Sub-Inhibitory Concentrations of Human α-defensin Potentiate Neutralizing Antibodies against HIV-1 gp41 Pre-Hairpin Intermediates in the Presence of Serum

被引:21
作者
Demirkhanyan, Lusine [1 ]
Marin, Mariana [1 ]
Lu, Wuyuan [2 ,3 ]
Melikyan, Gregory B. [1 ,4 ]
机构
[1] Emory Univ, Childrens Ctr, Div Pediat Infect Dis, Atlanta, GA 30322 USA
[2] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA
[3] Univ Maryland, Sch Med, Dept Biochem, Baltimore, MD 21201 USA
[4] Childrens Healthcare Atlanta, Atlanta, GA USA
关键词
HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODIES; GLYCOPROTEIN-MEDIATED FUSION; PROXIMAL EXTERNAL REGION; 6-HELIX BUNDLE FORMATION; N-TRIMER REGION; ENVELOPE GLYCOPROTEIN; CONFORMATIONAL-CHANGES; SMALL-MOLECULE; TYPE-1; ENTRY;
D O I
10.1371/journal.ppat.1003431
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Human defensins are at the forefront of the host responses to HIV and other pathogens in mucosal tissues. However, their ability to inactivate HIV in the bloodstream has been questioned due to the antagonistic effect of serum. In this study, we have examined the effect of sub-inhibitory concentrations of human alpha-defensin HNP-1 on the kinetics of early steps of fusion between HIV-1 and target cells in the presence of serum. Direct measurements of HIV-cell fusion using an enzymatic assay revealed that, in spite of the modest effect on the extent of fusion, HNP-1 prolonged the exposure of functionally important transitional epitopes of HIV-1 gp41 on the cell surface. The increased lifetime of gp41 intermediates in the presence of defensin was caused by a delay in the post-coreceptor binding steps of HIV-1 entry that correlated with the marked enhancement of the virus' sensitivity to neutralizing anti-gp41 antibodies. By contrast, the activity of antibodies to gp120 was not affected. HNP-1 appeared to specifically potentiate antibodies and peptides targeting the first heptad repeat domain of gp41, while its effect on inhibitors and antibodies to other gp41 domains was less prominent. Sub-inhibitory concentrations of HNP-1 also promoted inhibition of HIV-1 entry into peripheral blood mononuclear cells by antibodies and, more importantly, by HIV-1 immune serum. Our findings demonstrate that: (i) sub-inhibitory doses of HNP-1 potently enhance the activity of a number of anti-gp41 antibodies and peptide inhibitors, apparently by prolonging the lifetime of gp41 intermediates; and (ii) the efficiency of HIV-1 fusion inhibitors and neutralizing antibodies is kinetically restricted. This study thus reveals an important role of alpha-defensin in enhancing adaptive immune responses to HIV-1 infection and suggests future strategies to augment these responses.
引用
收藏
页数:15
相关论文
共 86 条
[1]   The cytoplasmic tail slows the folding of human immunodeficiency virus type 1 Env from a late prebundle configuration into the six-helix bundle [J].
Abrahamyan, LG ;
Mkrtchyan, SR ;
Binley, J ;
Lu, M ;
Melikyan, GB ;
Cohen, FS .
JOURNAL OF VIROLOGY, 2005, 79 (01) :106-115
[2]   Human immunodeficiency virus type 1 gp41 antibodies that mask membrane proximal region epitopes: Antibody binding kinetics, induction, and potential for regulation in acute infection [J].
Alam, S. Munir ;
Scearce, Richard M. ;
Parks, Robert J. ;
Plonk, Kelly ;
Plonk, Steven G. ;
Sutherland, Laura L. ;
Gorny, Miroslaw K. ;
Zolla-Pazner, Susan ;
VanLeeuwen, Stacie ;
Moody, M. Anthony ;
Xia, Shi-Mao ;
Montefiori, David C. ;
Tomaras, Georgia D. ;
Weinhold, Kent J. ;
Karim, Salim Abdool ;
Hicks, Charles B. ;
Liao, Hua-Xin ;
Robinson, James ;
Shaw, George M. ;
Haynes, Barton F. .
JOURNAL OF VIROLOGY, 2008, 82 (01) :115-125
[3]   A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity [J].
Baba, M ;
Nishimura, O ;
Kanzaki, N ;
Okamoto, M ;
Sawada, H ;
Iizawa, Y ;
Shiraishi, M ;
Aramaki, Y ;
Okonogi, K ;
Ogawa, Y ;
Meguro, K ;
Fujino, M .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (10) :5698-5703
[4]   Chemokine receptors as HIV-1 coreceptors: Roles in viral entry, tropism, and disease [J].
Berger, EA ;
Murphy, PM ;
Farber, JM .
ANNUAL REVIEW OF IMMUNOLOGY, 1999, 17 :657-700
[5]   Design of a novel peptide inhibitor of HIV fusion that disrupts the internal trimeric coiled-coil of gp41 [J].
Bewley, CA ;
Louis, JM ;
Ghirlando, R ;
Clore, GM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (16) :14238-14245
[6]   HIV Entry and Envelope Glycoprotein-mediated Fusion [J].
Blumenthal, Robert ;
Durell, Stewart ;
Viard, Mathias .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2012, 287 (49) :40841-40849
[7]   GENERATION OF HUMAN MONOCLONAL-ANTIBODIES AGAINST HIV-1 PROTEINS - ELECTROFUSION AND EPSTEIN-BARR-VIRUS TRANSFORMATION FOR PERIPHERAL-BLOOD LYMPHOCYTE IMMORTALIZATION [J].
BUCHACHER, A ;
PREDL, R ;
STRUTZENBERGER, K ;
STEINFELLNER, W ;
TRKOLA, A ;
PURTSCHER, M ;
GRUBER, G ;
TAUER, C ;
STEINDL, F ;
JUNGBAUER, A ;
KATINGER, H .
AIDS RESEARCH AND HUMAN RETROVIRUSES, 1994, 10 (04) :359-369
[8]   Direct Antibody Access to the HIV-1 Membrane-Proximal External Region Positively Correlates with Neutralization Sensitivity [J].
Chakrabarti, B. K. ;
Walker, L. M. ;
Guenaga, J. F. ;
Ghobbeh, A. ;
Poignard, P. ;
Burton, D. R. ;
Wyatt, R. T. .
JOURNAL OF VIROLOGY, 2011, 85 (16) :8217-8226
[9]   Dual role of α-defensin-1 in anti-HIV-1 innate immunity [J].
Chang, TL ;
Vargas, J ;
DelPortillo, A ;
Klotman, ME .
JOURNAL OF CLINICAL INVESTIGATION, 2005, 115 (03) :765-773
[10]   Human domain antibodies to conserved sterically restricted regions on gp120 as exceptionally potent cross-reactive HIV-1 neutralizers [J].
Chen, Weizao ;
Zhu, Zhongyu ;
Feng, Yang ;
Dimitrov, Dimiter S. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (44) :17121-17126