Expression and function of CCR5 and CXCR4 on human Langerhans cells and macrophages: Implications for HIV primary infection

Zaitseva, Marina; Blauvelt, Andrew; Lee, S; Lapham, Cheryl; Klaus-Kovtun, Vera; Mostowski, Howard; Manischewitz, Jody; Golding, Hana

doi:10.1038/nm1297-1369

Cited by 360 publications

(250 citation statements)

References 36 publications

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“…CCR5 ϩ immature DC (iDC) differentiated from CD34 ϩ HPC, or freshly isolated from the skin, have been shown to express low to undetectable membrane CXCR4 and to selectively replicate R5 viruses (8,34,35). Maturation induced by short-term culture of epidermal LC, or by adding monocyte-conditioned medium (MCM) or trimeric CD40 ligand (CD40LT) to in vitro differentiated DC, results in decreased CCR5 expression and CXCR4 up-regulation, but increased permissivity to both X4 and R5 strains (8,34). However, at variance with CD4 ϩ T lymphocytes (36) that require activation signals to complete HIV reverse transcription and support virus replication, virus production appears 10-to 100-fold lower in mDC than in iDC (34,35).…”

Section: Endritic Cells (Dc)mentioning

confidence: 99%

The Maturation of Dendritic Cells Results in Postintegration Inhibition of HIV-1 Replication

Bakri

Schiffer

Zennou

et al. 2001

The Journal of Immunology

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Maturation of dendritic cells (DC) is known to result in decreased capacity to produce HIV due to postentry block of its replicative cycle. In this study, we compared the early phases of this cycle in immature DC (iDC) and mature DC (mDC) generated from monocytes cultured with GM-CSF and IL-4, trimeric CD40 ligand (DCCD40LT), or monocyte-conditioned medium (DCMCM) being added or not from day 5. Culture day 8 cells exposed to X4 HIV-1LAI or R5 HIV-1Ba-L were analyzed by semiquantitative R-U5 PCR, which detects total HIV DNA. CXC chemokine receptor 4low (CXCR4low) CCR5+ iDC harbored similar viral DNA amounts when exposed to either strain. HIV-1LAI entered more efficiently into DCCD40LT or DCMCM with up-regulated CXCR4. CCR5low DCCD40LT still allowed entry of HIV-1Ba-L, whereas CCR5− DCMCM displayed reduced permissivity to this virus. Comparing amounts of late (long terminal repeat (LTR)-gag PCR) and total (R-U5 PCR) viral DNA products showed that HIV-1Ba-L reverse transcription was more efficient than that of HIV-1LAI, but was not affected by DC maturation. Southern blot detection of linear, circular, and integrated HIV DNA showed that maturation affected neither HIV-1 nuclear import nor integration. When assessing virus transcription by exposing iDC to pNL4-3.GFP or pNL4-3.Luc viruses pseudotyped with the G protein of vesicular stomatitis virus (VSV-G), followed by culture with or without CD40LT or MCM, GFP and luciferase activities decreased by 60–75% in mDC vs iDC. Thus, reduced HIV replication in mDC is primarily due to a postintegration block occurring mainly at the transcriptional level. We could not relate this block to altered expression and nuclear localization of NF-κB proteins and SP1 and SP3 transcription factors.

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Section: Endritic Cells (Dc)mentioning

confidence: 99%

The Maturation of Dendritic Cells Results in Postintegration Inhibition of HIV-1 Replication

Bakri

Schiffer

Zennou

et al. 2001

The Journal of Immunology

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“…Although they do not express DC-SIGN, LCs express CD4 and HIV chemokine coreceptors, and these molecules have been shown to mediate infection of LCs (11)(12)(13)(14). Immature LCs express surface CCR5, but not surface CXCR4, immediately after isolation from skin; CCR5 on LCs also mediates fusion with cells expressing the HIV envelope protein gp120 (11). Likewise, Patterson et al (15) examined human cervix and found that CCR5 mRNA expression was at least 10-fold higher than CXCR4 mRNA expression in this tissue.…”

mentioning

confidence: 99%

R5 HIV productively infects Langerhans cells, and infection levels are regulated by compoundCCR5polymorphisms

