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New Cell Receptor For HIV Identified

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A cellular protein that helps guide immune cells to the gut has been newly identified as a target of HIV when the virus begins its assault on the body’s immune system, according to researchers from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH).

“The identification of this new receptor opens up new avenues of investigation that may help further elucidate the complex mechanisms of the pathogenesis of HIV infection,” says NIAID Director Anthony S. Fauci, M.D., chief of the Institute’s Laboratory of Immunoregulation (LIR) and senior author of the new study.

Several other immune cell receptors bind to HIV. Most important among these, the CD4 molecule, identified as an HIV receptor in 1984, functions as the principal receptor for HIV. The CCR5 and CXCR4 molecules, discovered in 1996, serve as co-receptors that HIV uses to enter its target cells. In the new study, which appears online Feb. 10, 2008 in Nature Immunology, NIAID scientists identify a cell adhesion molecule known as integrin alpha 4 beta 7 as another potentially important receptor for HIV.

Early in the course of HIV infection, the virus rapidly invades and replicates in gut-associated lymphoid tissue (GALT), the immune cells of the gut. Once seeded with HIV, the gut is rapidly depleted of CD4+ T cells, the main target of HIV, triggering the process that ultimately leads to AIDS.

“In the very early days of infection, it is in the GALT where most of the damage caused by HIV occurs,” says Elena Martinelli, Ph.D., a lead author of the paper and a fellow in Dr. Fauci’s laboratory. “The gut is where the virus really takes hold. We found that integrin alpha 4 beta 7, whose natural function is to direct T cells to the GALT, is also a receptor for HIV. It is very unlikely that this is a coincidence.”

Dr. Martinelli, along with Claudia Cicala, Ph.D., James Arthos, Ph.D., and their colleagues found that the gp120 protein, part of the HIV envelope, binds to integrin alpha 4 beta 7 on CD4+ T cells, which promotes the formation of a stable junction, or synapse, between neighboring cells.

“A synapse is a junction that allows two cells to adhere in a stable way,” says Dr. Arthos. “Many viruses have found a way to trick cells into forming these stable junctions. Now it appears that HIV can also trigger synapse formation.”

Specifically, a short piece of the HIV gp120 protein in a region known as the V2 loop recognizes the alpha 4 chain of the integrin molecule on host cells. This stretch of the V2 loop is similar to part of the naturally occurring molecules that bind integrin alpha 4 beta 7. Thus, it appears that HIV is mimicking the natural molecular partners, or ligands, that normally bind to the receptor. The authors note, however, that some HIV isolates react more strongly to integrin alpha 4 beta 7 than others.

“The ability of a particular virus to bind to integrin alpha 4 beta 7 may determine whether it will have a major impact in targeting the gut lymphoid tissue,” says Dr. Fauci. “This finding could be a significant determinant in the pathogenic mechanisms that lead to AIDS.”

As part of the natural homing process, integrin alpha 4 beta 7 binds to its natural ligands and activates a protein known as LFA-1. According to Dr. Arthos, HIV can co-opt this process by mimicking the cells’ alpha 4 beta 7 receptor natural ligands. When HIV gp120 protein binds to the alpha 4 beta 7 receptor it facilitates the formation of a synapse. Thus, HIV tricks an infected cell into binding to an uninfected cell, enabling HIV to readily gain access to the uninfected cell.

“While this study provides important new information concerning the various mechanisms by which HIV debilitates the human immune system, it also raises new questions and challenges that our laboratory and others will pursue,” notes Dr. Cicala.

Nat Immunol. 2008 Feb 10 [Epub ahead of print]
HIV-1 envelope protein binds to and signals through integrin alpha(4)beta(7), the gut mucosal homing receptor for peripheral T cells.
Arthos J, Cicala C, Martinelli E, Macleod K, Van Ryk D, Wei D, Xiao Z, Veenstra TD, Conrad TP, Lempicki RA, McLaughlin S, Pascuccio M, Gopaul R, McNally J, Cruz CC, Censoplano N, Chung E, Reitano KN, Kottilil S, Goode DJ, Fauci AS.

[1] Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. [2] These authors contributed equally to this work.

