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. 2020 Mar 10;11(2):e00176-20.
doi: 10.1128/mBio.00176-20.

Maternal Broadly Neutralizing Antibodies Can Select for Neutralization-Resistant, Infant-Transmitted/Founder HIV Variants

David R Martinez #  1   2 , Joshua J Tu #  2 , Amit Kumar  2 , Jesse F Mangold  2 , Riley J Mangan  2 , Ria Goswami  2 , Elena E Giorgi  3 , Juilin Chen  1   2 , Michael Mengual  4 , Ayooluwa O Douglas  2 , Holly Heimsath  2 , Kevin O Saunders  2   5 , Nathan I Nicely  2 , Joshua Eudailey  2 , Giovanna Hernandez  2 , Papa Kwadwo Morgan-Asiedu  2 , Kevin Wiehe  2 , Barton F Haynes  2   4 , M Anthony Moody  2   6 , Celia LaBranche  5 , David C Montefiori  2   5 , Feng Gao #  4 , Sallie R Permar #  7   2   6
Affiliations

Maternal Broadly Neutralizing Antibodies Can Select for Neutralization-Resistant, Infant-Transmitted/Founder HIV Variants

David R Martinez et al. mBio. .

Abstract

Each year, >180,000 infants become infected via mother-to-child transmission (MTCT) of HIV despite the availability of effective maternal antiretroviral treatments, underlining the need for a maternal HIV vaccine. We characterized 224 maternal HIV envelope (Env)-specific IgG monoclonal antibodies (MAbs) from seven nontransmitting and transmitting HIV-infected U.S. and Malawian mothers and examined their neutralization activities against nontransmitted autologous circulating viruses and infant-transmitted founder (infant-T/F) viruses. Only a small subset of maternal viruses, 3 of 72 (4%), were weakly neutralized by maternal linear V3 epitope-specific IgG MAbs, whereas 6 out of 6 (100%) infant-T/F viruses were neutralization resistant to these V3-specific IgG MAbs. We also show that maternal-plasma broadly neutralizing antibody (bNAb) responses targeting the V3 glycan supersite in a transmitting woman may have selected for an N332 V3 glycan neutralization-resistant infant-T/F virus. These data have important implications for bNAb-eliciting vaccines and passively administered bNAbs in the setting of MTCT.IMPORTANCE Efforts to eliminate MTCT of HIV with antiretroviral therapy (ART) have met little success, with >180,000 infant infections each year worldwide. It is therefore likely that additional immunologic strategies that can synergize with ART will be required to eliminate MTCT of HIV. To this end, understanding the role of maternal HIV Env-specific IgG antibodies in the setting of MTCT is crucial. In this study, we found that maternal-plasma broadly neutralizing antibody (bNAb) responses can select for T/F viruses that initiate infection in infants. We propose that clinical trials testing the efficacy of single bNAb specificities should not include HIV-infected pregnant women, as a single bNAb might select for neutralization-resistant infant-T/F viruses.

Keywords: HIV; MTCT; antibody; bNAbs; infant-T/F virus; mother-to-child transmission; neutralization; vertical transmission; virus.

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Figures

FIG 1
FIG 1
Immunogenetic characteristics of Env-specific IgG MAbs isolated from HIV-infected U.S. and Malawian women. (A and B) VH gene usage of Env-specific IgG MAbs isolated from nontransmitting and transmitting women. (C) VH somatic hypermutation frequency of HIV Env-specific IgG MAbs isolated from nontransmitting (blue) (NT) and transmitting (red) (T) women. n.s., differences were not statistically significant. (D) VH somatic hypermutation frequency of gp120, V1V2, V3, and CD4 binding site-specific IgG MAbs. VH somatic hypermutation frequencies were statistically significantly different across different epitope specificities (ANOVA P = 0.014). (E) HCDR3 amino acid length of Env-specific IgG MAbs. The P value in panel D compares the VH somatic hypermutation frequency of V1V2 to those of V3, the CD4 binding site, and gp120-specific IgG MAbs in both nontransmitting and transmitting women.
FIG 2
FIG 2
Neutralization of HIV clade B and clade C tier 1a viruses by maternal-Env-specific IgG MAbs produced by large scale. (A and B) HIV Env-specific IgG MAbs isolated from nontransmitting (blue) and transmitting (red) women against SF162.LS, MN.3, and MW965.
FIG 3
FIG 3
The breadth and specificity of plasma neutralizing responses in nontransmitting and transmitting HIV-infected women. (A) Plasma neutralizing antibody responses against the nine-virus global panel in nontransmitting (blue) and transmitting (red) women. (B) Mapping of plasma broadly neutralizing responses in nontransmitting and transmitting HIV-infected women with broad neutralization against V2 glycan, V3 glycan, and CD4bs mutant viruses that knocked out bNAb activity. (C) Neutralization activity of transmitting HIV-infected woman 9105 against the wild-type BJOX2000, BJOX2000 N332A mutant, wild-type TRO.11, and TRO.11 N332A mutant viruses. PTID, patient identifier; WT and wt, wild type.
FIG 4
FIG 4
Neutralization sensitivity of circulating nontransmitted maternal viruses and infant-T/F viruses to broadly neutralizing antibodies. (A) Neutralization sensitivity to VRC01 CD4bs-specific IgG bNAb, DH512 MPER-specific IgG bNAb, PG9 V2 glycan-specific IgG bNAb, and PGT128 V3 glycan-specific IgG bNAb. (B) Differential neutralization sensitivities of infant-T/F and maternal circulating Env variants to PG16 and PGT45 V2 glycan-targeting bNAbs. (C) Differential neutralization sensitivities of infant-T/F and maternal circulating Env variants to PGT121, 10-1074, and DH270 V3 glycan-specific IgG bNAbs. Maternal Env variants from transmitting women are shown in the red font, and infant-T/F viruses are in the black font. The variants that are closest to the most genetically distinct maternal variants are arranged top to bottom with respect to their paired infant-T/F viruses.
FIG 5
FIG 5
Maternal N332 glycan-targeting memory B cells and infant-T/F virus V3 glycan genetic signatures in mother-infant pair 9105. (A) N332 V3 glycan-specific peripheral blood memory B cells as defined by CD19+ IgD– and CD38 all are shown by the red gate. (B) OD binding of N332 glycan-targeting monoclonal antibody H691380 isolated from woman 9105 against the Man9-V3 peptide. The dashed lined denotes the positivity cutoff. (C) V3 loop amino acid residues in woman 9105 nontransmitted maternal Env variants and infant-T/F virus 9112. Maternal Env amplicons from transmitting women are shown in the red font, and the infant-T/F virus is in the black font.
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