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Resistance of Subtype C HIV-1 Strains to Anti-V3 Loop Antibodies

DOI: 10.1155/2012/803535

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HIV-1’s subtype C V3 loop consensus sequence exhibits increased resistance to anti-V3 antibody-mediated neutralization as compared to the subtype B consensus sequence. The dynamic 3D structure of the consensus C V3 loop crown, visualized by ab initio folding, suggested that the resistance derives from structural rigidity and non-β-strand secondary protein structure in the N-terminal strand of the β-hairpin of the V3 loop crown, which is where most known anti-V3 loop antibodies bind. The observation of either rigidity or non-β-strand structure in this region correlated with observed resistance to antibody-mediated neutralization in a series of chimeric pseudovirus (psV) mutants. The results suggest the presence of an epitope-independent, neutralization-relevant structural difference in the antibody-targeted region of the V3 loop crown between subtype C and subtype B, a difference that we hypothesize may contribute to the divergent pattern of global spread between these subtypes. As antibodies to a variable loop were recently identified as an inverse correlate of risk for HIV infection, the structure-function relationships discussed in this study may have relevance to HIV vaccine research. 1. Introduction Subtype C infections now represent the majority of HIV-1 infections worldwide [1], suggesting greater in vivo or host-pathogen fitness. By contrast, in direct in vitro competition assays, R5 subtype B isolates outcompete R5 subtype C isolates [2], suggesting greater in vitro infective fitness. Thus, more rapid in vivo spread of subtype C infections may be occurring despite an apparent greater in vitro fitness of subtype B. Differential susceptibility to human antibody-mediated neutralization could result in differing extents of global spread between different subtypes. The V3 loop is often referred to as the principal neutralizing determinant of HIV-1 viruses as several of the early and recent studies describing human antibodies that could neutralize HIV-1 were dominated by anti-V3 loop antibodies [3–6]. Indeed, several observations suggest a conformational or functional difference between subtype B and subtype C V3 loops [7], but the nature of the difference has not been elucidated. The V3 loop is also the site of CCR5 and CXCR4 engagement, a necessary determinant of virus entry [8–13]. Thus, antibody neutralization determinants and infective determinants coincide to the same location on the HIV-1 envelope glycoprotein surface, and disturbances to one are likely to affect the other. A comparison of antibody-mediated neutralizations of SF162 chimeric