Infection with human immunodeficiency virus 1 (HIV-1) results in the dissemination of virus to gut-associated lymphoid tissue. Subsequently, HIV-1 mediates massive depletion of gut CD4(+) T cells, which contributes to HIV-1-induced immune dysfunction. The migration of lymphocytes to gut-associated lymphoid tissue is mediated by integrin alpha(4)beta(7). We demonstrate here that the HIV-1 envelope protein gp120 bound to an activated form of alpha(4)beta(7). This interaction was mediated by a tripeptide in the V2 loop of gp120, a peptide motif that mimics structures presented by the natural ligands of alpha(4)beta(7). On CD4(+) T cells, engagement of alpha(4)beta(7) by gp120 resulted in rapid activation of LFA-1, the central integrin involved in the establishment of virological synapses, which facilitate efficient cell-to-cell spreading of HIV-1.

Diversity of integrins

17 INTEGRIN-ALPHA chains and 8 INTEGRIN-BETA chains have been identified. The association of an INTEGRIN-ALPHA chain and INTEGRIN-BETA chain leads to 25 different integrins.
There are classified in:

  • VLA
  • Cytoadhesins
  • Leu-cam

Integrins ©Copyright 2006 IMGT

(1) α1β1 Alpha1/beta1 is a receptor for collagen-I, collagen-IV and laminin (E1 region). It is expressed on activated T cells, monocytes, smooth muscle cells and melanoma cells. This integrin is also known as VLA-1 (very late activation antigen 1).
(2) α2β1 Alpha2/beta1 is a receptor for collagen-I to -VI, laminin and possibly fibronectin. It is expressed on B and T lymphocytes, platelets, fibroblasts, endothelial cells and melanoma cells. This integrin is also known as VLA-2 (very late activation antigen 2), GPIa-IIa (glycoprotein Ia-IIa on platelets) and ECMRII (extracellular matrix receptor II).
(3) α3β1 Alpha3/beta1 is a receptor for epiligrin, laminin (E3 fragment), nidogen/entactin, fibronectin and collagen-1. It is expressed on B lymphocytes, kidney glomerulus and most cultured cell lines. This integrin is also known as VLA-3 (very late activation atigen 3), VCA-2 (very common antigen 2), ECMRI (extracellular matrix receptor I) and Gapb-3 (galactoprotein b3).
(4) α4β1 Alpha4/beta1 is a receptor for fibronectin containing the CS-1 region, which is situated within the IIICS region, and VCAM-1 (vascular cellular adhesion molecule 1). It is present on lymphocytes, monocytes, eosinophils, NK cells and thymocytes. This integrin plays a role in the invasion of inflammated tissues, and has also been implicated in skeletal myogenesis, neural crest migration and proliferation, lymphocyte maturation and morphogenesis of the placenta and heart. VCAM-1 is an adhesion molecule which is present on cytokine-activated endothelial cells, while fibronectin is part of the extracellular matrix. Alpha4/beta1 is thus involved in both cell-cell and cell-extracellular matrix adhesion. This integrin is also known as VLA-4 (very late activation antigen 4) and LPAM-2 (lymphocyte Peyer’s patch HEV adhesion molecule 2 (mouse)).
(5) α5β1 Alpha5/beta1 is a receptor for fibronectin. It is expressed on memory T cells, monocytes, platelets and fibroblasts. This integrin is also known as VLA-5 (very late activation antigen 5), FNR (fibronectin receptor), GPIc-IIa (glycoprotein Ic-IIa on platelets) and ECMRVI (extracellular matrix receptor VI).
(6) αVβ1 AlphaV/beta1 is a receptor for fibronectin.
(7) α6β1 The alpha6/beta1 integrin is expressed on platelets, lymphocytes, monocytes, thymocytes and epithelial cells, on which it functions as a laminin receptor for laminin-1, laminin-2 and laminin-4 in vivo. It is also a receptor for laminin-5, but not in vivo. For laminin-1, the binding site has been localized in the E8 domain of this extracellular matrix molecule. This receptor is also known as VLA-6 (very late activation antigen 6) and GPIc-IIa (glycoprotein Ic-IIa on platelets).
(8) α7β1 The alpha7/beta1 integrin is expressed on skeletal and cardiac muscle at specific stages during muscle development. It is a receptor for laminin-1 and binds to its E8 domain. This integrin is also found localized in focal contacts when melanoma cells attach to laminin-1, while normal melanocytes do not express this integrin. Since alpha7/beta1 is developmentally regulated in muscle cells, it is thought that this integrin has a role in their development. The expression of the three known splice variants is in addition developmentally regulated. Expression of alpha7B precedes the xpression of alpha7A and alpha7C. Alpha7/beta1 is also a trophoblast specific laminin receptor on which it may serve a specific function during the early postimplantation period. This integrin is also known as VLA-7 (very late activation antigen 7).
