Scientists Discover Antibody Able to Kill Nearly All HIV Strains

Discovery Hints at Possible Treatment, Cure for HIV

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Faced with obstacles in the development of a traditional HIV vaccine, scientists have placed greater focus in recent years on identifying naturally-occurring immune mechanisms that may help the body fight, or even prevent, HIV infection.

The evidence for this approach is strong. We already know, for example, that there is a subset of individuals called elite controllers who appear able to control HIV without the use of drugs.

In looking closely at these individuals, researchers have been able to isolate a number of factors associated with this natural protection.

Chief among these are a type of immune proteins called broadly neutralizing antibodies (bNAbs), which are frequently seen in elite controllers and, unlike "typical" antibodies, are able to neutralize a broad diversity of HIV strains.

In November 2016, scientists with the National Institutes of Health announced the discovery a new bNAb, called N6, which was able to neutralize 98 percent of all HIV strains in pre-clinical lab tests. This novel immune agent, isolated from a HIV elite controller, was reportedly 10 times more effective in killing HIV than its any other currently known bNAb.

Understanding Broadly Neutralizing Antibodies

Antibodies are Y-shaped proteins produced by the immune system to help fight disease-causing pathogens like bacteria or viruses.

By and large, most are programmed to fight one type of pathogen and one pathogen alone—a problematic situation given that HIV is constantly mutating and is able to elude detection simply by becoming unrecognizable to the defensive antibody.

By contrast, bNAbs are able to track HIV even as it morphs and mutates, identifying the virus not by its structural conformation but by receptors on the surface of the virus (called CD4 binding sites), which are far less susceptible to change.

While bNAbs are most frequently associated with elite control, they will, in fact, develop in all persons with HIV, albeit at a far slower rate.

In many elite controllers, the presence of bNAbs is considered innate, meaning that they are present at the time of infection. In non-elite controllers, bNAbs will generally appear within 2-3 years of initial infection, by which time the virus will have embedded itself in cells and tissues called latent reservoirs, where it will remain largely hidden from immune detection.

Scientists now believe that if they can spur the immune system to produce bNAbs "on demand," they may be able to either prevent infection or slow the course of disease, without or without the aid of medications.

The Natural History of Broadly Neutralizing Antibodies

While scientists first began to identify bNAbs back in the early 1990s, it was only in 2009 that a number of highly effective candidates drew the attention of vaccine researchers. Among these was VRC01, a bNAb which had been isolated from an African American man and was later shown to neutralize 90 percent of all HIV-1 strains.

VRC01 works by attaching to the CD4 binding site on the surface of the virus, preventing HIV from to entering a vulnerable host cell. Early animal trials investigating VRC01 showed promise, with primates injected with the antibodies demonstrating viral control for a period of six months.

Human trials, by contrast, have been largely disappointing. A 2016 study from the AIDS Clinical Trial Group showed that intravenous infusions of VRC01, while well tolerated, did little to sustain viral control in participants who had been pulled off their drugs. Multiple injections were unable to improve upon these results.

The discovery of the new N6 antibody is considered significant among those who see it a natural successor to VRC01, both in its genetic lineage and potency. And there is strong evidence to support these views.

Previous to N6, most bNAb candidates have either been extremely broad but mildly potent (as was the case with VRC01) or extremely potent but less broad. N6 appears, at least in pre-clinical trials, to be effective on both fronts, neutralizing 98% of 181 different HIV strains (including 16 of 20 strains immune to other bNAB of its class).

Much of its effectiveness can be attributed the antibody’s unusual structure, which allows it to avoid carbohydrate "door jams" that prevent other bNAbs from attaching to the virus.

Will N6 Open the Doorway to an HIV Cure?

Should N6 be able to achieve the same results in human trials, it would be the first such agent to compensate for the diversity of HIV, both on an individual and population-based level.

That’s not to say it won’t hit the same obstacles seen the early VRC01 trials, wherein direct inoculation failed to replicate the benefits of elite control. Similarly, there is little evidence to suggest that we can induce the immune system to produce these antibodies on its own, at least in quantities sufficient enough to be considered protective.

One of the biggest challenges facing researchers is the fact that the induction of a single bNAb has proven extremely difficult. Typically speaking, when scientists try to induce a response, the body will answer with a contradictory response, one that effectively dampens the effect. Essentially it’s the body’s way of "putting the brakes" on the immune system to ensure it neither under-activates (as happens with autoimmune diseases) or under-activates (as happens with immune suppressive disorders).

Further complicating matters are the latent reservoirs where HIV can remain shielded from detection for years and even decades. The problem is this: only first-circulating virus can be neutralized by bNAbs; those hidden away in cellular reservoirs cannot. It is only by "kicking" HIV out of hiding that bNAbs have a chance of effecting a permanent, sterilizing cure. The multi-pronged strategy, popularly known as "kick-kill," is today considered a priority among leading HIV research teams.

The Future of bNAb Research

Whether scientists can overcome any of these obstacles has yet to be seen. What we do know for certain is that N6 far surpasses any other bNAbs currently under investigation, both in its breadth and neutralizing potential.

Due to its potency, N6 would appear to have an advantage over VRC01 insofar as it may be able to be injected subcutaneously, rather than by IV.  Moreover, its ability to neutralize nearly all HIV strains means that it could use as a means to both treat and prevent infection.

While one needs to approach the research with a note of caution, on paper it all seems rather promising. The next stage of would expand to in vivo animal trials, likely to begin sometime in early 2017.

Meanwhile, two Phase II trials are set to begin in 2017, exploring the use of VRC01 as a form of HIV prevention (popularly known as HIV pre-exposure prophylaxis, or PrEP). 

The large-scale human trials will determine whether VRC01 can provide a protective benefit among HIV-negative persons provided two intravenous infusions. The first will take place in 24 sites in Brazil, Peru, and the United States, with an enrollment of 2,700 men and transgender persons who have sex with men. The second will recruit 1,500 women in Botswana, Kenya, Malawi, Mozambique, South Africa, Tanzania, and Zimbabwe.

Sources:

Bar, K.; Harrison, L.; Overton, E.; et al. "ACTG 5340: The Effect of VRC01 on Viral Kinetics After Analytic Treatment Interruption." Conference on Retroviruses and Opportunistic Infections (CROI); Boston, Massachusetts; February 22-25, 2016; Conference abstract 32LB.

Chun, T.; Sneller,M.; Seamon, C.; et al. "Effect of Infusion of Broadly Neutralizing Antibody VRC01 on HIV Plasma Rebound." Conference on Retroviruses and Opportunistic Infections (CROI); Boston, Massachusetts; February 22-25, 2016; Conference abstract 311LB.

Eroskin, A.; LeBlanc, A.; Weekes, D.; et al.  "bNAber: database of broadly neutralizing antibodies." Nucleic Acid Research. January 2014; 42(database Issue):D1133-1139.

HIV Preventions Trials Network (HPTN). "HPTN Studies: Study List – HVTN 704/HPTN 085 and HVTN 703/HPTN 081." Washington, DC.

Huang, J.; Kang, B.; Ishida, E.; et al. "Identification of a CD4-Binding Site Antibody to HIV That Evolved Near-Pan Neutralization Breadth." Immunity. November 15, 2016; 45(5):1108-1121; DOI: 10.1016/j.immuni.2016.10.027.

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