On March 29th, PLoS Pathogens published a paper reporting that women superinfected with two HIV variants are more likely to generate antibody responses capable of neutralizing a broad array of viral strains (known as broadly neutralizing antibodies or bNAbs). The work was conducted by the laboratory of Julie Overbaugh at the Fred Hutchinson Cancer Research Center (FHCRC) in collaboration with the University of Nairobi. FHCRC issued a press release to publicize the work entitled “Study finds HIV ‘superinfection’ boosts immune response.” In retrospect, this may have been a poor choice of words, as it can easily be misinterpreted to suggest that the immune response of the superinfected women was boosted in a way that was beneficial to them; today at least one press story has done just that, stating: “A new study suggests that women who have been infected by two variations of HIV may have a better chance of suppressing the virus then those only infected with one.” This is completely untrue.
As with prior studies identifying bNAbs in people with HIV, the responses identified by Overbaugh’s lab were of no benefit to the individuals they were sampled from. The bNAbs are not present at high enough titers to lead to control of HIV viral load or slowed disease progression in chronic infection. The study is nevertheless potentially important for preventive vaccine development, because if similar bNAbs could be induced by a vaccine they might well be able to prevent the acquisition of HIV infection (which involves exposure to a relatively small amount of virus). Similar confusion occurred with the prior studies reporting bNAb isolation, and it is clearly exacerbated by the adoption among vaccine researchers of the term “elite neutralizer” to describe the individuals bNAbs can be sampled from, which is easily mixed up with “elite controller,” the designation given to a different subset of individuals with HIV who maintain undetectable viral loads in the absence of treatment.
In terms of what the study does actually show, it offers intriguing and potentially important evidence that HIV variability can be linked to the generation of antibodies with broad neutralizing activity. This phenomenon has been suggested before by Guido van der Groen, based on studies of individuals infected with recombinant HIVs (viruses made of two different clades that have recombined). However, while van der Groen mentioned the association during a talk at a meeting in 2000, it does not appear that the data were subsequently published (I covered the van der Groen's talk for the Sept-Nov 2000 issue of the IAVI Report, see page 17).
The findings may offer encouragement to the researcher Julie Hurwitz, who has long been working to develop an antibody-based HIV vaccine that comprises a cocktail of multiple different Env proteins derived from a variety of strains. The one currently ongoing HIV vaccine efficacy trial, HTVN 505, involves candidates that encode Env proteins from HIV clades A, B and C, so the results (expected in 2015) may also contribute to understanding whether mixing diverse antigens can increase the chance of generating bNAbs.
PLoS Pathog 8(3): e1002611. doi:10.1371/journal.ppat.1002611
Valerie Cortez1,2,3, Katherine Odem-Davis3, R. Scott McClelland2, Walter Jaoko4, Julie Overbaugh3
1 Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, Washington, United States of America, 2 Department of Epidemiology, University of Washington, Seattle, Washington, United States of America, 3 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America, 4 Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya
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.