Change in Coreceptor Use Correlates with Disease Progression in HIV-1–Infected Individuals

Connor, Ruth I.; Sheridan, Kristine E.; Ceradini, Daniel J.; Choe, Sunny; Landau, Nathaniel R.

doi:10.1084/jem.185.4.621

Cited by 1,261 publications

(1,030 citation statements)

References 38 publications

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“…Later in the course of HIV-1 disease, the virus frequently expands its coreceptor use to include CXC chemokine receptor (CXCR) 4, CCR3, CCR2, and other coreceptors in addition to CCR5, resulting in a selective advantage for the virus (2). The emergence of CXCR4-dependent HIV-1 (X4 HIV-1) strains precedes a more rapid decline in CD4 ϩ T cell counts and progression to AIDS, suggesting that X4 strains contribute to AIDS pathogenesis (3).…”

Section: Opposite Effects Of Il-10 On the Ability Of Dendritic Cells mentioning

confidence: 99%

Opposite Effects of IL-10 on the Ability of Dendritic Cells and Macrophages to Replicate Primary CXCR4-Dependent HIV-1 Strains

Ancuța

Bakri

Chomont

et al. 2001

The Journal of Immunology

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We investigated the effect of IL-10 on replication of primary CXCR4-dependent (X4) HIV-1 strains by monocyte-derived dendritic cells (DCs) and macrophages (MΦs). MΦs efficiently replicated CXCR4-dependent HIV-1 (X4 HIV-1) strains NDK and VN44, whereas low levels of p24 were detected in supernatants of infected DCs. IL-10 significantly increased X4 HIV-1 replication by DCs but blocked viral production by MΦs as determined by p24 levels and semiquantitative nested PCR. IL-10 up-regulated CXCR4 mRNA and protein expression on DCs and MΦs, suggesting that IL-10 enhances virus entry in DCs but blocks an entry and/or postentry step in MΦs. The effect of IL-10 on the ability of DCs and MΦs to transmit virus to autologous CD4+ T lymphocytes was investigated in coculture experiments. DCs exhibited a greater ability than did MΦs to transmit a vigorous infection to CD4+ T cells despite their very low replication capacity. IL-10 had no effect on HIV-1 replication in DC:T cell cocultures but markedly decreased viral production in MΦ:T cell cocultures. These results demonstrate that IL-10 has opposite effects on the replication of primary X4 HIV-1 strains by DCs and MΦs. IL-10 increases X4-HIV-1 replication in DCs but does not alter their capacity to transmit virus to CD4+ T lymphocytes. These findings suggest that increased levels of IL-10 observed in HIV-1-infected patients with disease progression may favor the replication of X4 HIV-1 strains in vivo.

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Section: Opposite Effects Of Il-10 On the Ability Of Dendritic Cells mentioning

confidence: 99%

Opposite Effects of IL-10 on the Ability of Dendritic Cells and Macrophages to Replicate Primary CXCR4-Dependent HIV-1 Strains

Ancuța

Bakri

Chomont

et al. 2001

The Journal of Immunology

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“…Most importantly, the chemokine receptors CCR5 and CXCR4 have been identified as the two major co-receptors for the human immunodeficiency virus type 1, HIV-1, which infects CD4 + target cells [1][2][3][4][5][6]. CCR5 is expressed on memory T lymphocytes, macrophages, and dendritic cells and is mainly associated with transmission of viruses during primary infection [2], while CXCR4 seems to be important at later stages of the disease [7,8].…”

