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

Although a major goal of human immunodeficiency virus type 1 (HIV-1) vaccine efforts is to elicit broad and potent neutralizing antibodies (NAbs), there are no data that directly demonstrate a role for such NAbs in protection from HIV-1 infection in exposed humans. The setting of mother-to-child transmission provides an opportunity to examine whether NAbs provide protection from HIV-1 infection because infants acquire passive antibodies from their mothers prior to exposure to HIV-1 through breastfeeding. We evaluated the characteristics of HIV-1-specific NAbs in 100 breast-fed infants of HIV-1-positive mothers who were HIV-1 negative at birth and monitored them until age 2. A panel of eight viruses that included variants representative of those in the study region as well as more diverse strains was used to determine the breadth of the infant NAbs. From their mothers, infants acquired broad and potent NAbs that were capable of recognizing heterologous circulating HIV-1 variants of diverse subtypes, but the presence of NAbs of broad HIV-1 specificity was not associated with transmission risk. There was also no correlation between responses to any particular virus tested, which included a range of diverse variants that demonstrated different neutralization profiles, including recognition by specific antibodies with known epitope targets. The eight viruses tested exhibited neutralization profiles to a variety of monoclonal antibodies (2F5, PG9, and VRC01) similar to those of viruses present in pregnant women in the cohort. These results suggest that the breadth and potency of the heterologous antibody response in exposed infants, measured against a virus panel comprised of variants typical of those circulating in the population, does not predict protection.

mentioning

confidence: 77%

The Breadth and Potency of Passively Acquired Human Immunodeficiency Virus Type 1-Specific Neutralizing Antibodies Do Not Correlate with the Risk of Infant Infection

Lynch

Nduati

Blish

et al. 2011

“…One study suggested HIV-1C viruses newly transmitted from mother-to-child were more fit, had significantly fewer PNG sites, and were more resistant to autologous maternal serum than nontransmitted viruses (60). For studies that analyzed vertical transmission stratified by timing, viral populations have been reported to have different properties if transmitted in utero (IU) or intrapartum (IP) (3,11,30).…”

Section: Subtype C Human Immunodeficiency Virus Type 1 (Hiv-1c) Contimentioning

confidence: 99%

“…Animal studies have demonstrated that neutralizing antibodies elicited by a simian immunodeficiency virus (SIV) vaccine can at least slow disease progression (56), while direct administration of antibodies matched to the chal-lenge virus can block transmission (16,44). Studies of natural MCTC have yielded conflicting results (2,3,7,20,26,31,32,48), although possibly for identifiable reasons. The breadth of the neutralizing antibody response may depend on the subtype of HIV-1 being studied (5,10), and neutralizing antibody levels may be associated with the timing of transmission (3).…”

Section: Subtype C Human Immunodeficiency Virus Type 1 (Hiv-1c) Contimentioning

confidence: 99%

“…Studies of natural MCTC have yielded conflicting results (2,3,7,20,26,31,32,48), although possibly for identifiable reasons. The breadth of the neutralizing antibody response may depend on the subtype of HIV-1 being studied (5,10), and neutralizing antibody levels may be associated with the timing of transmission (3). A comprehensive picture of the effect of neutralizing antibodies on MTCT is difficult to obtain because of small sample sizes and different subtypes and methods involved in the reports.…”

Section: Subtype C Human Immunodeficiency Virus Type 1 (Hiv-1c) Contimentioning

confidence: 99%

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The Genetic Bottleneck in Vertical Transmission of Subtype C HIV-1 Is Not Driven by Selection of Especially Neutralization-Resistant Virus from the Maternal Viral Population

Russell¹,

Kwiek

Keys

et al. 2011

Subtype C human immunodeficiency virus type 1 (HIV-1C) continues to cause the majority of new cases of mother-to-child transmission (MTCT), and yet there are limited data on HIV-1C transmission. We amplified env from plasma RNA for 19 HIV-1C MTCT pairs, 10 transmitting in utero (IU) and 9 transmitting intrapartum (IP). There was a strong genetic bottleneck between all mother-infant pairs, with a majority of transmission events involving the transmission of a single virus. env genes of viruses transmitted to infants IP, but not IU, encoded Env proteins that were shorter and had fewer putative N-linked glycosylation sites in the V1-V5 region than matched maternal sequences. Viruses pseudotyped with env clones representative of each maternal and infant population were tested for neutralization sensitivity. The 50% inhibitory concentration of autologous serum was similar against both transmitted (infant) and nontransmitted (maternal) viruses in a paired analysis. Mother and infant Env proteins were also similar in sensitivity to soluble CD4, to a panel of monoclonal antibodies, and to heterologous HIV-1C sera. In addition, there was no difference in the breadth or potency of neutralizing antibodies between sera from 50 nontransmitting and 23 IU and 23 IP transmitting HIV-1C-infected women against four Env proteins from heterologous viruses. Thus, while a strong genetic bottleneck was detected during MCTC, with viruses of shorter and fewer glycosylation sites in env present in IP transmission, our data do not support this bottleneck being driven by selective resistance to antibodies.

“…The sub-Saharan region hosts the core of the pediatric HIV epidemic (46) mostly due to the transmission of subtype C strains, accounting for roughly 50% of all infections worldwide (19). Remarkably, it has been estimated that 60 to 80% of untreated infected mothers do not transmit the infection, suggesting that some yet-to-be-defined viral and/or host factors, including the generation and the transmission of neutralizing and/or blocking antibodies, can play a role in preventing MTCT transmission (6,47,48). This study focused on maternal gp41-specific antibodies, with particular reference to the mother-to-child transmission of their neutralizing potential via passive immunity.…”

mentioning

confidence: 99%

Passively Transmitted gp41 Antibodies in Babies Born from HIV-1 Subtype C-Seropositive Women: Correlation between Fine Specificity and Protection

Diomede

Nyoka

Pastori

et al. 2012

e HIV-exposed, uninfected (EUN) babies born to HIV-infected mothers are examples of natural resistance to HIV infection. In this study, we evaluated the titer and neutralizing potential of gp41-specific maternal antibodies and their correlation with HIV transmission in HIV-infected mother-child pairs. Specific gp41-binding and -neutralizing antibodies were determined in a cohort of 74 first-time mother-child pairs, of whom 40 mothers were infected with HIV subtype C. Within the infected mother cohort, 16 babies were born infected and 24 were PCR negative and uninfected at birth (i.e., exposed but uninfected). Thirty-four HIV-uninfected and HIV-unexposed mother-child pairs were included as controls. All HIV-positive mothers and their newborns showed high IgG titers to linear epitopes within the HR1 region and to the membrane-proximal (MPER) domain of gp41; most sera also recognized the disulfide loop immunodominant epitope (IDE). Antibody titers to the gp41 epitopes were significantly lower in nontransmitting mothers (P < 0.01) and in the EUN babies (P < 0.005) than in HIV-positive mother-child pairs. Three domains of gp41, HR1, IDE, and MPER, elicited antibodies that were effectively transmitted to EUN babies. Moreover, in EUN babies, epitopes overlapping the 2F5 epitope (ELDKWAS), but not the 4E10 epitope, were neutralization targets in two out of four viruses tested. Our findings highlight important epitopes in gp41 that appear to be associated with exposure without infection and would be important to consider for vaccine design.