CXCR4 as a Functional Coreceptor for Human Immunodeficiency Virus Type 1 Infection of Primary Macrophages

Simmons, Graham; Reeves, Jacqueline D.; McKnight, Áine; Dejucq, Nathalie; Hibbitts, Samantha Jayne; Power, Christine; Aarons, Emma; Schols, Dominique; Clercq, Erik De; Proudfoot, Amanda E. I.; Clapham, Paul R.

doi:10.1128/jvi.72.10.8453-8457.1998

Cited by 139 publications

(49 citation statements)

References 52 publications

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“…The HIV strains inhibited included those using both CCR5 and CXCR4 coreceptors (2028), those using CXCR4 alone (2044 and IIIB) or those using CCR5 alone (SF162 and BaL). With the exception of IIIB, all can infect both macrophages as well as CD4 + T cells [43]. These data support a target upstream of viral fusion events (or upstream of those fusion events involving HIV coreceptors).…”

Section: Discussionmentioning

confidence: 53%

Apolipoprotein E‐derived antimicrobial peptide analogues with altered membrane affinity and increased potency and breadth of activity

et al. 2007

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Host‐derived anti‐infective proteins represent an important source of sequences for designing antimicrobial peptides (AMPs). However such sequences are often long and comprise diverse amino acids with uncertain contribution to biological effects. Previously, we identified a simple highly cationic peptide derivative of human apolipoprotein E (apoEdp) that inhibited a range of microorganisms. Here, we have dissected the protein chemistry underlying this activity. We report that basic residues and peptide length of around 18 residues were required for activity; however, the Leu residues can be substituted by several other residues without loss of activity and, when substituted with Phe or Trp, resulted in peptides with increased potency. These apoEdp‐derived AMPs (apoE‐AMPs) showed no cytotoxicity and minimal haemolytic activity, and were active against HIV and Plasmodium via an extracellular target. CXCR4 and CCR5 strains of HIV were inhibited though an early stage in viral infection upstream of fusion, and a lack of inhibition of vesicular stomatitis virus G protein pseudotyped HIV‐1 suggested the anti‐HIV activity was relatively selective. Inhibition of Plasmodium invasion of hepatocytes was observed without a direct action on Plasmodium integrity or attachment to cells. The Trp‐substituted apoE‐AMP adhered to mammalian cells irreversibly, explaining its increased potency; NMR experiments confirmed that the aromatic peptides also showed stronger perturbation of membrane lipids (relative to apoEdp). Our data highlight the contribution of specific amino acids to the activity of apoEdp (and also potentially unrelated AMPs) and suggest that apoE‐AMPs may be useful as lead agents for preventing the early stages of HIV and Plasmodium cellular entry.

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Section: Discussionmentioning

confidence: 53%

Apolipoprotein E‐derived antimicrobial peptide analogues with altered membrane affinity and increased potency and breadth of activity

et al. 2007

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“…Whereas AMD2763 was found to inhibit HIV replication in various human T cells at a concentration of 0.14Ϫ1.4 M [96], AMD3100 inhibited HIV replication within the nanomole range [97]. The inhibitory effects of AMD3100 on X4 HIV-1 strains have been demonstrated in a wide variety of cells expressing CXCR4, including PBMCs, and, vice versa, various X4, R5/X4 but not R5 HIV-1 viruses have proven sensitive to AMD3100 in PBMCs and M/M [99,[101][102][103]. Recently, a follow-up drug has been reported.…”

