Neutralizing antibody responses drive the evolution of human immunodeficiency virus type 1 envelope during recent HIV infection

Abstract

HIV type 1 (HIV-1) can rapidly escape from neutralizing antibody responses. The genetic basis of this escape in vivo is poorly understood. We compared the pattern of evolution of the HIV-1 env gene between individuals with recent HIV infection whose virus exhibited either a low or a high rate of escape from neutralizing antibody responses. We demonstrate that the rate of viral escape at a phenotypic level is highly variable among individuals, and is strongly correlated with the rate of amino acid substitutions. We show that dramatic escape from neutralizing antibodies can occur in the relative absence of changes in glycosylation or insertions and deletions ("indels") in the envelope; conversely, changes in glycosylation and indels occur even in the absence of neutralizing antibody responses. Comparison of our data with the predictions of a mathematical model support a mechanism in which escape from neutralizing antibodies occurs via many amino acid substitutions, with low cross-neutralization between closely related viral strains. Our results suggest that autologous neutralizing antibody responses may play a pivotal role in the diversification of HIV-1 envelope during the early stages of infection.

Fig. 1.

Dynamics of neutralizing antibody titers and viral loads. (a–c) Patterns of neutralization titers in three representative patients, with strong, weak, and undetectable neutralizing antibody responses. (d) A strong negative correlation between the slope of neutralizing antibody titer (in log₁₀ units per year) by virus sampling time and by plasma sampling time (in years). The dashed line represents the mean slope of neutralizing antibody by virus sampling time. The solid line is a linear regression line, and the points corresponding to the patients depicted in a–c are shown.

Fig. 2.

Associations between the rate of phenotypic escape from nAbs and viral genetic variation. (a) The rate of amino acid evolution, expressed as the nonsynonymous to synonymous substitution rate ratio, dN/dS, for the whole envelope, gp120, and the constant and variable regions of gp120 for individuals whose virus exhibited slow (S) or rapid (R) escape from neutralizing antibodies. Error bars represent 95% confidence intervals, obtained by using profile likelihood. (b) The total number of PNGS, as measured by using bulk sequences at baseline and at follow-up (≈1 year) for individuals with slow (open circles) or rapid viral escape (filled circles). (c and d) The length of the V1–V2 loop, as measured by using clonal sequencing at baseline and follow up.

Fig. 3.

Patterns of clonal evolution in two patients, one whose virus exhibited rapid escape from neutralizing antibodies (01-0127) and one whose virus exhibited slow escape from neutralizing antibodies (01-0083). (a and b) Nonsynonymous, dN, and synonymous, dS, divergence from baseline virus (in %) over time, averaged over the whole envelope sequence. (c and d) The difference in nonsynonymous and synonymous substitution rates, dN - dS, per codon, scaled such that the average number of synonymous changes per codon site is 1. Circles represent sites at which dN - dS is significantly greater than zero (i.e., positive selection) at the P = 0.05 significance level. Solid lines indicate specific regions of envelope. (e and f) The number of PNGS over time. (g and h) The length of the V1–V2 and V4 regions of the viral envelope (in amino acids), measured by using multiple clonal sequences. Note that patterns of length variation and glycosylation remain relatively stable over the first 6 months of follow-up in patient 01-0127, despite significant viral escape from neutralizing antibodies.

Fig. 4.

Simulations of the dynamics of virus and neutralizing antibody responses based on the model of Haraguchi and Sasaki (42), under low and high cross-reactivity of neutralizing antibody responses. (a and b) Log viral load over time. (c and d) Genetic diversity over time and divergence from the infecting strain. (e and f) Autologous neutralization between neutralizing antibody and virus sampled at different times, controlling for the total viral population size. Parameter values were chosen to illustrate the different dynamic regimes, and are as follows: r = 1, D = 1, α₀ = 1, β₀ = 1, σ_α = 2 (low cross reactivity), and σ_β = 2 (high cross reactivity). Initial conditions for both simulations: B(t = 0, x = y) = 0.1, y ∈ (0,∞) (uniform distribution of activated B cells in antigen space), N(t = 0, x = 0) = 0.1, N(t = 0, x = y) = 0, y > 0 (single viral variant at time 0).