Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012;8(3):e1002611.
doi: 10.1371/journal.ppat.1002611. Epub 2012 Mar 29.

HIV-1 superinfection in women broadens and strengthens the neutralizing antibody response

Valerie Cortez  1 , Katherine Odem-Davis, R Scott McClelland, Walter Jaoko, Julie Overbaugh
Affiliations

HIV-1 superinfection in women broadens and strengthens the neutralizing antibody response

Valerie Cortez et al. PLoS Pathog. 2012.

Abstract

Identifying naturally-occurring neutralizing antibodies (NAb) that are cross-reactive against all global subtypes of HIV-1 is an important step toward the development of a vaccine. Establishing the host and viral determinants for eliciting such broadly NAbs is also critical for immunogen design. NAb breadth has previously been shown to be positively associated with viral diversity. Therefore, we hypothesized that superinfected individuals develop a broad NAb response as a result of increased antigenic stimulation by two distinct viruses. To test this hypothesis, plasma samples from 12 superinfected women each assigned to three singly infected women were tested against a panel of eight viruses representing four different HIV-1 subtypes at matched time points post-superinfection (~5 years post-initial infection). Here we show superinfected individuals develop significantly broader NAb responses post-superinfection when compared to singly infected individuals (RR = 1.68, CI: 1.23-2.30, p = 0.001). This was true even after controlling for NAb breadth developed prior to superinfection, contemporaneous CD4+ T cell count and viral load. Similarly, both unadjusted and adjusted analyses showed significantly greater potency in superinfected cases compared to controls. Notably, two superinfected individuals were able to neutralize variants from four different subtypes at plasma dilutions >1∶300, suggesting that their NAbs exhibit elite activity. Cross-subtype breadth was detected within a year of superinfection in both of these individuals, which was within 1.5 years of their initial infection. These data suggest that sequential infections lead to augmentation of the NAb response, a process that may provide insight into potential mechanisms that contribute to the development of antibody breadth. Therefore, a successful vaccination strategy that mimics superinfection may lead to the development of broad NAbs in immunized individuals.

PubMed Disclaimer

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Viral characteristics of 12 cases of SI.
Subject IDs are shown to the left with time since initial infection plotted at the bottom. Red bars denote the interval during which SI occurred, with closed circles representing the last time point in which SI was last undetected and the time point at which SI was first detected. Black triangles mark the midpoint of this interval, which was used as the estimated time of the SI event. The individual's viral load (log10 copies/ml) at the corresponding time points is noted above each red bar, with (∧) denoting increases in viral load >0.5 log10 copies/ml. Subtyping in the two columns on the right are based on env sequences. However, the data for those individuals with an (*) by their superinfecting virus subtype based on gag sequences alone as the superinfecting env sequence was not detected at time points tested. Virus outcome was based on the longitudinal analyses previously described –. Persistence was defined as the detection of co-existence of the superinfecting virus with the initial virus following its introduction, while we classified replacement superinfections as the dominance of the superinfecting virus based on lack of detection of the initial virus post-SI .
Figure 2
Figure 2. Post-SI neutralization profiles for superinfected and non-superinfected plasmas tested against heterologous HIV-1 variants.
Subject IDs are shown to in the first column. Superinfected individuals denoted with borders and “SI” before ID number, with the three matched controls listed below. The next columns lists the years post initial infection (YPI*) that was tested, which was used to match cases and controls. The following columns list the years post-SI (YPSI#) for each superinfected case. All samples were chosen near 5 years post-initial infection. However, some samples were taken 1–2 years before or after this time point because of sample availability. Subsequent columns contain the IC50 for each plasma-virus pair, which is the reciprocal dilution of plasma that led to a 50% reduction in infectivity. Plasma samples that showed neutralization below the limit of detection were designated an IC50 value of 50, the midpoint between our starting dilution (1∶100) and 0. IC50s are shown as a heat map to represent increasing neutralization sensitivity, with white boxes for values below 100, light blue boxes for values between 101 and 300, darker blue boxes for values between 301 and 500, and the darkest blue boxes for values greater than 501. The NAb response breadth and potency scores that are shown here were calculated after taking the average log2 IC50s from the two experiments.
Figure 3
Figure 3. Summary of differences in NAb breadth and potency scores between superinfected and non-superinfected women.
Each case and the three matched controls are denoted by a single color. Mean scores shown with horizontal bar. Breadth and potency comparisons post-SI are shown in panels (A) and (C), respectively. Breadth and potency comparisons pre-SI are shown in panels (B) and (D), respectively.
Figure 4
Figure 4. Pre-SI neutralization profiles for superinfected and non-superinfected plasmas tested against heterologous HIV-1 variants.
The layout for this figure is as described in the legend for Figure 2. Heterologous HIV-1 variants tested were the same as in the post-SI screen. IC50s are similarly shown with darker colors denoting greater neutralization sensitivity. Plasmas not tested are indicated by a pair of dashes.
Figure 5
Figure 5. Elite neutralizers QB850 and QA013 develop breadth within 1 year following SI.
The kinetics of the NAb responses for QB850 (A) and QA013 (B) are shown versus years post-initial infection. Viruses of the same subtype are shown with the same line color. Geometric mean IC50s for the entire 8-virus panel are shown in the dashed black lines. The approximate time of SI, calculated as described in Figure 1, is indicated by the corresponding red arrows for each individual.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Mascola JR, Montefiori DC. The role of antibodies in HIV vaccines. Ann Rev Immunol. 2010;28:413–444. - PubMed
    1. McElrath MJ, Haynes BF. Induction of immunity to human immunodeficiency virus type-1 by vaccination. Immunity. 2010;33:542–554. - PMC - PubMed
    1. Stamatatos L, Morris L, Burton DR, Mascola JR. Neutralizing antibodies generated during natural HIV-1 infection: good news for an HIV-1 vaccine? Nature. 2009;15:866–70. - PubMed
    1. Walker LM, Huber M, Doores KJ, Falkowska E, Pejchal R, et al. Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature. 2011;477:466–470. - PMC - PubMed
    1. Wu X, Zhou T, Zhu J, Zhang B, Georgiev I, et al. Focused Evolution of HIV-1 Neutralizing Antibodies Revealed by Structures and Deep Sequencing. Science. 2011;333:1593–1602. - PMC - PubMed

Publication types