[1]  K. K. Ari?n, G. Vanham, and E. J. Arts, “Is HIV-1 evolving to a less virulent form in humans?” Nature Reviews Microbiology, vol. 5, no. 2, pp. 141–151, 2007.
[2]  S. C. Ball, A. Abraha, K. R. Collins et al., “Comparing the ex vivo fitness of CCR5-tropic human immunodeficiency virus type 1 isolates of subtypes B and C,” Journal of Virology, vol. 77, no. 2, pp. 1021–1038, 2003.
[3]  J. R. Rusche, K. Javaherian, C. McDanal et al., “Antibodies that inhibit fusion of human immunodeficiency virus-infected cells bind a 24-amino acid sequence of the viral envelope, gp120,” Proceedings of the National Academy of Sciences of the United States of America, vol. 85, no. 9, pp. 3198–3202, 1988.
[4]  T. J. Palker, M. E. Clark, A. J. Langlois et al., “Type-specific neutralization of the human immunodeficiency virus with antibodies to env-encoded synthetic peptides,” Proceedings of the National Academy of Sciences of the United States of America, vol. 85, no. 6, pp. 1932–1936, 1988.
[5]  J. Goudsmit, C. Debouck, R. H. Meloen et al., “Human immunodeficiency virus type 1 neutralization epitope with conserved architecture elicits early type-specific antibodies in experimentally infected chimpanzees,” Proceedings of the National Academy of Sciences of the United States of America, vol. 85, no. 12, pp. 4478–4482, 1988.
[6]  C. C. Huang, M. Tang, M. Y. Zhang et al., “Structural biology: structure of a V3-containing HIV-1 gp120 core,” Science, vol. 310, no. 5750, pp. 1025–1028, 2005.
[7]  M. B. Patel, N. G. Hoffman, and R. Swanstrom, “Subtype-specific conformational differences within the V3 region of subtype B and subtype C human immunodeficiency virus type 1 Env proteins,” Journal of Virology, vol. 82, no. 2, pp. 903–916, 2008.
[8]  L. Xiao, S. M. Owen, I. Goldman et al., “CCR5 coreceptor usage of non-syncytium-inducing primary HIV-1 is independent of phylogenetically distinct global HIV-1 isolates: delineation of consensus motif in the V3 domain that predicts CCR-5 usage,” Virology, vol. 240, no. 1, pp. 83–92, 1998.
[9]  T. Shioda, J. A. Levy, and C. Cheng-Mayer, “Macrophage and T cell-line tropisms of HIV-1 are determined by specific regions of the envelope gp120 gene,” Nature, vol. 349, no. 6305, pp. 167–169, 1991.
[10]  S. S. Hwang, T. J. Boyle, H. K. Lyerly, and B. R. Cullen, “Identification of the envelope V3 loop as the primary determinant of cell tropism in HIV-1,” Science, vol. 253, no. 5015, pp. 71–74, 1991.
[11]  R. A. M. Fouchier, M. Groenink, N. A. Kootstra et al., “Phenotype-associated sequence variation in the third variable domain of the human immunodeficiency virus type 1 gp120 molecule,” Journal of Virology, vol. 66, no. 5, pp. 3183–3187, 1992.
[12]  J. J. De Jong, A. De Ronde, W. Keulen, M. Tersmette, and J. Goudsmit, “Minimal requirements for the human immunodeficiency virus type 1 V3 domain to support the syncytium-inducing phenotype: analysis by single amino acid substitution,” Journal of Virology, vol. 66, no. 11, pp. 6777–6780, 1992.
[13]  J. De Jong, F. Simon, G. Van Der Groen et al., “V3 loop sequence analysis of seven HIV type 1 group O isolates phenotyped in peripheral blood mononuclear cells and MT-2 cells,” AIDS Research and Human Retroviruses, vol. 12, no. 16, pp. 1503–1507, 1996.
[14]  T. Cardozo, J. Swetnam, A. Pinter et al., “Worldwide distribution of HIV type 1 epitopes recognized by human anti-V3 monoclonal antibodies,” AIDS Research and Human Retroviruses, vol. 25, no. 4, pp. 441–450, 2009.
[15]  R. L. Stanfield, M. K. Gorny, S. Zolla-Pazner, and I. A. Wilson, “Crystal structures of human immunodeficiency virus type 1 (HIV-1) neutralizing antibody 2219 in complex with three different V3 peptides reveal a new binding mode for HIV-1 cross-reactivity,” Journal of Virology, vol. 80, no. 12, pp. 6093–6105, 2006.
[16]  R. L. Stanfield, M. K. Gorny, C. Williams, S. Zolla-Pazner, and I. A. Wilson, “Structural Rationale for the Broad Neutralization of HIV-1 by Human Monoclonal Antibody 447–52D,” Structure, vol. 12, no. 2, pp. 193–204, 2004.
[17]  C. P. Krachmarov, W. J. Honnen, S. C. Kayman, M. K. Gorny, S. Zolla-Pazner, and A. Pinter, “Factors determining the breadth and potency of neutralization by V3-specific human monoclonal antibodies derived from subjects infected with clade A or clade B strains of human immunodeficiency virus type 1,” Journal of Virology, vol. 80, no. 14, pp. 7127–7135, 2006.
[18]  D. Almond, et al., “Dynamic characterization of the V3 loop crown,” Antiviral Therapy, vol. 12, supplement 2, pp. P13–P31, 2007.
[19]  A. Verma and W. Wenzel, “Conformational landscape of the HIV-V3 hairpin loop from all-atom free-energy simulations,” Journal of Chemical Physics, vol. 128, no. 10, Article ID 105103, 6 pages, 2008.
[20]  D. Almond, T. Kimura, X. Kong, J. Swetnam, S. Zolla-Pazner, and T. Cardozo, “Structural conservation predominates over sequence variability in the crown of HIV type 1's V3 loop,” AIDS Research and Human Retroviruses, vol. 26, no. 6, pp. 717–723, 2010.
[21]  R. Abagyan and M. Totrov, “Biased probability Monte Carlo conformational searches and electrostatic calculations for peptides and proteins,” Journal of Molecular Biology, vol. 235, no. 3, pp. 983–1002, 1994.
[22]  M. Totrov and R. Abagyan, “Rapid boundary element solvation electrostatics calculations in folding simulations: successful folding of a 23-residue peptide,” Biopolymers, vol. 60, no. 2, pp. 124–133, 2001.
[23]  C. P. Krachmarov, S. C. Kayman, W. J. Honnen, O. Trochev, and A. Pinter, “V3-specific polyclonal antibodies affinity purified from sera of infected humans effectively neutralize primary isolates of human immunodeficiency virus type 1,” AIDS Research and Human Retroviruses, vol. 17, no. 18, pp. 1737–1748, 2001.
[24]  R. I. Connor, B. K. Chen, S. Choe, and N. R. Landau, “Vpr is required for efficient replication of human immunodeficiency virus type-1 in mononuclear phagocytes,” Virology, vol. 206, no. 2, pp. 935–944, 1995.
[25]  M. Sharon, N. Kessler, R. Levy, S. Zolla-Pazner, M. G?rlach, and J. Anglister, “Alternative conformations of HIV-1 V3 loops mimic β hairpins in chemokines, suggesting a mechanism for coreceptor selectivity,” Structure, vol. 11, no. 2, pp. 225–236, 2003.
[26]  B. Gaschen, J. Taylor, K. Yusim et al., “Diversity considerations in HIV-1 vaccine selection,” Science, vol. 296, no. 5577, pp. 2354–2360, 2002.
[27]  S. Zolla-Pazner, P. Zhong, K. Revesz et al., “The cross-clade neutralizing activity of a human monoclonal antibody is determined by the GPGR V3 motif of HIV type 1,” AIDS Research and Human Retroviruses, vol. 20, no. 11, pp. 1254–1258, 2004.
[28]  B. F. Haynes, “Case control study of the RV144 trial for immune correlates: the analysis and way forward,” in AIDS Vaccine, Mary Ann Leibert, Bangkok, Thailand, 2011.


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