(9) α8β1 Alpha8/beta1 is a receptor for fibronectin.
(10) α9β1  
(11) αDβ2  
(12) αLβ2 AlphaL/beta2 is a receptor for ICAM-1 to 3 (intercellular adhesion molecule 1 to 3). This integrin is only present on leukocytes and plays an important role in interactions between members of this family (eg. B cell to T cell). AlphaL/beta2 is also involved in the interactions between cytotoxic cells and their target cells. On top of this, alphaL/beta2 is crucial for the invasion of leukocytes in tissues. ICAM-1 is expressed on leukocytes and other cells, amongst them are endothelial cells, but only after they have been activated by cytokines for example which are produced in immune reactions and inflammated tissues. ICAM-2 is present on a lot of cells and does not change after cytokine activation. ICAM-3 is primarily expressed on resting lymphocytes and plays a role in the onset of immune reactions. AlphaL/beta2 is normally not activated, but adhesion is induced by activation of the leukocyte, for example by PAF (platelet activating factor) which is produced in inflammated tissues. This integrin is also known as LFA-1 (leukocyte function associated antigen 1).
(13) αMβ2 AlphaM/beta2 is a receptor for iC3b (inactivated form of C3b), factor X (coagulation factor X), fibrinogen and ICAM-1 (intercellular adhesion molecule 1). It is expressed on monocytes, macrophages, NK cells and granulocytes. Alpha-M/beta-2 is important in adherence of monocytes and neutrophils to vascular endothelium, as well as in subsequent extravasation. It also plays a role in phagocytosis of complement coated particles. This integrin is also known as Mac-1 (macrophage receptor 1) and iC3b receptor 3 (CR3).
(14) αXβ2 alphaX/beta2 is a receptor for fibrinogen. It is found on monocytes, macrophages, granulocytes, NK cells and activated lymphocytes. This integrin is also known as p150 and iC3b receptor 4 (CR4).
(15) αVβ3 AlphaV/beta3 is a receptor for fibrinogen, fibronectin, von Willebrand’s factor, vitronectin, Thrombospondin (Tsp), osteopontin and bone sialoprotein 1 (Bsp1). It is expressed on endothelial cells, some B cells, platelets and monocytes. alphaVb-beta3 mediates platelet aggregation and endothelial cell adhesion to ECM proteins. This integrin is also known as VNR (vitronectin receptor).
(16) α-IIbβ3 Alpha-IIb/beta3 is a receptor for fibrinogen, fibronectin, von Willebrand’s factor and vitronectin. It is expressed on platelets. This integrin is also known as GPIIb-IIIa (glycoprotein IIb-IIIa on platelets).
(17) αRβ3  
(18) α6β4 The alpha6/beta4 integrin is expressed on different cell types. They are expressed on immature thymocytes, on squamous epithedlia, on subsets of endothelial cells, on Schwann cells and also on fibroblasts in the peripheral nervous system. In stratified epithelia like the skin, alpha6/beta4 is concentrated in dense structures which are called hemidesmosomes. These dense structures are involved in the attachment of basal cells to the underlying basement membranes. This is achieved by connection of the intermediate filaments to the extracellular matrix via this integrin. All the other integrins use actin filaments for this purpose instead of intermediate filaments. The ligands for the alpha6/beta4 integrin are laminin-1 and laminin-5. The afffinity for laminin-5 however is much stronger. In hemidesmosomes it is found attached to laminin-5. The different alpha6 splice variants do not influence the ligand specificities of the integrin. From studies with knockout mice it was found that in the absense of the integrin (beta4 knockout or alpha6 knockout) no hemidesmosomes were present, suggesting that the integrin is neccesary for the formation or initiation of hemidesmosomes. these mice showed severe blistering of the skin and died soon after birth.
(19) αVβ5 AlphaV/beta5 is a receptor for vitronectin. It is expressed on hepatoma cells, fibroblasts and carcinoma cells. This integrin is also known as alphaV/betaS and alphaV/beta3B.
(20) αVβ6 AlphaV/beta6 is a receptor for fibronectin. It is expressed on carcinoma cells.
(21) αVβ8  
(22) α4β7 The alpha4/beta7 integrin is a receptor for MadCAM, fibronectin and VCAM-1. This integrin is only found on leukocytes which are directed to the Peyer’s patches of the gut. MadCAM which is an addressin, is only found on Peyer’s patch endothelium. The alpha4/beta7 integrin is also known as LPAM-1.
(23) αIELβ7 This integrin is also known as M290 IELb (mouse intraepithelial lymphocyte antigen recognized by monoclonal antibody M290).



Written by huehueteotl

February 13, 2008 at 9:48 am

One Response

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