Please welcome this month's Scicurious Guest Writer, Jill Roughan!!
These days, contracting HIV isnt the death sentence it once was. Research within the last 30 years since its discovery has led to the development of anti-viral medications that allow someone who is infected with the virus to live a long, healthy life. But only if you have the treatment available to you. In sub-Saharan Africa, where HIV infection is most prevalent, treatment is expensive, difficult to take, and/or unavailable. Without proper medication, half of all people with HIV eventually develop, and will die from, complications of AIDS (1). To date, AIDS is estimated to have killed over twenty-five million people and is considered among the most devastating pandemics in recorded history (2).
HIV is passed on from person to person predominantly through direct contact with bodily fluids (3). Once its inside the host, it targets the T cells of the immune system, infecting and using them as virus-making factories to make a lot of copies of itself (4). The newly made viruses then leave the T cell and go on to infect and destroy other healthy T cells as they continue to multiply inside the body. T cells invaded by the virus can no longer properly fight infections. It may take years for the virus to damage enough T cells for that person to get sick and develop AIDS. Although the HIV-positive person may feel fine, the virus is silently reproducing itself and destroying T cells (5). Effective anti-viral medications can control the viral replication, but will not eliminate it completely and thus there is always the risk of the carrier passing the virus along (6). Bottom line, anti-viral therapy has been an incredible accomplishment in the field, but it is not good enough. We need to prevent HIV from setting up shop in the first place and develop a vaccine to end the AIDS epidemic (7).
Despite many efforts, decades of research and clinical trials, an HIV vaccine has not been forthcoming. Skeptics have begun to doubt that its even possible. However, a recent study published in Science offers hope, and gives us a glimpse of where successful HIV vaccine design may be going (8). The scientists were interested in making broadly neutralized antibodies (bNAbs) against the virus (9). This technique is used in most vaccines that we have today, like the flu and hepatitis. You administer a piece of the coating or capsid of the virus (called immunogen) into an individual. This sounds an alarm and activates your immune system to start making antibodies that circulate in your body. Antibodies bind the virus so it cant bind to cells, inhibiting (aka. neutralizing) infection (10). The term broadly refers to the ability of an antibody to neutralize multiple viral strains which would be necessary for a fast-mutating virus like HIV making it harder to evolve resistance. The vaccine activates the immune system to make antibodies ahead of time, so if youre infected with the real virus later youll already have antibodies made to eliminate it.
In natural settings, the immune system is capable of making bNAbs to HIV, but usually this is long after the virus has replicated and spread throughout the host and is unable to control it. In this attempt to design a vaccine, the scientists decided to go at it backward, using an already isolated bNAb to HIV to reverse engineer an immunogen, and use that immunogen to teach the immune system how to make the proper antibodies. The immune system keeps a supply of millions and possibly billions of different antibodies on hand to be prepared for any foreign invader. It does this by constantly creating millions of new B cells. Antibodies are derived from B cells. Almost every B cellthrough random genetic shufflingproduces a unique antibody that it displays on its surface (11). When a virus like HIV enters a person, the viral coat or capsid of the virus interacts with many antibodies that are stuck on the surface of germ-line B cells until it finds a match. This initial interaction is weak but signals the cell that the antibody just needs a little tweaking to make the interaction stronger and more effective at neutralizing. The antibody will then undergo sequential rounds of mutation resulting in custom made antibodies against the original virus (12). Therefore, to teach the immune system to make specialized HIV antibodies, the scientists needed to start by targeting the correct B cell, one that could make the right antibodies.
To determine which B cell to target, the scientists analyzed the structure of VRC01, a bNAb isolated from an asymptomatic HIV carrier that can neutralize 90 percent of known HIV strains (13). They used computer modeling and in vitro screening to produce a modified HIV immunogen, matched to VRC01, that could bind and stimulate the germ-line and produce more mature B cells. Next, they produced an artificial HIV virus that had 60 copies of their designed immunogen packed closely together, a big ball of the same immunogen over and over, and began testing in vitro. They found that the particle worked well at activating the germ-line B cells, essentially mimicking HIV infection. With these B cells activated, they have a higher chance of producing bNAbs to combat the infection. Producing those bNAbs could kick off an effective immune response to HIV. Demonstrating this could prove the basis for an effective vaccine, provoking an immune response to HIV long before exposure, and ensuring that, if HIV infection occurs, it will be neutralized.
(VRC01, the bNAb isolated from an asymptomatic human. Source)
While the next steps will need to be tested in animals, it is quite a feat to mimic an immune response to HIV infection. Moreover, the implications of this study go far beyond the HIV pandemic. This technique could be used as a model system to combat other infections, such as malaria, and Hepatitis C Virus. If we can find ways to harness the bNAbs, we could not only stop HIV in its tracks, but could attack other fast mutating viral diseases. And all we have to do is put our best (germ-line) B cell forward.
Jill Roughan (@jillroughan) is senior research associate at International AIDS Vaccine Intiative/The Scripps Research Institute in La Jolla, CA and she earned her Ph.D. in Immunology from Tufts Medical School in Boston, MA. Jill loves germinal center reactions, virus-host interactions and mid-day headstands.
4. Douek et al., HIV preferentially infects HIV-specific CD4+ T cells, Nature, 2002 May 2;417(6884):95-8.
5. Cooper A et al. HIV-1 causes CD4 cell death through DNA-dependent protein kinase during viral integration. Nature DOI:10.1038/nature12274 (2013).
6. Johnson, WE, Viral persistence: HIV's strategies of immune system evasion, Annu Rev Med. 2002;53:499-518
7. Koff, WC, at al., Accelerating next-generation vaccine development for global disease prevention, Science, 2013 May 31;340(6136).
8. Jardine, J, et al., Rational HIV immunogen design to target specific germline B cell receptors, Science, 2013 May 10;340(6133):711-6.
9.Burton, DR et al., A Blueprint for HIV Vaccine Discovery, Cell Host Microbe, 2012 Oct 18;12(4):396-407
10. Walker, LM, Broad neutralization coverage of HIV by multiple highly potent antibodies, Nature, 2011 Sep 22;477(7365):466-70.
11. Nemazee, D, Receptor editing in B cells, Adv Immunol. 2000;74:89-126
12. McHeyzer-Williams, M, Molecular programming of B cell memory, Nat Rev Immunol. 2011 Dec 9;12(1):24-34. doi: 10.1038/nri3128
13. Wu, X, et al., Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1, Science 13 August 2010: Vol. 329 no. 5993 pp. 856-861