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Journal of Virology, June 2007, p. 5658-5668, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.00257-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Unique Mutational Patterns in the Envelope {alpha}2 Amphipathic Helix and Acquisition of Length in gp120 Hypervariable Domains Are Associated with Resistance to Autologous Neutralization of Subtype C Human Immunodeficiency Virus Type 1{triangledown}

Rong Rong,1 S. Gnanakaran,5 Julie M. Decker,6,7 Frederic Bibollet-Ruche,6,7 Jesse Taylor,5,{dagger} Jeffrey N. Sfakianos,8 John L. Mokili,5,{ddagger} Mark Muldoon,9 Joseph Mulenga,10 Susan Allen,3 Beatrice H. Hahn,6,7 George M. Shaw,6,7 Jerry L. Blackwell,2,4 Bette T. Korber,5,11 Eric Hunter,1,2 and Cynthia A. Derdeyn1,2*

Department of Pathology and Laboratory Medicine,1 Yerkes National Primate Research Center,2 Department of International Health,3 Division of Infectious Diseases, Emory University, Atlanta, Georgia,4 Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico,5 Department of Medicine,6 Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama,7 Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut,8 Department of Mathematics, University of Manchester Institute of Science and Technology, Manchester, United Kingdom,9 Zambia Blood Transfusion Service, Lusaka, Zambia,10 The Santa Fe Institute, Santa Fe, New Mexico,11

Received 6 February 2007/ Accepted 7 March 2007

Autologous neutralizing antibodies (NAb) against human immunodeficiency virus type 1 generate viral escape variants; however, the mechanisms of escape are not clearly defined. In a previous study, we determined the susceptibilities of 48 donor and 25 recipient envelope (Env) glycoproteins from five subtype C heterosexual transmission pairs to NAb in donor plasma by using a virus pseudotyping assay, thereby providing an ideal setting to probe the determinants of susceptibility to neutralization. In the present study, acquisition of length in the Env gp120 hypervariable domains was shown to correlate with resistance to NAb in donor plasma (P = 0.01; Kendall's tau test) but not in heterologous plasma. Sequence divergence in the gp120 V1-to-V4 region also correlated with resistance to donor (P = 0.0002) and heterologous (P = 0.001) NAb. A mutual information analysis suggested possible associations of nine amino acid positions in V1 to V4 with NAb resistance to the donor's antibodies, and five of these were located within an 18-residue amphipathic helix ({alpha}2) located on the gp120 outer domain. High nonsynonymous-to-synonymous substitution (dN/dS) ratios, indicative of positive selection, were also found at these five positions in subtype C sequences in the database. Nevertheless, exchange of the entire {alpha}2 helix between resistant donor Envs and sensitive recipient Envs did not alter the NAb phenotype. The combined mutual information and dN/dS analyses suggest that unique mutational patterns in {alpha}2 and insertions in the V1-to-V4 region are associated with NAb resistance during subtype C infection but that the selected positions within the {alpha}2 helix must be linked to still other changes in Env to confer antibody escape. These findings suggest that subtype C viruses utilize mutations in the {alpha}2 helix for efficient viral replication and immune avoidance.

* Corresponding author. Mailing address: Emory Vaccine Center, Emory University, 954 Gatewood Rd., Suite 1024, Atlanta, GA 30329. Phone: (404) 727-8594. Fax: (404) 727-9316. E-mail: cynthia.derdeyn{at}emory.edu

{triangledown} Published ahead of print on 14 March 2007.

{dagger} Present address: La Jolla Institute for Allergy and Immunology, La Jolla, California.

{ddagger} Present address: Department of Statistics, Oxford University, Oxford, United Kingdom.

Journal of Virology, June 2007, p. 5658-5668, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.00257-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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