Diversity and function of maternal HIV-1-specific antibodies at the time of vertical transmission

Abstract

20 21 # Corresponding author: Julie Overbaugh, joverbau@fredhutch.org 22 23 Word count (abstract): 249 24 Word count (text): 6137 25 Abstract 26Infants of HIV positive mothers can acquire HIV infection by various routes, but even in 27 the absence of antiviral treatment, the majority of these infants do not become infected. There is 28 evidence that maternal antibodies may provide some protection from infection, but gestational 29 maternal antibodies have not yet been characterized in detail. One of the most studied 30 vertically-infected infants is BG505, as the virus from this infant yielded an Envelope protein that 31 was successfully developed as a stable trimer. Here, we isolated and characterized 39 HIV-32 specific neutralizing monoclonal antibodies (nAbs) from MG505, the mother of BG505, at a time 33 point just prior to vertical transmission. These nAbs belonged to 21 clonal families, employed a 34 variety of VH genes, many were specific for the HIV-1 Env V3 loop, and this V3 specificity 35 correlated with measurable antibody-dependent cellular cytotoxicity (ADCC) activity. The 36 isolated nAbs did not recapitulate the full breadth of heterologous nor autologous virus 37 neutralization by contemporaneous plasma. Notably, we found that the V3-targeting nAb 38 families neutralized one particular maternal Env variant even though all tested variants had low 39 V3 sequence diversity and were measurably bound by these nAbs. None of the nAbs 40 neutralized the BG505 transmitted virus. Furthermore, the MG505 nAb families were found at 41 relatively low frequencies within the maternal B cell repertoire: all less than 0.25% of total IgG 42 sequences. Our findings demonstrate the diversity of HIV-1 nAbs that exist within a single 43 mother, resulting in a collection of antibody specificities that can shape the transmission 44 bottleneck. 46Importance 47 Mother-to-child-transmission of HIV-1 offers a unique setting in which maternal 48 antibodies both within the mother and passively-transferred to the infant are present at the time 49 of viral exposure. Untreated HIV-exposed human infants are infected at a rate of 30-40%, 50 meaning that some infants do not get infected despite continued exposure to virus. Since the 51 potential of HIV-specific immune responses to provide protection against HIV is a central goal of 52 HIV vaccine design, understanding the nature of maternal antibodies may provide insights into 53 immune mechanisms of protection. In this study, we isolated and characterized HIV-specific 54 antibodies from the mother of an infant whose transmitted virus has been well studied. 55 56 negative at birth but was detected positive at 6 weeks of life, having been infected by a single 91 transmitted variant from mother MG505 (1). At the time of transmission, MG505 had already 92 developed a relatively broad nAb response (22). While the infant was ultimately not protected 93 from the particular transmitted virus that seeded the infection, BG505 did not acquire a myriad 94 of other maternal variants that coexiste...