Section: Targeting the Hiv Coreceptorsmentioning

confidence: 99%

Specific CD4 down-modulating compounds with potent anti-HIV activity

Vermeire

Schols

2003

Journal of Leukocyte Biology

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Despite the availability of the current clinically approved anti-HIV drugs, new classes of effective antiviral agents are still urgently needed to combat AIDS. A promising approach for drug development and vaccine design involves targeting research on HIV-1 entry, a multistep process that comprises viral attachment, coreceptor interactions, and fusion. Determination of the viral entry process in detail has enabled the design of specific agents that can inhibit each step in the HIV entry process. Therapeutic agents that interfere with the binding of the HIV envelope glycoprotein gp120 to the CD4 receptor (e.g., PRO 542, PRO 2000, and CV-N) or the coreceptors CCR5 and CXCR4 (e.g., SCH-C and AMD3100) are briefly outlined in this review. The anti-HIV activity of cyclotriazadisulfonamides, a novel class of compounds with a unique mode of action by down-modulating the CD4 receptor in lymphocytic and monocytic cells, is especially highlighted. On the basis of the successful results of T-20, the first approved entry inhibitor, the development of effective antiretrovirals that block HIV entry will certainly be further encouraged.

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“…Others, however, utilise only CXCR4 for entry yet infect macrophages efficiently (9). We and others have found that such strains infect D32D32 CCR5 macrophages and that this infection can be inhibited by specific ligands to CXCR4 (33)(34)(35). Thus, both CCR5 and CXCR4 act as functional co-receptors on primary macrophages.…”

Section: Co-receptors As Determinants Of Cell Tropism and Pathogenesismentioning

confidence: 85%

“…We have shown that multi-co-receptor-using isolates rely predominantly on CCR5 for macrophage infection (33). The reduced level of infection by such strains in D32D32 CCR5 macrophages is completely inhibited by ligands to CXCR4.…”

Section: Role Of Alternative Co-receptors In Vivomentioning

confidence: 90%

“…The reduced level of infection by such strains in D32D32 CCR5 macrophages is completely inhibited by ligands to CXCR4. Macrophage infection by different HIV-1 strains that together used at least eight different co-receptors was solely explained by the use of either CCR5 or CXCR4 (33,55,56). Thus, no evidence of alternative co-receptor use was found.…”

Section: Role Of Alternative Co-receptors In Vivomentioning

confidence: 94%

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Co‐receptor use by HIV and inhibition of HIV infection by chemokine receptor ligands

Simmons

Reeves

Hibbitts

et al. 2000

Immunological Reviews

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109

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Human and simian immunodeficiency viruses (HIV and SIV) require a seven transmembrane chemokine (7TM) receptor in addition to CD4 for efficient entry into cells. CCR5 and CXCR4 act as major co-receptors for non-syncytium-inducing and syncytium-inducing strains respectively. We have examined the co-receptor requirement for HIV-1 infection of cells of macrophage lineage. Both CCR5 and CXCR4 can operate as functional co-receptors for infection in these cell types. Other co-receptors utilised by multi-co-receptor-using strains of HIV-1, including CCR3 and STRL33, were not used for macrophage infection. HIV-2 and SIV strains, however, can replicate in both peripheral blood mononuclear cells (PBMCs) and other primary cell types such as fibroblasts independently of CCR5 or CXCR4. HIV co-receptors, particularly CCR5, will be major targets for new therapeutics in this decade. We have therefore investigated different chemokines and derivatives that bind co-receptors for their capacity to inhibit HIV infection. These included derivatives of a CCR5 ligand, RANTES, with modified N-termini as well as Kaposi's sarcoma-associated herpesvirus-encoded chemokines that bind a wide range of co-receptors, including CCR5, CXCR4, CCR3 and CCR8, as well as the orphan 7TM receptors GPR1 and STRL33. One compound, aminooxypentane or AOP-RANTES, was a particularly potent inhibitor of HIV infection on PBMCs, macrophages and CCR5+ cell lines and demonstrated the great promise of therapeutic strategies aimed at CCR5.

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CXCR4 as a Functional Coreceptor for Human Immunodeficiency Virus Type 1 Infection of Primary Macrophages

Cited by 139 publications

References 52 publications

Apolipoprotein E‐derived antimicrobial peptide analogues with altered membrane affinity and increased potency and breadth of activity

Apolipoprotein E‐derived antimicrobial peptide analogues with altered membrane affinity and increased potency and breadth of activity

Specific CD4 down-modulating compounds with potent anti-HIV activity

Co‐receptor use by HIV and inhibition of HIV infection by chemokine receptor ligands

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