Dynamics of viral evolution and neutralizing antibody response after HIV-1 superinfection

Abstract

Investigating the incidence and prevalence of HIV-1 superinfection is challenging due to the complex dynamics of two infecting strains. The superinfecting strain can replace the initial strain, be transiently expressed, or persist along with the initial strain in distinct or in recombined forms. Various selective pressures influence these alternative scenarios in different HIV-1 coding regions. We hypothesized that the potency of the neutralizing antibody (NAb) response to autologous viruses would modulate viral dynamics in env following superinfection in a limited set of superinfection cases. HIV-1 env pyrosequencing data were generated from blood plasma collected from 7 individuals with evidence of superinfection. Viral variants within each patient were screened for recombination, and viral dynamics were evaluated using nucleotide diversity. NAb responses to autologous viruses were evaluated before and after superinfection. In 4 individuals, the superinfecting strain replaced the original strain. In 2 individuals, both initial and superinfecting strains continued to cocirculate. In the final individual, the surviving lineage was the product of interstrain recombination. NAb responses to autologous viruses that were detected within the first 2 years of HIV-1 infection were weak or absent for 6 of the 7 recently infected individuals at the time of and shortly following superinfection. These 6 individuals had detectable on-going viral replication of distinct superinfecting virus in the env coding region. In the remaining case, there was an early and strong autologous NAb response, which was associated with extensive recombination in env between initial and superinfecting strains. This extensive recombination made superinfection more difficult to identify and may explain why the detection of superinfection has typically been associated with low autologous NAb titers.

Fig 1

Relative proportion of original and superinfecting lineages during the follow-up of the 7 subjects. The y axis represents 7 individuals identified as being superinfected, and the x axis is the time from the estimated date of initial infection. Circles represent sampled time points. Blue, initial lineage; red, superinfecting lineages; purple, recombinant strains. Slices represent the relative proportion of each lineage. Classes A and B are associated with a weak autologous NAb response. In the class C individual, there was a strong autologous NAb response toward SI strains. The time point indicated by an asterisk was after initiation of antiretroviral therapy.

Fig 2

Highlighter plots of aligned env from three representative individuals with distinct dynamics. In the plots, base differences from the top master sequence are highlighted with colored ticks. Lineages are indicated with colored brackets: original, blue; SI, red; and recombinant strains, purple. K9 is an example of the extinction of the original lineage. R5 shows the cocirculation of both original and superinfected lineages. G5 depicts intense recombination events between the initial lineage and SI lineages associated with escape from contemporaneous autologous NAb response.

Fig 3

(A) BMCMC tree of partial env sequences for individuals K9, R5, and G5. The sequences from the original lineage are depicted in blue. The sequences from the SI lineage are depicted in red, while those in purple represent potential recombinant sequences between original and SI strains. Background sequences are labeled with black triangles. Posterior probably of main lineages are indicated at the root. Tip labels indicate time points of sampling (TP) and month after infection (M). Scale bars represent genetic distances in substitutions/site. (B) Time-scaled BMCMC phylogenetic trees of partial env sequences for individuals K9, R5, and G5. The sequences from the original lineage are depicted in blue. The sequences from the SI lineage are depicted in red, while those in purple represent potential recombinant sequences between original and SI strains. Tip labels indicated time points of sampling (TP) and month after infection (M). The trees represent the ancestral relationships of sequences belonging to each lineage. The x axis represents time in years before the latest sampling date. Scale bars represent time in years.

Fig 4

Trend of mean viral diversification within env regions across the 7 superinfected subjects. Mean env viral diversity at each time point is plotted relative to the time since the estimated date of infection (EDI). Participant S1 is shown as the dark blue line, K6 as the red line, K9 as the green line, P2 as the purple line, D2 as the black line, R5 as the orange line, and G5 as the light blue line. Colored stars indicate the earliest time point with evidence of superinfection for each individual. Crosses indicate times of recombinant events identified in subject G5. The highest diversity within each subject corresponded to the time of superinfecting event(s) and, for G5, to the time when recombination was evident.