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Journal of Virology, February 2009, p. 1240-1259, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01743-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 2 (HIV-2)/HIV-1 Envelope Chimeras Detect High Titers of Broadly Reactive HIV-1 V3-Specific Antibodies in Human Plasma{triangledown}

Katie L. Davis,1 Frederic Bibollet-Ruche,2 Hui Li,2 Julie M. Decker,2 Olaf Kutsch,1,2 Lynn Morris,3 Aidy Salomon,4,5 Abraham Pinter,4,5 James A. Hoxie,6 Beatrice H. Hahn,1,2 Peter D. Kwong,7 and George M. Shaw1,2*

Departments of Microbiology,1 Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294,2 AIDS Virus Research Unit, National Institute for Communicable Diseases, Johannesburg, South Africa,3 Public Health Research Institute, Newark, New Jersey 07103,4 New Jersey School of Medicine, University of Medicine and Dentistry, Newark, New Jersey, 07103,5 Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104,6 Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 208927

Received 18 August 2008/ Accepted 7 November 2008

Deciphering antibody specificities that constrain human immunodeficiency virus type 1 (HIV-1) envelope (Env) diversity, limit virus replication, and contribute to neutralization breadth and potency is an important goal of current HIV/AIDS vaccine research. Transplantation of discrete HIV-1 neutralizing epitopes into HIV-2 scaffolds may provide a sensitive, biologically functional context by which to quantify specific antibody reactivities even in complex sera. Here, we describe a novel HIV-2 proviral scaffold (pHIV-2KR.X7) into which we substituted the complete variable region 3 (V3) of the env gene of HIV-1YU2 or HIV-1Ccon to yield the chimeric proviruses pHIV-2KR.X7 YU2 V3 and pHIV-2KR.X7 Ccon V3. These HIV-2/HIV-1 chimeras were replication competent and sensitive to selective pharmacological inhibitors of virus entry. V3 chimeric viruses were resistant to neutralization by HIV-1 monoclonal antibodies directed against the CD4 binding site, coreceptor binding site, and gp41 membrane proximal external region but exhibited striking sensitivity to HIV-1 V3-specific monoclonal antibodies, 447-52D and F425 B4e8 (50% inhibitory concentration of [IC50] <0.005 µg/ml for each). Plasma specimens from 11 HIV-1 clade B- and 10 HIV-1 clade C-infected subjects showed no neutralizing activity against HIV-2 but exhibited high-titer V3-specific neutralization against both HIV-2/HIV-1 V3 chimeras with IC50 measurements ranging from 1:50 to greater than 1:40,000. Neutralization titers of B clade plasmas were as much as 1,000-fold lower when tested against the primary HIV-1YU2 virus than with the HIV-2KR.X7 YU2 V3 chimera, demonstrating highly effective shielding of V3 epitopes in the native Env trimer. This finding was replicated using a second primary HIV-1 strain (HIV-1BORI) and the corresponding HIV-2KR.X7 BORI V3 chimera. We conclude that V3 is highly immunogenic in vivo, eliciting antibodies with substantial breadth of reactivity and neutralizing potential. These antibodies constrain HIV-1 Env to a structure(s) in which V3 epitopes are concealed prior to CD4 engagement but do not otherwise contribute to neutralization breadth and potency against most primary virus strains. Triggering of the viral spike to reveal V3 epitopes may be required if V3 immunogens are to be components of an effective HIV-1 vaccine.

* Corresponding author. Mailing address: Departments of Medicine and Microbiology, University of Alabama at Birmingham, 720 20th Street South, Kaul 816, Birmingham, AL 35294. Phone: (205) 934-0412. Fax: (205) 934-1580. E-mail: gshaw{at}uab.edu

{triangledown} Published ahead of print on 19 November 2008.

Journal of Virology, February 2009, p. 1240-1259, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01743-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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