Neutralizing Antibody Escape during HIV-1 Mother-to-Child Transmission Involves Conformational Masking of Distal Epitopes in Envelope

HIV-1 variants transmitted to infants are often resistant to maternal neutralizing antibodies (NAbs), suggesting that they have escaped maternal NAb pressure. To define the molecular basis of NAb escape that contributes to selection of transmitted variants, we analyzed 5 viruses from 2 mother-to-child transmission pairs, in which the infant virus, but not the maternal virus, was resistant to neutralization by maternal plasma near transmission. We generated chimeric viruses between maternal and infant envelope clones obtained near transmission and examined neutralization by maternal plasma. The molecular determinants of NAb escape were distinct, even when comparing two maternal variants to the transmitted infant virus within one pair, in which insertions in V4 of gp120 and substitutions in HR2 of gp41 conferred neutralization resistance. In another pair, deletions and substitutions in V1 to V3 conferred resistance, but neither V1/V2 nor V3 alone was sufficient. Although the sequence determinants of escape were distinct, all of them involved modifications of potential N-linked glycosylation sites. None of the regions that mediated escape were major linear targets of maternal NAbs because corresponding peptides failed to compete for neutralization. Instead, these regions disrupted multiple distal epitopes targeted by HIV-1-specific monoclonal antibodies, suggesting that escape from maternal NAbs occurred through conformational masking of distal epitopes. This strategy likely allows HIV-1 to utilize relatively limited changes in the envelope to preserve the ability to infect a new host while simultaneously evading multiple NAb specificities present in maternal plasma.

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Neutralizing antibodies and viral characteristics in mother-to-child transmission of HIV-1

AIDS ◽

10.1097/00002030-199311002-00010 ◽

1993 ◽

Vol 7 ◽

pp. S45-48 ◽

Cited By ~ 37

Author(s):

Gabriella Scarlatti ◽

Thomas Leitner ◽

Vida Hodara ◽

Eva Halapi ◽

Paolo Rossi ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Mother To Child Transmission ◽

Child Transmission ◽

Mother To Child ◽

Hiv 1

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Revisiting the Role of Neutralizing Antibodies in Mother-to-Child Transmission of HIV-1

Yearbook of Obstetrics Gynecology and Women s Health ◽

10.1016/s1090-798x(08)70067-5 ◽

2007 ◽

Vol 2007 ◽

pp. 89-90

Author(s):

J.S. Dungan

Keyword(s):

Neutralizing Antibodies ◽

Mother To Child Transmission ◽

Child Transmission ◽

Mother To Child ◽

Hiv 1

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Revisiting the Role of Neutralizing Antibodies in Mother‐to‐Child Transmission of HIV‐1

The Journal of Infectious Diseases ◽

10.1086/503778 ◽

2006 ◽

Vol 193 (11) ◽

pp. 1504-1511 ◽

Cited By ~ 39

Author(s):

Francis Barin ◽

Gonzague Jourdain ◽

Sylvie Brunet ◽

Nicole Ngo‐Giang‐Huong ◽

Supawadee Weerawatgoompa ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Mother To Child Transmission ◽

Child Transmission ◽

Mother To Child ◽

Hiv 1

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The role of neutralizing antibodies in prevention of HIV-1 infection: what can we learn from the mother-to-child transmission context?

Retrovirology ◽

10.1186/1742-4690-10-103 ◽

2013 ◽

Vol 10 (1) ◽

Cited By ~ 21

Author(s):

Martine Braibant ◽

Francis Barin

Keyword(s):

Neutralizing Antibodies ◽

Mother To Child Transmission ◽

Child Transmission ◽

Mother To Child ◽

Hiv 1 ◽

Prevention Of Hiv

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Coadministration of CH31 Broadly Neutralizing Antibody Does Not Affect Development of Vaccine-Induced Anti-HIV-1 Envelope Antibody Responses in Infant Rhesus Macaques

Journal of Virology ◽

10.1128/jvi.01783-18 ◽

2018 ◽

Vol 93 (5) ◽

Cited By ~ 6

Author(s):

Maria Dennis ◽

Joshua Eudailey ◽

Justin Pollara ◽

Arthur S. McMillan ◽

Kenneth D. Cronin ◽

...

