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. 2015 Sep 9;18(3):354-62.
doi: 10.1016/j.chom.2015.08.006.

Strain-Specific V3 and CD4 Binding Site Autologous HIV-1 Neutralizing Antibodies Select Neutralization-Resistant Viruses

M Anthony Moody  1 , Feng Gao  2 , Thaddeus C Gurley  3 , Joshua D Amos  3 , Amit Kumar  3 , Bhavna Hora  3 , Dawn J Marshall  3 , John F Whitesides  3 , Shi-Mao Xia  3 , Robert Parks  3 , Krissey E Lloyd  3 , Kwan-Ki Hwang  3 , Xiaozhi Lu  3 , Mattia Bonsignori  3 , Andrés Finzi  4 , Nathan A Vandergrift  5 , S Munir Alam  6 , Guido Ferrari  7 , Xiaoying Shen  3 , Georgia D Tomaras  8 , Gift Kamanga  9 , Myron S Cohen  10 , Noel E Sam  11 , Saidi Kapiga  12 , Elin S Gray  13 , Nancy L Tumba  13 , Lynn Morris  14 , Susan Zolla-Pazner  15 , Miroslaw K Gorny  16 , John R Mascola  17 , Beatrice H Hahn  18 , George M Shaw  18 , Joseph G Sodroski  19 , Hua-Xin Liao  5 , David C Montefiori  20 , Peter T Hraber  21 , Bette T Korber  21 , Barton F Haynes  22
Affiliations

Strain-Specific V3 and CD4 Binding Site Autologous HIV-1 Neutralizing Antibodies Select Neutralization-Resistant Viruses

M Anthony Moody et al. Cell Host Microbe. .

Abstract

The third variable (V3) loop and the CD4 binding site (CD4bs) of the HIV-1 envelope are frequently targeted by neutralizing antibodies (nAbs) in infected individuals. In chronic infection, HIV-1 escape mutants repopulate the plasma, and V3 and CD4bs nAbs emerge that can neutralize heterologous tier 1 easy-to-neutralize but not tier 2 difficult-to-neutralize HIV-1 isolates. However, neutralization sensitivity of autologous plasma viruses to this type of nAb response has not been studied. We describe the development and evolution in vivo of antibodies distinguished by their target specificity for V3 and CD4bs epitopes on autologous tier 2 viruses but not on heterologous tier 2 viruses. A surprisingly high fraction of autologous circulating viruses was sensitive to these antibodies. These findings demonstrate a role for V3 and CD4bs antibodies in constraining the native envelope trimer in vivo to a neutralization-resistant phenotype, explaining why HIV-1 transmission generally occurs by tier 2 neutralization-resistant viruses.

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Figures

Figure 1
Figure 1. Clonal lineages derived from CH0457
A: The kite-shaped gate shows a diagonal of gp120ConC core+/+ memory B cells that were sorted as single cells. Antigen-specific cell frequency was similar in both samples; wk 8 shown. B: IgG1 gp120 V3 mAbs (CH14, CH48) were not related to other isolated mAbs. Lineage CH13 had 6 IgG1 mAbs (VH1~69/JH3; VK1~39/JK4); mean heavy chain (HC) mutation frequency = 9.8%. Lineage CH27 had 3 mAbs—2 IgA2 (CH27, CH28) and a IgG1 (CH44) (VH3~66/JH2; VK3~20/JK1); mean HC mutation frequency = 15.7%. Trees plotted on the same scale. C: Residues critical for lineage CH13 and lineage CH27 mAb binding (Tables S2–3) highlighted in the structure of gp120C.YU2 (CD4 light gray, gp120 light blue, mAb 17b not shown). Mapped residues are largely located within the CD4-gp120 contact surface. V1/V2 not shown because it was absent in the crystal structure. D. CH14 and CH48 binding to peptides reflective of multiple HIV-1 clades. Both bound V3 loop peptides (residues 301–325) across multiple clades; no binding found for other epitopes.
Figure 2
Figure 2. Heterologous neutralization by mAbs from CH0457
Neutralization of mAbs against tier 1 and tier 2 viruses from diverse clades shown in colored boxes (EC50). Control (HIVIG-C) and CH0457 serum from wks 8 and 96 shown; serum shown as reciprocal ED50. Lineage CH13 mAbs and non-lineage mAbs (CH14, CH48) potently neutralized tier 1 viruses but only neutralized one tier 2 virus (C.246F_C1G). Lineage CH27 neutralized one tier 1 virus but 23/40 (58%) tier 2 viruses. CH0457 serum from wks 8 and 96 neutralized all tier 1 viruses at >1:20, and 37/40 (93%) and 31/40 (78%) of tier 2 viruses, respectively.
Figure 3
Figure 3. Heterologous neutralization by mAbs from CH505
V3 mAbs DH151 and DH228 from CH505 tested against heterologous HIV isolates. Tier 1 isolates (2/4) neutralized; 0/16 tier 2 isolates neutralized.
Figure 4
Figure 4. Autologous neutralization and Env sequence phylogenies
Neutralization heat map of autologous serum and mAbs shown (AC). Each row in the neutralization panel (A) of 84 CH0457 pseudoviruses and phylogeny tree (B) is a distinct Env isolate spanning wk 0 (enrollment; red) to wk 96 after enrollment (purple). PBMC provirus sequences are grey. Autologous serum neutralization (reciprocal dilution) and isolated mAbs (µg/mL) shown for (A) lineage CH13 mAbs (tier 1 CD4bs), lineage CH27 mAbs (tier 2 CD4bs), and CH14 and CH48 (tier 1 V3); and (C) CH505 mAbs DH151 and DH228 (tier 1 V3) and lineage CH103 (tier 2 CD4bs). (D) CH505 Env phylogeny spans transmission (wk 0, red) through wk 100 (purple). A high fraction of circulating viruses were sensitive to autologous mAbs.
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