Maternal but Not Infant Anti-HIV-1 Neutralizing Antibody Response Associates with Enhanced Transmission and Infant Morbidity

Abstract

A significant number of infants acquire HIV-1 through their infected mother's breast milk, primarily due to limited access to antiretrovirals. Passive immunization with neutralizing antibodies (nAbs) may prevent this transmission. Previous studies, however, have generated conflicting results about the ability of nAbs to halt mother-to-child transmission (MTCT) and their impact on infant outcomes. This study compared plasma neutralizing activity in exposed infants and the infected mothers (n = 63) against heterologous HIV-1 variants and the quasispecies present in the mother. HIV-exposed uninfected infants (HEU) (n = 42), compared to those that eventually acquired infection (n = 21), did not possess higher nAb responses against heterologous envelopes (P = 0.46) or their mothers' variants (P = 0.45). Transmitting compared to nontransmitting mothers, however, had significantly higher plasma neutralizing activity against heterologous envelopes (P = 0.03), although these two groups did not have significant differences in their ability to neutralize autologous strains (P = 0.39). Furthermore, infants born to mothers with greater neutralizing breadth and potency were significantly more likely to have a serious adverse event (P = 0.03). These results imply that preexisting anti-HIV-1 neutralizing activity does not prevent breast milk transmission. Additionally, high maternal neutralizing breadth and potency may adversely influence both the frequency of breast milk transmission and subsequent infant morbidity.IMPORTANCE Passive immunization trials are under way to understand if preexisting antibodies can decrease mother-to-child HIV-1 transmission and improve infant outcomes. We examined the influence of preexisting maternal and infant neutralizing activity on transmission and infant morbidity in a breastfeeding mother-infant cohort. Neutralization was examined against both the exposure strains circulating in the infected mothers and a standardized reference panel previously used to estimate breadth. HIV-exposed uninfected infants did not possess a broader and more potent response against both the exposure and heterologous strains compared to infants that acquired infection. Transmitting, compared to nontransmitting, mothers had significantly higher neutralization breadth and potency but similar responses against autologous variants. Infants born to mothers with higher neutralization responses were more likely to have a serious adverse event. Our results suggest that preexisting antibodies do not protect against breast milk HIV-1 acquisition and may have negative consequences for the baby.

Keywords: HIV; MTCT; antibodies; breast milk; infant mortality.

FIG 1

Breadth and potency are similar as assessed by the percentage of neutralization at the highest tested antibody concentration or IC₅₀. (A) Each square in the heat map represents the average percentage of neutralization for each virus-MAb combination tested: <50%, yellow; 50 to 70%, light orange; 70 to 90%, dark orange; >90%, red. All MAbs were tested at a concentration of 50 µg/ml. Virus subtypes are indicated by color: A, khaki; B, gray; C, turquoise; G, lime green; AC, pink; CRF01_AE, dark green; and CRF07_BC, purple. The branches show the hierarchical clustering with bootstrap probability for 100 iterations. (B) Correlation between BP score estimated from the percentage of neutralization value at 50 µg/ml (y axis) and BP-IC₅₀ (x axis). All IC₅₀s are obtained from the Los Alamos database. (C) Correlation between breadth assessed using either the percentage of neutralization at 50 µg/ml (y axis) or the IC₅₀ (x axis).

FIG 2

Infant neutralization response against a heterologous global Env panel. (A) Each square in the heat map represents the average percentage of neutralization for each virus-plasma combination tested: <50%, yellow; 50 to 70%, light orange; 70 to 90%, dark orange; >90%, red. Virus subtypes are indicated by color: A, khaki; B, gray; C, turquoise; G, lime green; AC, pink; CRF01_AE, dark green; and CRF07_BC, purple. On the left, blue denotes AI infants and green denotes HEU infants. The branches show the hierarchical clustering with bootstrap probability for 100 iterations. (B and C) Comparison of (B) breadth and potency score (BP) and (C) breadth alone between AI and HEU infants. Colors signify matched pairs. Each dot represents an average value from a minimum of 2 independent neutralization experiments for each infant. (D) Correlation between infant BP score and number of days after birth that samples were collected. The red and black dots indicate AI and HEU infants, respectively.

FIG 3

Maternal neutralization response against a heterologous global Env panel. (A) Each square in the grid represents the average percentage of neutralization for each virus-plasma combination tested: <50%, yellow; 50 to 70%, light orange; 70 to 90%, dark orange; >90%, red. Virus subtypes are indicated by color: A, khaki; B, gray; C, turquoise; G, lime green; AC, pink; CRF01_AE, dark green; and CRF07_BC, purple. On the left, blue denotes transmitting mothers (TMs) and green denotes nontransmitting mothers (NTMs). The branches show the hierarchical clustering with bootstrap probability for 100 iterations. (B and C) Comparison of (B) breadth and potency score (BP) and (C) breadth alone between TMs and NTMs. Colors signify matched pairs. Each dot represents an average value from a minimum of 2 independent neutralization experiments. (D) Kaplan-Meir curve estimating time (days) to a grade 4 SAE or death for infants born to mothers with BP greater than or equal to the cohort median (red) or less than the cohort median (black).

FIG 4

Infant and maternal BP score correlations. (A to F) Correlation between (A) infant BP score and maternal plasma virus level, (B) infant BP score and maternal CD4⁺ T-cell counts, (C) maternal BP scores and maternal plasma virus level, (D) maternal BP scores and maternal CD4⁺ T-cell counts, (E) infant and maternal BP scores, and (F) difference between maternal and infant BP scores and interval duration between birth and sample collection. The red dots indicate TMs and their AI infants. The black dots indicate NTMs and their HEU infants.

FIG 5

Neutralization response against maternal variants among infants that acquired infection and those that remained uninfected. (A and B) Area under the inhibition curve (AUC) values among AI versus HEU infants examined as (A) independent groups (Mann-Whitney test) and (B) matched pairs (linear regression model). Colors signify matched pairs for both analyses. (C) Correlation between infant AUC neutralization response against maternal strains and heterologous virus (BP score). The red and black dots indicate AI and HEU infants, respectively.

FIG 6

Autologous neutralization response among transmitting and nontransmitting mothers. (A and B) Autologous neutralization represented by (A) area under the neutralization curve (AUC) between TMs and NTMs examined as (A) independent groups (Mann-Whitney test) and (B) matched pairs (linear regression model). Colors signify matched pairs for both analyses. (C) Correlation between maternal neutralization response against autologous virus (AUC) and heterologous virus (BP score). The red and black dots indicate TMs and NTMs, respectively.