HIV/AIDS Presents an Unprecedented Challenge to Developing a Vaccine

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As the world focuses on Ebola, we must not forget that HIV/AIDS presents a far greater challenge in the world of vaccines.

Thirty years ago this past April, my colleagues and I reported that a new retrovirus, now known as HIV, was the agent causing AIDS. At the time, it was a pandemic with far greater mortality and morbidity than Ebola -- and one with greater implications including life-long infection with sure death along with a tainted global blood supply -- neither of which are the case with Ebola. Furthermore, Ebola seems to be straightforward, on the fast track to a successful vaccine, which have already been effective in monkeys.

It is often reported erroneously by media that during this press conference U.S. Health and Human Services Secretary Margaret Heckler said that there would be a vaccine in two years. One can verify in public transcripts of the press conference that this is not what Secretary Heckler said, though she is forever criticized and falsely attributed to this made-up quote. What Secretary Heckler did in fact say was that we could now grow the virus permanently in cell line culture, which was one of the substantive advances we made that allowed us to get the blood test. This new biotechnical advance also allowed others to test and develop HIV medicine, including the first successful drug therapy, AZT.

Secretary Heckler concluded the press conference saying that because of this new advance, a vaccine could be tested in a couple of years, which was in fact the case. No one expected to have an effective vaccine out of the gate. In fact, developing an effective HIV preventive vaccine has turned out to be a huge, complex challenge.

As written by my colleagues, George Lewis and Anthony Devico, and me in aperspective published Monday by the Proceedings of the National Academy of Sciences, we outline the unprecedented challenges facing the field ,and one particularly that does not get much attention but we believe is the key to solving the vaccine problem.

Unlike Ebola, at the heart of the challenge is that HIV is a human retrovirus, and by nature irreversibly infects an individual permanently in a few days. Thus, unlike viruses for which we have successfully developed vaccines, such as polio, the immune system has no time to recognize HIV and produce antibodies to fight it. HIV has already begun inserting its genes into its human host's genome. We believe an effective vaccine must achieve "sterilizing immunity," or the ability to completely block infection at the entry point.

Previously, five large HIV vaccine trials failed to do this, including one that increased risk for HIV infection. However, a sixth large HIV vaccine study, the U.S. Army RV144 Thailand vaccine trial succeeded in 2009 to show modest antibody-associated protection in the first few months of infection. But, similar to our Institute's HIV vaccine candidate results in monkey tests, as the particular protective antibodies faded in the U.S. Army vaccine trial, so did protection. In reviewing the literature, there is a common theme which has gone unnoticed -- these antibodies uniformly don't persist.

There is something about the virus' envelope protein -- not unique in biology but unusual that the antibodies last less in time. This is the crux of one of the chief problems in the field.

How do we solve this so we can save people from HIV infection? One approach to solving this problem is to boost repeatedly when antibody levels decrease below protective levels. However, there are serious problems with this approach. First are logistics. For example, one cannot go to every village in a resource-poor country, recruit people and then continually boost them. Second, HIV variants emerge and as this happens, we cannot be sure that boosting will work on those variants. Moreover, in the literature there is evidence that constant boosting alters the function of antibodies by diminishing them. And, if that's not enough, incessant boosting activates T cells, which are the necessary targets of HIV infection. So you make more of these T cells and HIV says, bravo, thank you. Herein lays a fundamental immunologic challenge, while we try to make antibodies long-lasting we are destroying the efficacy of the vaccine because more target cells are produced. We must solve this challenge, to solve the AIDS problem.

Robert C. Gallo, MD directs the Institute of Human Virology and is a professor at the University of Maryland School of Medicine in Baltimore and is co-founder and Scientific Director of the Global Virus Network. He is best known for his co-discovery of HIV as the cause of AIDS and development of the HIV blood test.


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