Impact of amino acid substitutions in the V2 and C2 regions of human immunodeficiency virus type 1 CRF01_AE envelope glycoprotein gp120 on viral neutralization susceptibility to broadly neutralizing antibodies specific for the CD4 binding site

Retrovirology

Masanori Kameoka³  Naokazu Takeda³  Kazuyoshi Ikuta³  Kenzo Tokunaga⁴  Panasda Isarangkura-na-ayuthaya¹  Piraporn Utachee² 

[1] National Institute of Health, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand;Thailand-Japan Research Collaboration Center on Emerging and Re-emerging Infections (RCC-ERI), Nonthaburi, Thailand;Department of International Health, Kobe University Graduate School of Health Sciences, Hyogo, Japan;Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan

关键词: Neutralizing antibody;    VRC01;    IgG1 b12;    gp120;    Envelope glycoprotein;    CRF01_AE;    Human immunodeficiency virus type 1;   

Others  :  802015
DOI  :  10.1186/1742-4690-11-32

 received in 2014-01-09, accepted in 2014-04-09,  发布年份 2014

【 摘 要 】

Background

The CD4 binding site (CD4bs) of envelope glycoprotein (Env) gp120 is a functionally conserved, important target of anti-human immunodeficiency virus type 1 (HIV-1) neutralizing antibodies. Two neutralizing human monoclonal antibodies, IgG1 b12 (b12) and VRC01, are broadly reactive neutralizing antibodies which recognize conformational epitopes that overlap the CD4bs of Env gp120; however, many CRF01_AE viruses are resistant to neutralization mediated by these antibodies. We examined the mechanism underlying the b12 resistance of the viruses using CRF01_AE Env (AE-Env)-recombinant viruses in this study.

Results

Our results showed that an amino acid substitution at position 185 in the V2 region of gp120 played a crucial role in regulating the b12 susceptibility of AE-Env-recombinant viruses by cooperating with 2 previously reported potential N-linked glycosylation (PNLG) sites at positions 186 (N186) and 197 (N197) in the V2 and C2 regions of Env gp120. The amino acid residue at position 185 and 2 PNLG sites were responsible for the b12 resistance of 21 of 23 (>91%) AE-Env clones tested. Namely, the introduction of aspartic acid at position 185 (D185) conferred b12 susceptibility of 12 resistant AE-Env clones in the absence of N186 and/or N197, while the introduction of glycine at position 185 (G185) reduced the b12 susceptibility of 9 susceptible AE-Env clones in the absence of N186 and/or N197. In addition, these amino acid mutations altered the VRC01 susceptibility of many AE-Env clones.

Conclusions

We propose that the V2 and C2 regions of AE-Env gp120 contain the major determinants of viral resistance to CD4bs antibodies. CRF01_AE is a major circulating recombinant form of HIV-1 prevalent in Southeast Asia. Our data may provide important information to understand the molecular mechanism regulating the neutralization susceptibility of CRF01_AE viruses to CD4bs antibodies.

【 授权许可】

   
2014 Utachee et al.; licensee BioMed Central Ltd.

【 图 表 】

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