Section: Introductionmentioning

confidence: 99%

JM4 is a four‐transmembrane protein binding to the CCR5 receptor

2005

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The CC chemokine receptor 5 (CCR5) is a major coreceptor for human immunodeficiency virus (HIV) and CCR5 mutants lacking the carboxy (C)-terminus interfere with HIV infection. Therefore, we analysed the C-terminus of CCR5 and here describe Jena-Muenchen 4 (JM4), a novel CCR5-interacting protein. JM4 is membrane-associated, co-precipitates with CCR5, and is ubiquitously expressed. It shares about 62% sequence similarity with JWA and glutamate transporter-associated protein 3-18 (GTRAP3-18), a regulator of an amino acid transporter. JWA, like JM4, is a four-transmembrane protein, which binds to the CCR5 receptor. Furthermore, JM4, JWA, and GTRAP3-18 co-localise and heterodimerise indicating a functional relationship. JM4 co-localises with calnexin in the endoplasmic reticulum and with the mannose 6-phosphate receptor in the Golgi. JM4 and GTRAP3-18 harbor a Rab-acceptor motif, indicating a function in vesicle formation at the Golgi complex. In conclusion, we describe a CCR5-interacting protein, which is suggested to function in trafficking and membrane localisation of the receptor, possibly also other receptors or amino acid transporters.

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“…Early in the course of an HIV infection, preferentially CCR5-positive cells are infected with HIV-1 (14). A small fraction of these cells, mainly CD4 ϩ T cells, macrophages, and potentially dendritic cells, become latently infected and function as an endogenous source for HIV-1 (15).…”

Section: Discussionmentioning

confidence: 99%

“…Besides its role in inflammation, CCR5 is the primary coreceptor for M-tropic HIV-1 strains that predominate early in the course of an infection (13,14). Transmission of HIV-1 depends on the presence of CCR5, as individuals with a homozygous ⌬32 deletion of the CCR5 allele are highly resistant against infection with HIV-1 (11).…”

mentioning

confidence: 99%

Depletion of CCR5-Expressing Cells with Bispecific Antibodies and Chemokine Toxins: A New Strategy in the Treatment of Chronic Inflammatory Diseases and HIV

Brühl¹,

Cihak

Stangassinger

et al. 2001

The Journal of Immunology

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The chemokine receptor CCR5 is expressed on the majority of T cells and monocytes in the inflammatory infiltrate of diseases such as rheumatoid arthritis, renal diseases, and multiple sclerosis. In contrast, little expression of CCR5 is found on peripheral blood leukocytes. A specific depletion of CCR5+ cells could therefore be a useful strategy to reduce the cellular infiltrate in chronic inflammations. Moreover, CCR5 is the major coreceptor for M-tropic HIV-1 strains. Depletion of CCR5+ leukocytes may help to eliminate cells latently infected with HIV-1. We designed two constructs that specifically destroy chemokine receptor-positive cells. The first construct, a bispecific Ab, binds simultaneously to CCR5 and CD3. Thereby it redirects CD3+ T cells against CCR5+ target cells. The Ab specifically depletes CCR5+ T cells and monocytes, but is inactive against cells that do not express CCR5. Furthermore, ex vivo the bispecific Ab eliminated >95% of CCR5+ monocytes and T cells from the synovial fluid of patients with arthritis. Also, we designed a fusion protein of the chemokine RANTES and a truncated version of Pseudomonas exotoxin A. The fusion protein binds to CCR5 and down-modulates the receptor from the cell surface. The chemokine toxin completely destroyed CCR5+ Chinese hamster ovary cells at a concentration of 10 nM, whereas no cytotoxic effect was detectable against CCR5− Chinese hamster ovary cells. Both constructs efficiently deplete CCR5-positive cells, appear as useful agents in the treatment of chronic inflammatory diseases, and may help to eradicate HIV-1 by increasing the turnover of latently infected cells.

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Change in Coreceptor Use Correlates with Disease Progression in HIV-1–Infected Individuals

Cited by 1,261 publications

References 38 publications

Opposite Effects of IL-10 on the Ability of Dendritic Cells and Macrophages to Replicate Primary CXCR4-Dependent HIV-1 Strains

Opposite Effects of IL-10 on the Ability of Dendritic Cells and Macrophages to Replicate Primary CXCR4-Dependent HIV-1 Strains

JM4 is a four‐transmembrane protein binding to the CCR5 receptor

Depletion of CCR5-Expressing Cells with Bispecific Antibodies and Chemokine Toxins: A New Strategy in the Treatment of Chronic Inflammatory Diseases and HIV

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