Keyword(s):

De Novo ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Mother To Child Transmission ◽

Child Transmission ◽

Broadly Neutralizing Antibody ◽

Env Protein ◽

The Impact ◽

Mother To Child ◽

Hiv 1

ABSTRACT Prevention of mother-to-child transmission (MTCT) is an indispensable component in combatting the global AIDS epidemic. A combination of passive broadly neutralizing antibody (bnAb) infusion and active vaccination promises to provide protection of infants against MTCT from birth through the breastfeeding period and could prime the immune system for lifelong immunity. In this study, we investigate the impact of a single infusion of CD4 binding site (CD4bs) bnAb administered at birth on de novo antibody responses elicited by concurrent active HIV envelope vaccination. Four groups of infant macaques received active immunizations with subunit Env protein or modified vaccinia Ankara (MVA)-vectored Env and subunit Env protein, with or without a single intravenous coadministration of CH31 bnAb at birth. Vaccinated animals were monitored to evaluate binding and functional antibody responses elicited by the active vaccinations. Despite achieving plasma concentrations that were able to neutralize tier 2 viruses, coadministration of CH31 did not have a large impact on the kinetics, magnitude, specificity, or avidity of vaccine-elicited binding or functional antibody responses, including epitope specificity, the development of CD4bs antibodies, neutralization, binding to infected cells, or antibody-dependent cell-mediated cytotoxicity (ADCC). We conclude that infusion of CD4bs bnAb CH31 at birth does not interfere with de novo antibody responses to active vaccination and that a combination of passive bnAb infusion and active HIV-1 Env vaccination is a viable strategy for immediate and prolonged protection against MTCT. IMPORTANCE Our study is the first to evaluate the impact of passive infusion of a broadly neutralizing antibody in newborns on the de novo development of antibody responses following active vaccinations in infancy. We demonstrated the safety and the feasibility of bnAb administration to achieve biologically relevant levels of the antibody and showed that the passive infusion did not impair the de novo antibody production following HIV-1 Env vaccination. Our study paves the way for further investigations of the combination strategy using passive plus active immunization to provide protection of infants born to HIV-1-positive mothers over the entire period of risk for mother-to-child transmission.

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Induction of Neutralizing Responses against Autologous Virus in Maternal HIV Vaccine Trials

mSphere ◽

10.1128/msphere.00254-20 ◽

2020 ◽

Vol 5 (3) ◽

Author(s):

Eliza D. Hompe ◽

Jesse F. Mangold ◽

Amit Kumar ◽

Joshua A. Eudailey ◽

Erin McGuire ◽

...

Keyword(s):

Pregnant Women ◽

Neutralizing Antibody ◽

Maternal Plasma ◽

Hiv Vaccine ◽

Antibody Responses ◽

Virus Neutralization ◽

Mother To Child Transmission ◽

Child Transmission ◽

Maternal Hiv ◽

Mother To Child

ABSTRACT A maternal vaccine capable of boosting neutralizing antibody (NAb) responses directed against circulating viruses in HIV-infected pregnant women could effectively decrease mother-to-child transmission of HIV. However, it is not known if an HIV envelope (Env) vaccine administered to infected pregnant women could enhance autologous virus neutralization and thereby reduce this risk of vertical HIV transmission. Here, we assessed autologous virus NAb responses in maternal plasma samples obtained from AIDS Vaccine Evaluation Group (AVEG) protocols 104 and 102, representing historical phase I safety and immunogenicity trials of recombinant HIV Env subunit vaccines administered to HIV-infected pregnant women (ClinicalTrials registration no. NCT00001041). Maternal HIV Env-specific plasma binding and neutralizing antibody responses were characterized before and after vaccination in 15 AVEG 104 (n = 10 vaccine recipients, n = 5 placebo recipients) and 2 AVEG 102 (n = 1 vaccine recipient, n = 1 placebo recipient) participants. Single-genome amplification (SGA) was used to obtain HIV env gene sequences of autologous maternal viruses for pseudovirus production and neutralization sensitivity testing in pre- and postvaccination plasma of HIV-infected pregnant vaccine recipients (n = 6 gp120, n = 1 gp160) and placebo recipients (n = 3). We detected an increase in Env subunit MN gp120-specific IgG binding in the group of vaccine recipients between the first immunization visit and the last visit at delivery (P = 0.027, 2-sided Wilcoxon test). While no difference was observed in the levels of autologous virus neutralization potency between groups, in both groups maternal plasma collected at delivery more effectively neutralized autologous viruses from early pregnancy than late pregnancy. Immunization strategies capable of further enhancing these autologous virus NAb responses in pregnant women will be important to block vertical transmission of HIV. IMPORTANCE Maternal antiretroviral therapy (ART) has effectively reduced but not eliminated the burden of mother-to-child transmission of HIV across the globe, as an estimated 160,000 children were newly infected with HIV in 2018. Thus, additional preventive strategies beyond ART will be required to close the remaining gap and end the pediatric HIV epidemic. A maternal active immunization strategy that synergizes with maternal ART could further reduce infant HIV infections. In this study, we found that two historic HIV Env vaccines did not enhance the ability of HIV-infected pregnant women to neutralize autologous viruses. Therefore, next-generation maternal HIV vaccine candidates must employ alternate approaches to achieve potent neutralizing antibody and perhaps nonneutralizing antibody responses to effectively impede vertical virus transmission. Moreover, these approaches must reflect the broad diversity of HIV strains and widespread availability of ART worldwide.

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