November 12, 2015

WHAT’S UP, DOC? | Antibodies to Prevent HIV Infection

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By TONY SUN

Immunologist and physician Anthony Fauci reminds us that “more people are getting infected [with HIV] than we are able to put on therapy… an economically unsustainable situation.” Fauci recognizes two options — either prevent infection or wean people off therapy. This article focuses on the first option: prevention and vaccination.

So when will an effective HIV vaccine be available? That is the question. In fact, it was one posed to the National Institutes of Health director in the 1980s, when the virus became accepted as the most probable cause of the AIDS epidemic. The director was confident that a vaccine would be available after a few years. So research trials were initiated, based on the same principles that produced effective vaccines against other viruses. The principle of vaccination is simple: expose people to a weaker version of a virus, or to broken-down components of a virus, and the person’s immune system will respond and “remember” it on next encounter. Vaccination works, until it doesn’t, and that’s exactly what happened in the early HIV vaccination trials. But the silver lining is that this failure shifted focus from vaccination to treatment, spurring development of highly effective anti-HIV drugs. AZT, now called Zidovudine, became the first anti-HIV drug approved by the United States government in 1987. Fast forward another decade, and anti-HIV drugs have changed America’s perspective of HIV infection from a death sentence to a chronic health problem that can be managed with medications. Today, the average life expectancy of an HIV-positive person in America is not much different than that of an HIV-negative person.

There is a caveat, though, in that these medications alter quality of life — they are expensive, they have noticeable side effects and patients have to stay on top of dosages and checkups in case resistance develops. So people continue to ask: Can a vaccine be developed to block HIV infection in the first place? Until recently, I might’ve given “no” as an answer, largely because of viral biology: it decimates the very system we need to defeat it, and it mutates effectively to escape most human antibodies. However, in the last 5 to 10 years, with the discovery of special antibodies called broadly neutralizing antibodies (bNAbs), the HIV vaccine field has regained momentum since the failed vaccine trials in the 1980s. Now, scientists and clinicians are asking: How can we surpass the successes of drug therapy, called HAART (highly active anti-retroviral therapy)?

The answer has to be vaccination, and the key to a natural* vaccine lies in harnessing the power of antibodies. From the 5-10 percent of patients (called elite controllers or elite neutralizers) that could produce bNAbs after several years of infection, scientists extracted their antibody-producing cells (called B cells) and used the cells to manufacture and study those special antibodies. Michel Nussenzweig’s group at Rockefeller University has made notable breakthroughs in HIV bNAb research. In his lab, postdoctoral fellow Johannes Scheid discovered a powerful bNAb called 3BNC117. Around the same time, postdoc Florian Klein used bNAbs to successfully control HIV levels in an animal model of infection. These back-to-back findings moved the Nussenzweig group to initiate Phase 1 clinical trials, led by infectious diseases fellow Marina Caskey, who used 3BNC117 to successfully suppress HIV levels in patients. The implications of this Phase 1 trial is that HIV-infected patients could get a once-a-month shot to control their infection instead of taking medications every day, since antibodies last so much longer than drugs. However, clinician Laura Walker warns that multiple bNAbs should be given for treatment, much like the anti-HIV drugs, to prevent resistance from developing. Another possibility, of course, is to first combine bNAbs with the anti-HIV drugs patients are on and slowly wean them off therapy.

Knowing now that bNAb therapy appears to work in human patients, the next step is to develop ways of getting the patients’ own bodies to produce these special antibodies. Moving in this direction, postdoc Pia Dosenovic from the Nussenzweig group discovered that a series of vaccinations will likely be required to direct immature antibodies to evolve into the final bNAb. So patients will probably have to get one vaccine followed by multiple booster vaccines that direct the immature antibodies to evolve into bNAbs. Essentially, the immune system is undergoing training to become better and better at defending itself against a formidable virus normally capable of evading the human immunity.

The idea of bNAbs is very exciting and could stop a three-decade long epidemic, but I want to make a note that curing patients already infected with HIV is a whole different issue, one that will require an entirely different approach from vaccination. My personal belief is that such a cure is implausible because the virus hides inside cells throughout the body. But please, prove me wrong. That being said, successful vaccination will prevent transmission and so the “cure” is more population-oriented than individual-oriented.

*I say “natural vaccine” because the goal is to elicit an immune response that is more or less the same as if the person got infected with HIV. Another approach to vaccination is through gene therapy. Martin Farzan’s group at the Scripps Institute recently used gene therapy to prevent the primate-human version of HIV (called SHIV) from infecting their macaques. Late in September this year, the Gates and Melinda foundation awarded $6 million to continue funding this research. Their approach seems to work, but the risks of gene therapy have to be worked out first before human trials can be started.

Tony Sun grad is in his final year at the Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional M.D.-Ph.D. Program in New York City. He may be reached at tos2014@med.cornell.edu.

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