January 17, 2017
Fervid research has uncovered dozens of antibodies that shield cells from HIV. These broadly neutralizing antibodies (bNAbs) protect monkeys from SHIV, the simian-HIV hybrid. Thousand-person human trials are already dripping bNAbs into high-risk men and women to see if they prevent HIV infection. And much work suggests bNAbs hold promise as keys to HIV vaccine design or as immune therapy delivered by passive immunization or viral vectors.
So what inspired the media handstands proclaiming the discovery of yet another bNAb—one explored so far only in lab tests, inflating a bNAb class already studded with candidates that show potential based on their antiviral activity in lab studies? While human trials of bNAbs are underway, this newest next-generation candidate is years away from human trials. So, does the world need even one probably costly, hard-to-administer bNAb when as-needed PrEP taken consistently before and after sex or PrEP plus antiretroviral therapy for HIV-discordant couples virtually eliminate HIV transmission?
It appears so. All the fuss focused on a bNAb tagged N6, isolated from a volunteer whose immune system had 21 years to mold and remodel the antibody into a form that neutralized 98 percent of global HIV strains Mark Connors and colleagues threw at it—the most ever harnessed by a single bNAb. The diverse and exacting studies performed by this team from the National Institute of Allergy and Infectious Diseases (NIAID) and other centers offer tantalizing evidence that N6 is indeed something special.
Previously studied bNAbs, Connors and coauthors note, are either strong (stalling HIV at a relatively low dose) or broad (blocking a high proportion of tested HIV strains). None claims both distinctions—but N6 does. The new bNAb boasts sweeping breadth, thwarting 98 percent of HIV strains tested, compared with 80 percent to 90 percent neutralization with other bNAbs in this class, which targets the CD4 binding site. But the other CD4-homing bNAbs, observe Scripps researchers Devin Sok and Dennis Burton, wield only “modest potency” compared with N6’s robust median 50 percent inhibitory concentration (IC50) of 0.04 µg/mL. A few other bNAbs in different classes flex even more inhibitory muscle than N6 (median IC50 0.003 µg/mL for bNAb PGDM1400) but have narrower breadth than N6 (83 percent of isolates neutralized by PGDM1400).
bNAbs affix themselves to some stretch of the HIV envelope protein that the virus uses to snag CD4 cells. But the gene that encodes the HIV envelope mutates manically to shirk the embrace of antibodies (and vaccines designed to elicit or transport antibodies). At the same time, HIV shrouds its envelope in a sugar coat poorly recognized by antibodies. So a key measure of bNAb prowess is how well it copes with HIV’s shape-shifting mutations. And by this measure, N6 is a star. Only 4 of 181 HIV strains tested (2 percent) proved highly resistant to N6. Among 20 HIV strains resistant to other bNAbs in the same class as N6, the new bNAb neutralized 16 (80 percent).
To learn how N6 dodges HIV’s resistance defenses, Connors and crew performed a series of rigorous structural analyses showing precisely how N6 seizes HIV’s envelope loops. N6 grabs HIV the same way we grab things—with a hand, or at least something that looks like a hand. Connors’s team asks us to visualize N6 and other antibodies in this class as an index finger and thumb that pinch a sugar-coated shape-shifting part of the HIV envelope called the V5 loop. To resist other CD4 binding site antibodies, HIV warps V5 in a way that pushes away these antibodies to prevent them from binding. Crystal structure analysis showed that, compared with the index finger and thumb of VRC01 (the most-studied bNAb in this class), the finger and thumb of N6 are shorter and differ subtly in rotation and tilt. These subtle changes allow N6 to avoid wrinkles in V5 that cause resistance to other bNAbs in the VRC01 class.
Besides clutching V5, bNAbs in this class finger two other HIV envelope regions, the CD4-binding loop and another loop labeled D. The twist and tilt of N6 relative to other bNAbs make it rely less on V5 and more on loop D to grip HIV. Because loop D shifts shape much less than V5, the N6 hand grabs it more reliably and firmly from one HIV strain to the next.
VRC01, the bNAb now in large placebo-controlled trials to prevent HIV infection in men and women, must be dripped into a vein for 30 to 60 minutes every 8 weeks. Because N6 is 5 to 10 times more potent than VRC01, simpler subcutaneous shots may be possible and at longer intervals. Connors and colleagues suggest the durability of N6 may be further tweaked by mutational manipulation. Anything that simplifies delivery of a preventive or therapeutic agent boosts its chances of successful clinical use.
Autoreactivity (sometimes called self-reactivity) occurs when an agent produced by an organism (like humans) works against that organism. Although autoreactivity may be a defining feature of bNAbs, researchers agree that it represents an obstacle to inducing bNAbs and may account for their rarity in people with HIV. Connors and colleagues performed four binding studies indicating minimal autoreactivity with N6, a benefit that bNAb experts Sok and Burton suggest may favor N6 use for prophylaxis or treatment.
To learn how N6 evolved in their volunteer, Connors and coworkers sequenced B-cell antigen receptors at three times—2012, 2014, and 2015. Hints from these studies and from phylogenetic (evolutionary) analyses may give researchers vital clues to targeting diverse HIV strains with vaccines or immunotherapies. Discovering features shared by N6 and other bNAbs could inform the design of better vaccine and immunotherapy candidates.
Together these propitious traits inspired Sok and Burton to proclaim N6 the “best-in-class” among CD4-binding bNAbs. And given the breadth and brawn of N6, it may not be a stretch to call it the best bNAb period. But caution remains the catchword for any agent at this earliest stage of research. So far everything we know about N6 comes from a single, though exhaustive, 14-page paper, plus supplementary online data. From this point agents like N6 typically require further lab work and studies in animals like mice and monkeys before starting small human trials to assess their safety and find the right dose. Only then can researchers test efficacy in bigger human trials. But bNAb development moves fast these days. The much-vaunted VRC01 got discovered in 2010, its first human trial began only 3 years later, and the above-noted phase 2 efficacy trials are recruiting HIV-negative volunteers right now. Connors told P-Values that several pharma and biotech companies are already collaborating with academic partners to develop N6 for potential clinical use.
Will N6 and other bNAbs play a practical role in global HIV control? A lab study testing seven bNAbs found that the CD4-focused antibody NIH45-46W neutralized 91 percent of 45 global HIV strains. Adding PGT128, a bNAb directed at the V3 loop of HIV’s envelope, crippled 96 percent of tested HIV strains. Supplementing that two-pronged attack with PGT121, another V3 loop grabber, neutralized all HIV strains tested. Perhaps N6 combined with just one more bNAb would protect CD4 cells from all HIV-1 strains.
But right now that approach would prove impractical as a vaccination strategy because large and costly vats of bNAbs would have to be brewed, delivered to big target populations, and injected (as things stand now) every few months. A phase 2 trial of PrEP with cabotegravir, the long-acting integrase inhibitor, is testing intramuscular shots given every 4 or 8 weeks. A PrEP bNAb duo that works when injected at longer intervals would hold a clear convenience advantage over cabotegravir, but potential costs remain unknown, and we have already ventured far into the realm of speculation.