Kawamura

Gulden

Sugaya

et al. 2003

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

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177

165

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Langerhans cells (LCs) are suspected to be initial targets for HIV after sexual exposure (by becoming infected or by capturing virus). Here, productive R5 HIV infection of LC ex vivo and LC-mediated transmission of virus to CD4 ؉ T cells were both found to depend on CCR5. By contrast, infection of monocyte-derived dendritic cells and transfer of infection from monocyte-derived dendritic cells to CD4 ؉ T cells were mediated by CCR5-dependent as well as DCspecific ICAM-3-grabbing nonintegrin-dependent pathways. Furthermore, in 62 healthy individuals, R5 HIV infection levels in LCs ex vivo were associated with CCR5 genotype. Specifically, genotyping for ORF⌬32 revealed that LCs isolated from ORF⌬32͞wt individuals were significantly less susceptible to HIV when compared with LCs isolated from ORFwt͞wt individuals (P ‫؍‬ 0.016). Strikingly, further genetic analyses of the A-2459G CCR5 promoter polymorphism in ORF⌬32͞wt heterozygous individuals revealed that LCs isolated from ؊2459A͞G ϩ ORF⌬32͞wt individuals were markedly less susceptible to HIV than were LCs from ؊2459A͞A ϩ ORF⌬32͞wt individuals (P ‫؍‬ 0.012). Interestingly, these genetic susceptibility data in LCs parallel those of genetic susceptibility studies performed in cohorts of HIV-infected individuals. Thus, we suggest that CCR5-mediated infection of LCs, and not capture of virus by LCs, provides a biologic basis for understanding certain aspects of host genetic susceptibility to initial HIV infection.

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“…CD11c ϩve and CD11c Ϫve blood DCs, Langerhans cells (LCs), and in vitro-derived monocytederived DCs (MDDCs) all express CD4 and CCR5 and can be productively infected in vitro. [8][9][10][11][12] However, HIV also bound several DC populations independently of CD4. 8,13,14 The heavy glycosylation of gp120 with mannose and fucose saccharides suggested HIV bound to cells also via lectin receptors.…”

mentioning

confidence: 99%

HIV gp120 receptors on human dendritic cells

Turville

Arthos

Donald

et al. 2001

Blood

184

170

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Dendritic cells (DCs) are important targets for human immunodeficiency virus (HIV) because of their roles during transmission and also maintenance of immune competence. Furthermore, DCs are a key cell in the development of HIV vaccines. In both these settings the mechanism of binding of the HIV envelope protein gp120 to DCs is of importance. Recently a single C-type lectin receptor (CLR), DC-SIGN, has been reported to be the predominant receptor on monocyte-derived DCs (MDDCs) rather than CD4. In this study a novel biotinylated gp120 assay was used to determine whether CLR or CD4 were predominant receptors on MDDCs and ex vivo blood DCs. CLR bound more than 80% of gp120 on MDDCs, with residual binding attributable to CD4, reconfirming that CLRs were the major receptors for gp120 on MDDCs. However, in contrast to recent reports, gp120 binding to at least 3 CLRs was observed: DC-SIGN, mannose receptor, and unidentified trypsin resistant CLR(s) . IntroductionDendritic cells (DCs) play a major role in human immunodeficiency virus (HIV) pathogenesis. Peripheral or surveillance mucosal DCs are one of the first cell types infected and are distributed in the vaginal, ectocervical, and anal mucosa, 1,2 allowing contact with HIV during mucosal exposure. Thus, after vaginal inoculation with simian immunodeficiency virus in macaques, DCs are the predominant cell type infected. 3 Furthermore, the ability of DCs to cluster with and stimulate T cells may also play a key role in establishing infection. DCs from skin, mucosa, and blood of humans and macaques can participate in highly productive HIV and simian immunodeficiency virus infection in DC-T-cell cocultures and illustrates the importance of this natural DC-T-cell synergy. [4][5][6][7] Key aspects of HIV binding to DC via gp120 are ill-defined, particularly to the different types of DCs. CD11c ϩve and CD11c Ϫve blood DCs, Langerhans cells (LCs), and in vitro-derived monocytederived DCs (MDDCs) all express CD4 and CCR5 and can be productively infected in vitro. [8][9][10][11][12] However, HIV also bound several DC populations independently of CD4. 8,13,14 The heavy glycosylation of gp120 with mannose and fucose saccharides suggested HIV bound to cells also via lectin receptors. Binding of gp120 to a novel C-type lectin receptor (CLR), originally identified from a placental complementary DNA (cDNA) library 15 on the basis of HIV gp120 binding and named clone 11, on MDDCs was recently reported. 14,16 The adhesion properties of this CLR were also defined and the receptor subsequently renamed DC-SIGN (dendritic cell specific ICAM-3 grabbing nonintegrin). Although MDDCs express a diverse and abundant array of CLRs in addition to DC-SIGN, [16][17][18][19][20][21][22][23][24] and given substantial overlap in saccharide recognition by such CLRs, they may also serve as receptors for gp120 on MDDCs. The roles of CD4 and CLRs on most other in vivo DC types are unknown.This study aimed to define the contributions of CD4 and CLRs in binding gp120, to address and identify the capacity o...

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Expression and function of CCR5 and CXCR4 on human Langerhans cells and macrophages: Implications for HIV primary infection

Cited by 360 publications

References 36 publications

The Maturation of Dendritic Cells Results in Postintegration Inhibition of HIV-1 Replication

The Maturation of Dendritic Cells Results in Postintegration Inhibition of HIV-1 Replication

R5 HIV productively infects Langerhans cells, and infection levels are regulated by compoundCCR5polymorphisms

HIV gp120 receptors on human dendritic cells

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