HIV-1 Superinfection in Women Broadens and Strengthens the Neutralizing Antibody Response

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.

Multiple Pathways of Escape from HIV Broadly Cross-Neutralizing V2-Dependent Antibodies

“…Two recent studies have shown that superinfection resulted in greater neutralizing breadth and potency (46,47). In one of these studies, broad and potent NAb responses developed in 2 elite neutralizers very soon after infection with a second virus, suggesting that the development of breadth was accelerated through superinfection (46).…”

“…In one of these studies, broad and potent NAb responses developed in 2 elite neutralizers very soon after infection with a second virus, suggesting that the development of breadth was accelerated through superinfection (46). Whether a similar situation provoked the exceptional breadth in CAP256 is unknown.…”

“…Whether a similar situation provoked the exceptional breadth in CAP256 is unknown. It is possible that superinfection with a discordant virus results in the broadening of the NAb response to multiple epitopes presented on discordant viruses (48), a model supported by the fact that greatest breadth was associated with intersubtype superinfection (46,47). It is also possible that superinfection focuses the NAb response onto conserved epitopes common to both infecting viruses.…”

HIV-1 neutralizing antibody response and viral genetic diversity characterized with next generation sequencing

“…Conversely, peak NAb breadth has also been positively correlated with contemporaneous gp160 clonal diversity (Euler et al, 2012). A positive correlation has also been reported between HIV-1 dual infection (which greatly increases env population diversity) and the development of NAb breadth (Cortez et al, 2012). In the present study, we leveraged the greater resolution of next generation sequencing (NGS) to examine the associations between viral genetic diversity and NAb breadth and potency in a well-characterized, antiretroviral therapy (ART)-naive cohort of individuals followed after primary infection.…”

Limited HIV-1 Superinfection in Seroconverters from the CAPRISA 004 Microbicide Trial

“…Previous analysis of high-risk women in Kenya found a significantly lower rate of SI compared to primary incidence (6). HIV SI can significantly impact HIV disease markers by increasing the HIV viral load temporarily or lastingly, by possibly accelerating disease progression, and by putatively increasing HIV-specific antibody responses (3,4,7,8).…”