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Natural anti-CCR5 antibodies in HIV-infection and -exposure.

Lopalco L - J Transl Med (2011)

Bottom Line: Natural antibodies constitute a first-line of defence against pathogens; they may also play other roles in immune regulation and homeostasis, through their ability to bind host antigens, surface molecules and receptors.Among natural anti-CCR5 antibodies, IgG and IgA to the ECL1 domain have been shown to block HIV effectively and durably without causing harm to the host.Their biological properties and their uncommon generation in subsets of HIV-infected and HIV-exposed individuals (so called ESN) will be introduced and discussed, with the aim at exploiting their potential in therapy and prevention.

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Affiliation: Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy. lopalco.lucia@hsr.it

ABSTRACT
Natural antibodies constitute a first-line of defence against pathogens; they may also play other roles in immune regulation and homeostasis, through their ability to bind host antigens, surface molecules and receptors. Natural anti-CCR5 antibodies can be decisive in preventing HIV infection in mucosal tissues and offer prompt and effective protection just at major sites of virus entry. Among natural anti-CCR5 antibodies, IgG and IgA to the ECL1 domain have been shown to block HIV effectively and durably without causing harm to the host. Their biological properties and their uncommon generation in subsets of HIV-infected and HIV-exposed individuals (so called ESN) will be introduced and discussed, with the aim at exploiting their potential in therapy and prevention.

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CCR5 coreceptor. Scheme illustrating the three-dimension structure of CCR5 coreceptor. Extracellular domains show the HIV binding sites and the immunodominant epitopes mapped by mAbs and by natural anti-CCR5 antibodies. Sites of O-Glycosylation (Ser6), palmitoylation (Cys321, 323 and 324) and phosphorylation (Ser336, 337, 342 and 349) are also shown. C20-C269 disulphide bond is represented in an open form.
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Figure 1: CCR5 coreceptor. Scheme illustrating the three-dimension structure of CCR5 coreceptor. Extracellular domains show the HIV binding sites and the immunodominant epitopes mapped by mAbs and by natural anti-CCR5 antibodies. Sites of O-Glycosylation (Ser6), palmitoylation (Cys321, 323 and 324) and phosphorylation (Ser336, 337, 342 and 349) are also shown. C20-C269 disulphide bond is represented in an open form.

Mentions: Several studies employing monoclonal antibodies have defined CCR5 epitopes involved in major receptor functions, such as binding to chemokines, activation, trafficking and HIV docking. Some of these antibodies, such as MC-1 or PA14, were found suitable to work as therapeutic inhibitors of viral entry, due to their ability in inhibiting gp120 binding or in promoting CCR5 internalization without triggering intracellular signaling; the humanized version of PA14, PRO140, has been tested in clinical studies [26,27,35]. A scheme representing CCR5 molecule, its binding domains and the key epitopes mapped on its structure is illustrated in Figure 1. Similarly to other G-protein coupled receptors (GPCRs) and membrane-associated proteins, CCR5 is poorly immunogenic; its four extracellular domains represent about one fourth of its whole sequence (90 out of 352 aminoacids); the two longer domains, the N-terminus and the second extracellular loop (ECL2), span about 30 aminoacids each [36]. These latter domains host immunodominant epitopes recognized by the majority of monoclonal antibodies, such as D2-Y3, Y10-D11 or K171-E172 [36]; both the N-terminus and the ECL2 domain are also involved in chemokine and HIV binding [26,36,37].


Natural anti-CCR5 antibodies in HIV-infection and -exposure.

Lopalco L - J Transl Med (2011)

CCR5 coreceptor. Scheme illustrating the three-dimension structure of CCR5 coreceptor. Extracellular domains show the HIV binding sites and the immunodominant epitopes mapped by mAbs and by natural anti-CCR5 antibodies. Sites of O-Glycosylation (Ser6), palmitoylation (Cys321, 323 and 324) and phosphorylation (Ser336, 337, 342 and 349) are also shown. C20-C269 disulphide bond is represented in an open form.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3105504&req=5

Figure 1: CCR5 coreceptor. Scheme illustrating the three-dimension structure of CCR5 coreceptor. Extracellular domains show the HIV binding sites and the immunodominant epitopes mapped by mAbs and by natural anti-CCR5 antibodies. Sites of O-Glycosylation (Ser6), palmitoylation (Cys321, 323 and 324) and phosphorylation (Ser336, 337, 342 and 349) are also shown. C20-C269 disulphide bond is represented in an open form.
Mentions: Several studies employing monoclonal antibodies have defined CCR5 epitopes involved in major receptor functions, such as binding to chemokines, activation, trafficking and HIV docking. Some of these antibodies, such as MC-1 or PA14, were found suitable to work as therapeutic inhibitors of viral entry, due to their ability in inhibiting gp120 binding or in promoting CCR5 internalization without triggering intracellular signaling; the humanized version of PA14, PRO140, has been tested in clinical studies [26,27,35]. A scheme representing CCR5 molecule, its binding domains and the key epitopes mapped on its structure is illustrated in Figure 1. Similarly to other G-protein coupled receptors (GPCRs) and membrane-associated proteins, CCR5 is poorly immunogenic; its four extracellular domains represent about one fourth of its whole sequence (90 out of 352 aminoacids); the two longer domains, the N-terminus and the second extracellular loop (ECL2), span about 30 aminoacids each [36]. These latter domains host immunodominant epitopes recognized by the majority of monoclonal antibodies, such as D2-Y3, Y10-D11 or K171-E172 [36]; both the N-terminus and the ECL2 domain are also involved in chemokine and HIV binding [26,36,37].

Bottom Line: Natural antibodies constitute a first-line of defence against pathogens; they may also play other roles in immune regulation and homeostasis, through their ability to bind host antigens, surface molecules and receptors.Among natural anti-CCR5 antibodies, IgG and IgA to the ECL1 domain have been shown to block HIV effectively and durably without causing harm to the host.Their biological properties and their uncommon generation in subsets of HIV-infected and HIV-exposed individuals (so called ESN) will be introduced and discussed, with the aim at exploiting their potential in therapy and prevention.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy. lopalco.lucia@hsr.it

ABSTRACT
Natural antibodies constitute a first-line of defence against pathogens; they may also play other roles in immune regulation and homeostasis, through their ability to bind host antigens, surface molecules and receptors. Natural anti-CCR5 antibodies can be decisive in preventing HIV infection in mucosal tissues and offer prompt and effective protection just at major sites of virus entry. Among natural anti-CCR5 antibodies, IgG and IgA to the ECL1 domain have been shown to block HIV effectively and durably without causing harm to the host. Their biological properties and their uncommon generation in subsets of HIV-infected and HIV-exposed individuals (so called ESN) will be introduced and discussed, with the aim at exploiting their potential in therapy and prevention.

Show MeSH
Related in: MedlinePlus