression Patterns of the HIV Type 1 Coreceptors CCR5 and CXCR4 on CD4⁺T Cells and Monocytes from Cord and Adult Blood

Cited by 81 publications

References 59 publications

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 ⁺ T Cells

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 ⁺ T Cells

Differential HIV-1 replication in neonatal and adult blood mononuclear cells is influenced at the level of HIV-1 gene expression

Activation of blood T lymphocytes down-regulates CXCR4 expression and interferes with propagation of X4 HIV strains

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Expression Patterns of the HIV Type 1 Coreceptors CCR5 and CXCR4 on CD4+T Cells and Monocytes from Cord and Adult Blood

Cited by 81 publications

References 59 publications

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 + T Cells

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 + T Cells

Differential HIV-1 replication in neonatal and adult blood mononuclear cells is influenced at the level of HIV-1 gene expression

Activation of blood T lymphocytes down-regulates CXCR4 expression and interferes with propagation of X4 HIV strains

Contact Info

Product

Resources

About

Expression Patterns of the HIV Type 1 Coreceptors CCR5 and CXCR4 on CD4⁺T Cells and Monocytes from Cord and Adult Blood

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 ⁺ T Cells

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 ⁺ T Cells