Skip to main content
Top
Published in: Current HIV/AIDS Reports 2/2018

Open Access 01-04-2018 | HIV Pathogenesis and Treatment (AL Landay and N Utay, Section Editors)

The Role of Integrin α4β7 in HIV Pathogenesis and Treatment

Authors: James Arthos, Claudia Cicala, Fatima Nawaz, Siddappa N. Byrareddy, Francois Villinger, Philip J. Santangelo, Aftab A. Ansari, Anthony S. Fauci

Published in: Current HIV/AIDS Reports | Issue 2/2018

Login to get access

Abstract

Purpose of Review

Acute HIV infection is characterized by high-level viral replication throughout the body’s lymphoid system, particularly in gut-associated lymphoid tissues resulting in damage to structural components of gut tissue. This damage is irreversible and believed to contribute to the development of immune deficiencies. Antiretroviral therapy (ART) does not restore gut structure and function. Studies in macaques point to an alternative treatment strategy that may ameliorate gut damage. Integrin α4β7 mediates the homing of lymphocytes to gut tissues. Vedolizumab, a monoclonal antibody (mAb) antagonist of α4β7, has demonstrated efficacy and has been approved for the treatment of inflammatory bowel disease in humans. Here, we describe our current knowledge, and the gaps in our understanding, of the role of α4β7 in HIV pathogenesis and treatment.

Recent Findings

When administered to macaques prior to infection, a nonhuman primate analogue of vedolizumab prevents transmission of SIV. In combination with ART, this mAb facilitates durable virologic control following treatment interruption.

