Mutations that confer resistance to broadly-neutralizing antibodies define HIV-1 variants of transmitting mothers from that of non-transmitting mothers

Kumar, Amit; Giorgi, Elena E.; Tu, Joshua J.; Martinez, David R.; Eudailey, Joshua; Mengual, Michael; Honnayakanahalli Marichannegowda, Manukumar; Van Dyke, Russell; Gao, Feng; Permar, Sallie R.

doi:10.1371/journal.ppat.1009478

Mutations that confer resistance to broadly-neutralizing antibodies define HIV-1 variants of transmitting mothers from that of non-transmitting mothers

Journal Article · Fri Apr 02 04:00:00 EDT 2021 · PLoS Pathogens

DOI:https://doi.org/10.1371/journal.ppat.1009478· OSTI ID:1804370

Kumar, Amit ^[1]; ^[2]; ^[1]; Martinez, David R. ^[3]; ^[1]; Mengual, Michael ^[4]; ^[5]; Van Dyke, Russell ^[6]; ^[7]; ^[8]

Duke Univ., Durham, NC (United States). Medical Center
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Duke Univ., Durham, NC (United States). Medical Center; Univ. of North Carolina, Chapel Hill, NC (United States)
Duke Univ., Durham, NC (United States). Medical Center; Univ. of California, Los Angeles, CA (United States)
Duke Univ., Durham, NC (United States). Medical Center; Univ. of Maryland, College Park, MD (United States)
Tulane Univ., New Orleans, LA (United States)
Duke Univ., Durham, NC (United States). Medical Center; Jinan Univ., Guangzhou, Guangdong (China)
Duke Univ., Durham, NC (United States). Medical Center; Cornell Univ., Ithaca, NY (United States). Weill Medical College

Despite considerable reduction of mother-to-child transmission (MTCT) of HIV through use of maternal and infant antiretroviral therapy (ART), over 150,000 infants continue to become infected with HIV annually, falling far short of the World Health Organization goal of reaching <20,000 annual pediatric HIV cases worldwide by 2020. Prior to the widespread use of ART in the setting of pregnancy, over half of infants born to HIV-infected mothers were protected against HIV acquisition. Yet, the role of maternal immune factors in this protection against vertical transmission is still unclear, hampering the development of synergistic strategies to further reduce MTCT. It has been established that infant transmitted/founder (T/F) viruses are often resistant to maternal plasma, yet it is unknown if the neutralization resistance profile of circulating viruses predicts the maternal risk of transmission to her infant. In this study, we amplified HIV-1 envelope genes (env) by single genome amplification and produced representative Env variants from plasma of 19 non-transmitting mothers from the U.S. Women Infant Transmission Study (WITS), enrolled in the pre-ART era. Maternal HIV Env variants from non-transmitting mothers had similar sensitivity to autologous plasma as observed for non-transmitting variants from transmitting mothers. In contrast, infant variants were on average 30% less sensitive to paired plasma neutralization compared to non-transmitted maternal variants from both transmitting and non-transmitting mothers (p = 0.015). Importantly, a signature sequence analysis revealed that motifs enriched in env sequences from transmitting mothers were associated with broadly neutralizing antibody (bnAb) resistance. Altogether, our findings suggest that circulating maternal virus resistance to bnAb-mediated neutralization, but not autologous plasma neutralization, near the time of delivery, predicts increased MTCT risk. These results caution that enhancement of maternal plasma neutralization through passive or active vaccination during pregnancy may potentially drive the evolution of variants fit for vertical transmission.

View Accepted Manuscript (DOE)

Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE National Nuclear Security Administration (NNSA); National Institutes of Health (NIH)

Grant/Contract Number:: 89233218CNA000001

OSTI ID:: 1804370

Report Number(s):: LA-UR--21-20584

Journal Information:: PLoS Pathogens, Journal Name: PLoS Pathogens Journal Issue: 4 Vol. 17; ISSN 1553-7374

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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