Neutralization escape variants of human immunodeficiency virus type 1 are transmitted from mother to infant

Abstract

Maternal passive immunity typically plays a critical role in protecting infants from new infections; however, the specific contribution of neutralizing antibodies in limiting mother-to-child transmission of human immunodeficiency virus type 1 is unclear. By examining cloned envelope variants from 12 transmission pairs, we found that vertically transmitted variants were more resistant to neutralization by maternal plasma than were maternal viral variants near the time of transmission. The vertically transmitted envelope variants were poorly neutralized by monoclonal antibodies b12 [corrected] 2G12, 2F5, and 4E10 individually or in combination. Despite the fact that the infant viruses were among the most neutralization resistant in the mother, they had relatively few glycosylation sites. Moreover, the transmitted variants elicited de novo neutralizing antibodies in the infants, indicating that they were not inherently difficult to neutralize. The neutralization resistance of vertically transmitted viruses is in contrast to the relative neutralization sensitivity of viruses sexually transmitted within discordant couples, suggesting that the antigenic properties of viruses that are favored for transmission may differ depending upon mode of transmission.

FIG. 1.

Neighbor-joining tree based on distance, showing the epidemiologic linkage between envelope sequences from mother (⧫) and infant (Δ) subjects within each transmission pair. A total of 78 nucleotide sequences spanning the V1-to-V5 region of envelope, with 150 reference sequences from group M HIV-1, were codon aligned and subjected to phylogenetic tree construction using the general time-reversible model. Two subtype K references were used as an outgroup. Horizontal branch lengths are drawn to scale. Subtypes and bootstrap values are indicated to the left of each node. The location of each mother-infant transmission pair is indicated.

FIG. 2.

Neutralization sensitivity of envelope variants for maternal plasma. (A) Percent neutralization versus plasma dilution of viruses pseudotyped with envelope variants from transmission pair G505. (B) Comparison of neutralization IC₅₀s between variants from mothers (◊) and those from infants (Δ) within each transmission pair. The horizontal bars indicate the median IC₅₀ for each subject. The vertical line divides the transmission pairs into two groups: to the left are pairs with lower median IC₅₀s of variants from infants; to the right are pairs with median IC₅₀s of variants from infants equal to or higher than the median IC₅₀s of variants from each paired mother. The dashed horizontal line indicates the lowest dilution tested. (C) Comparison of IC₅₀s between variants from mothers (◊) and from infants (Δ) performed by GEE using a logit link and exchangeable correlation structure. The P value of the comparison is shown. (D) Box plot of median IC₅₀ of variants from mothers and infants. The P value is for the comparison of the median IC₅₀ of variants from each infant to the median IC₅₀ of variants from the paired mother (two-sided Wilcoxon signed-rank test).

FIG. 3.

Comparison of amino acid V1-to-V5 sequences between maternal (◊) and infant (Δ) variants. (A) Plot of the length of sequences from each transmission pair. (B) Plot of the number of PNGS of sequences from each transmission pair. In panels A and B, the horizontal bars indicate the mean value for each subject. The vertical line divides the transmission pairs into two groups: to the left are pairs with lower mean values from infant; to the right are pairs with equal or higher mean values from infants compared to the mean value from each paired mother. (C) Comparison of length of the aggregate sequences from mothers and infants. (D) Comparison of number of PNGS of the aggregate sequences from mothers and infants. In panels C and D, P values are from analysis using a GEE model with a Gaussian link and exchangeable correlation structure. (E) Positions within the V1-to-V5 region of envelope where a PNGS was absent in variants from infant but present in variants from the paired mother. The number and proportion of maternal envelope variants containing the PNGS at the indicated positions are shown. The absence of PNGS caused by deletions or mutations is indicated by D or M, respectively. The PNGS positions were assigned according to the HXB2 amino acid sequence.

FIG. 4.

Correlation of neutralization sensitivity with V1-to-V5 length (A) and PNGS (B) in this region. The mean values of envelope variants from each mother (◊) and infant (Δ) were used. The coefficient R and P values were generated using Spearman's correlation.

FIG. 5.

Maximum likelihood analysis of nucleotide sequences spanning the V1-to-V5 region of envelope from six mother-infant transmission pairs. Horizontal branch lengths are drawn to scale. Each symbol represents an individual variant sequence. The panel at the top left corner is the key to the type of samples from which the envelope sequences were derived. The neutralization sensitivity of each variant to maternal plasma is indicated by the IC₅₀ value (rounded to integers) next to the corresponding symbol of the variant. IC₅₀s over 100 are highlighted.

FIG. 6.

Neutralization IC₅₀s of six envelope variants vertically transmitted by autologous infant longitudinal plasmas. Plasma collection times are indicated on the horizontal axes. Neutralization IC₅₀s are plotted on the vertical axes. The peak IC₅₀ values are indicated. Symbols in boldface indicate the time points when each infant first tested positive for HIV.