Summary

Targeting α4β7 represents a novel therapeutic approach to prevent and treat HIV infection.
Literature
1.
go back to reference Nelson JA, Wiley CA, Reynolds-Kohler C, Reese CE, Margaretten W, Levy JA. Human immunodeficiency virus detected in bowel epithelium from patients with gastrointestinal symptoms. Lancet. 1988;1(8580):259–62.CrossRefPubMed Nelson JA, Wiley CA, Reynolds-Kohler C, Reese CE, Margaretten W, Levy JA. Human immunodeficiency virus detected in bowel epithelium from patients with gastrointestinal symptoms. Lancet. 1988;1(8580):259–62.CrossRefPubMed
10.
go back to reference Barrett L, Fowke KR, Grant MD. Cytomegalovirus, aging, and HIV: a perfect storm. AIDS Rev. 2012;14(3):159–67.PubMed Barrett L, Fowke KR, Grant MD. Cytomegalovirus, aging, and HIV: a perfect storm. AIDS Rev. 2012;14(3):159–67.PubMed
11.
go back to reference Saison J, Cotte L, Chidiac C, Ferry T. Fatal cumulative toxicities of HAART in a stable, AIDS-free, HIV-infected patient. BMJ Case Rep. 2012;2012. Saison J, Cotte L, Chidiac C, Ferry T. Fatal cumulative toxicities of HAART in a stable, AIDS-free, HIV-infected patient. BMJ Case Rep. 2012;2012.
15.
go back to reference Sivro ASA, Sheward D, Joag V, Yegorov S, Liebenberg L, Balgobin A, Yende N, Garrett N, Samsunder N, Nawaz F, Cicala C, Arthos J, Fauci A, Anzala O, Kimani J, Bagaya B, Kiwanuka N, Williamson C, Kaul R, Passmore J, Phanuphak N, Ananworanich J, Ansari A, Karim Q, Karim S, McKinnon L. Integrin α4β7 expression on systemic CD4+ T cells predicts higher rates of HIV acquisition and disease progression. Sci Transl Med. 2018. Sivro ASA, Sheward D, Joag V, Yegorov S, Liebenberg L, Balgobin A, Yende N, Garrett N, Samsunder N, Nawaz F, Cicala C, Arthos J, Fauci A, Anzala O, Kimani J, Bagaya B, Kiwanuka N, Williamson C, Kaul R, Passmore J, Phanuphak N, Ananworanich J, Ansari A, Karim Q, Karim S, McKinnon L. Integrin α4β7 expression on systemic CD4+ T cells predicts higher rates of HIV acquisition and disease progression. Sci Transl Med. 2018.
16.
go back to reference Szabo MC, Butcher EC, McEvoy LM. Specialization of mucosal follicular dendritic cells revealed by mucosal addressin-cell adhesion molecule-1 display. J Immunol. 1997;158(12):5584–8.PubMed Szabo MC, Butcher EC, McEvoy LM. Specialization of mucosal follicular dendritic cells revealed by mucosal addressin-cell adhesion molecule-1 display. J Immunol. 1997;158(12):5584–8.PubMed
20.
go back to reference Shamri R, Grabovsky V, Feigelson SW, Dwir O, Van Kooyk Y, Alon R. Chemokine stimulation of lymphocyte alpha 4 integrin avidity but not of leukocyte function-associated antigen-1 avidity to endothelial ligands under shear flow requires cholesterol membrane rafts. J Biol Chem. 2002;277(42):40027–35. https://doi.org/10.1074/jbc.M206806200.CrossRefPubMed Shamri R, Grabovsky V, Feigelson SW, Dwir O, Van Kooyk Y, Alon R. Chemokine stimulation of lymphocyte alpha 4 integrin avidity but not of leukocyte function-associated antigen-1 avidity to endothelial ligands under shear flow requires cholesterol membrane rafts. J Biol Chem. 2002;277(42):40027–35. https://​doi.​org/​10.​1074/​jbc.​M206806200.CrossRefPubMed
22.
go back to reference Ansari AA, Byrareddy SN. The role of integrin expressing cells in modulating disease susceptibility and progression (January 2016). Int Trends Immun. 2016;4(1):11–27.PubMedPubMedCentral Ansari AA, Byrareddy SN. The role of integrin expressing cells in modulating disease susceptibility and progression (January 2016). Int Trends Immun. 2016;4(1):11–27.PubMedPubMedCentral
35.
42.
go back to reference Hindryckx P, Vande Casteele N, Novak G, Khanna R, D'Haens G, Sandborn WJ, et al. The expanding therapeutic armamentarium for inflammatory bowel disease: how to choose the right drug(s) for our patients? J Crohns Colitis. 2017. Hindryckx P, Vande Casteele N, Novak G, Khanna R, D'Haens G, Sandborn WJ, et al. The expanding therapeutic armamentarium for inflammatory bowel disease: how to choose the right drug(s) for our patients? J Crohns Colitis. 2017.
45.
go back to reference Lazarovits AI, Moscicki RA, Kurnick JT, Camerini D, Bhan AK, Baird LG, et al. Lymphocyte activation antigens. I. A monoclonal antibody, anti-Act I, defines a new late lymphocyte activation antigen. J Immunol. 1984;133(4):1857–62.PubMed Lazarovits AI, Moscicki RA, Kurnick JT, Camerini D, Bhan AK, Baird LG, et al. Lymphocyte activation antigens. I. A monoclonal antibody, anti-Act I, defines a new late lymphocyte activation antigen. J Immunol. 1984;133(4):1857–62.PubMed
46.
