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Journal of Virology, November 2009, p. 10941-10950, Vol. 83, No. 21
0022-538X/09/$08.00+0     doi:10.1128/JVI.00394-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

X4 Human Immunodeficiency Virus Type 1 gp120 Down-Modulates Expression and Immunogenicity of Codelivered Antigens{triangledown}

Avi-Hai Hovav,1* Michael Santosuosso,2 Maytal Bivas-Benita,3 Andre Plair,2 Alex Cheng,2 Mazal Elnekave,1 Elda Righi,2 Tao Chen,2 Satoshi Kashiwagi,2 Michael W. Panas,3 Shi-Hua Xiang,4 Karina Furmanov,1 Norman L. Letvin,3 and Mark C. Poznansky2

Institute of Dental Sciences, Hebrew University-Hadassah School of Dental Medicine, Jerusalem, Israel,1 Partners AIDS Research Center, Department of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129,2 Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115,3 Cancer Immunology and AIDS, Dana Farber Cancer Institute, Binney Street, Boston, Massachusetts 021154

Received 23 February 2009/ Accepted 28 July 2009

In order to increase the immune breadth of human immunodeficiency virus (HIV) vaccines, strategies such as immunization with several HIV antigens or centralized immunogens have been examined. HIV-1 gp120 protein is a major immunogen of HIV and has been routinely considered for inclusion in both present and future AIDS vaccines. However, recent studies proposed that gp120 interferes with the generation of immune response to codelivered antigens. Here, we investigate whether coimmunization with plasmid-encoded gp120 alters the immune response to other coadministered plasmid encoded antigens such as luciferase or ovalbumin in a mouse model. We found that the presence of gp120 leads to a significant reduction in the expression level of the codelivered antigen in vivo. Antigen presentation by antigen-presenting cells was also reduced and resulted in the induction of weak antigen-specific cellular and humoral immune responses. Importantly, gp120-mediated immune interference was observed after administration of the plasmids at the same or at distinct locations. To characterize the region in gp120 mediating these effects, we used plasmid constructs encoding gp120 that lacks the V1V2 loops ({Delta}V1V2) or the V3 loop ({Delta}V3). After immunization, the {Delta}V1V2, but not the {Delta}V3 construct, was able to reduce antigen expression, antigen presentation, and subsequently the immunogenicity of the codelivered antigen. The V3 loop dependence of this phenomenon seems to be limited to V3 loops known to interact with the CXCR4 molecule but not with CCR5. Our study presents a novel mechanism by which HIV-1 gp120 interferes with the immune response against coadministered antigen in a polyvalent vaccine preparation.

* Corresponding author. Mailing address: Institute of Dental Sciences, Hebrew University-Hadassah Faculty of Dental Medicine, P.O. Box 122722, Jerusalem 91120, Israel. Phone: 972-2-6758802. Fax: 972-2-6758561. E-mail: avihaih{at}ekmd.huji.ac.il

{triangledown} Published ahead of print on 19 August 2009.

Journal of Virology, November 2009, p. 10941-10950, Vol. 83, No. 21
0022-538X/09/$08.00+0     doi:10.1128/JVI.00394-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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