go back to reference Schweighoffer T, Tanaka Y, Tidswell M, Erle DJ, Horgan KJ, Luce GE, et al. Selective expression of integrin alpha 4 beta 7 on a subset of human CD4+ memory T cells with hallmarks of gut-trophism. J Immunol. 1993;151(2):717–29.PubMed Schweighoffer T, Tanaka Y, Tidswell M, Erle DJ, Horgan KJ, Luce GE, et al. Selective expression of integrin alpha 4 beta 7 on a subset of human CD4+ memory T cells with hallmarks of gut-trophism. J Immunol. 1993;151(2):717–29.PubMed
51.
go back to reference Ansari AA, Reimann KA, Mayne AE, Takahashi Y, Stephenson ST, Wang R, et al. Blocking of alpha4beta7 gut-homing integrin during acute infection leads to decreased plasma and gastrointestinal tissue viral loads in simian immunodeficiency virus-infected rhesus macaques. J Immunol. 2011;186(2):1044–59. https://doi.org/10.4049/jimmunol.1003052.CrossRefPubMed Ansari AA, Reimann KA, Mayne AE, Takahashi Y, Stephenson ST, Wang R, et al. Blocking of alpha4beta7 gut-homing integrin during acute infection leads to decreased plasma and gastrointestinal tissue viral loads in simian immunodeficiency virus-infected rhesus macaques. J Immunol. 2011;186(2):1044–59. https://​doi.​org/​10.​4049/​jimmunol.​1003052.CrossRefPubMed
58.
go back to reference Santangelo PCC, Byrareddy S, Ortiz K, Little D, Lindsay K, Gumber S, Hong J, Jelicic K, Zurla C, Villinger F, Ansari A, Fauci A, Arthos J. Early treatment of SIV+ macaques with an α4β7 mAb alters virus distribution and preserves CD4+ T cells in later stages of infection. Mucosal Immunol. 2018. Santangelo PCC, Byrareddy S, Ortiz K, Little D, Lindsay K, Gumber S, Hong J, Jelicic K, Zurla C, Villinger F, Ansari A, Fauci A, Arthos J. Early treatment of SIV+ macaques with an α4β7 mAb alters virus distribution and preserves CD4+ T cells in later stages of infection. Mucosal Immunol. 2018.
60.
go back to reference Dzutsev A, Hogg A, Sui Y, Solaymani-Mohammadi S, Yu H, Frey B, et al. Differential T cell homing to colon vs. small intestine is imprinted by local CD11c+ APCs that determine homing receptors. J Leukoc Biol. 2017. Dzutsev A, Hogg A, Sui Y, Solaymani-Mohammadi S, Yu H, Frey B, et al. Differential T cell homing to colon vs. small intestine is imprinted by local CD11c+ APCs that determine homing receptors. J Leukoc Biol. 2017.
61.
go back to reference Guzzo C, Ichikawa D, Park C, Phillips D, Liu Q, Zhang P, et al. Virion incorporation of integrin alpha4beta7 facilitates HIV-1 infection and intestinal homing. Sci Immunol. 2017;2(11). Guzzo C, Ichikawa D, Park C, Phillips D, Liu Q, Zhang P, et al. Virion incorporation of integrin alpha4beta7 facilitates HIV-1 infection and intestinal homing. Sci Immunol. 2017;2(11).
62.
go back to reference Kelly KA, Natarajan S, Ruther P, Wisse A, Chang MH, Ault KA. Chlamydia trachomatis infection induces mucosal addressin cell adhesion molecule-1 and vascular cell adhesion molecule-1, providing an immunologic link between the fallopian tube and other mucosal tissues. J Infect Dis. 2001;184(7):885–91. https://doi.org/10.1086/323341.CrossRefPubMed Kelly KA, Natarajan S, Ruther P, Wisse A, Chang MH, Ault KA. Chlamydia trachomatis infection induces mucosal addressin cell adhesion molecule-1 and vascular cell adhesion molecule-1, providing an immunologic link between the fallopian tube and other mucosal tissues. J Infect Dis. 2001;184(7):885–91. https://​doi.​org/​10.​1086/​323341.CrossRefPubMed
63.
go back to reference Kelly KA, Rank RG. Identification of homing receptors that mediate the recruitment of CD4 T cells to the genital tract following intravaginal infection with Chlamydia trachomatis. Infect Immun. 1997;65(12):5198–208.PubMedPubMedCentral Kelly KA, Rank RG. Identification of homing receptors that mediate the recruitment of CD4 T cells to the genital tract following intravaginal infection with Chlamydia trachomatis. Infect Immun. 1997;65(12):5198–208.PubMedPubMedCentral
Metadata
Title
The Role of Integrin α4β7 in HIV Pathogenesis and Treatment
Authors
James Arthos
Claudia Cicala
Fatima Nawaz
Siddappa N. Byrareddy
Francois Villinger
Philip J. Santangelo
Aftab A. Ansari
Anthony S. Fauci
Publication date
01-04-2018
Publisher
Springer US
Published in
Current HIV/AIDS Reports / Issue 2/2018
Print ISSN: 1548-3568
Electronic ISSN: 1548-3576
DOI
https://doi.org/10.1007/s11904-018-0382-3

Other articles of this Issue 2/2018

Current HIV/AIDS Reports 2/2018 Go to the issue

Co-infections and Comorbidity (S Naggie, Section Editor)

Serious Non-AIDS Conditions in HIV: Benefit of Early ART

The Science of Prevention (JD Stekler and J Baeten, Section Editors)

Genetic Cluster Analysis for HIV Prevention

The Science of Prevention (JD Stekler and J Baeten, Section Editors)

PrEP Stigma: Implicit and Explicit Drivers of Disparity

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.