HIV vaccine development

Published on June 30, 2015   46 min

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Hello. My name is Patricia Fast. I'm a pediatrician who's worked for about 20 years on AIDS vaccines, trying to develop an AIDS vaccine. Currently, I'm senior technical advisor for the International AIDS Vaccine Initiative, which is a nonprofit dedicated to the proposition that the world needs an AIDS vaccine. And I also teach part time as an adjunct associate professor at Stanford University.
As soon as the new lentivirus HIV-1, was discovered in 1984 as the cause of AIDS, there was great hope that a vaccine would soon be discovered. You probably know that lentiviruses are RNA viruses that insert a copy of their genome into the host genome as a way of replicating. There are two HIV viruses, HIV-1 and 2. Most of the research has been done on HIV-1 and I'll generally call it, in this lecture, HIV. The discovery soon afterward of a related lentivirus that caused AIDS in non-human primates, macaque monkeys, focused attention on this Simian Immunodeficiency Virus, or SIV model. Much later, it became evident that focusing on the dominant model, which was a strain of SIV called mac239, in rhesus macaques led to a bias in the research because SIV 239 is almost impossible to neutralize so it tended to minimize the importance of neutralizing antibodies. But we'll come back to that. Eventually, a hybrid virus was constructed between HIV and SIV. It's called SHIV. And rhesus monkeys could then be infected with a virus that carries the HIV envelope or the major protein on the surface of HIV, which it uses to access cells. So that allowed research into the importance of neutralizing antibodies. A little bit of work was originally done in chimpanzees, which can be infected with HIV, but seldom become ill. But antibodies were shown to prevent infection. But because chimpanzees are a protected species, the model was abandoned.
There were some false starts in the beginning of HIV vaccine research with the SIV model. A vaccine made of killed SIV was quickly shown to protect non-human primates from subsequent challenge with SIV, and that was a source of a lot of excitement. But hopes were dashed when it was discovered that this finding was an artifact. The antigens responsible for the protection were human antigens that were incorporated into the SIV membrane when SIV was grown in human cells. So both the vaccine and the challenge virus carried the human antigens and the immune response by the macaques to human antigens on the vaccine neutralized the virus, which was also grown in human cells. So this didn't apply in any way to HIV in human beings. An early finding of protection by a live attenuator or weakened SIV vaccine where a gene called Nef had been removed raised great hope and controversy. It was so exciting that some prominent physicians offered to volunteer for clinical trials of an attenuated HIV vaccine. Detractors, on the other hand, cited the risk that vaccine would regain virulence because the RNA genome of HIV mutates very quickly. In fact, the detractors were correct and the attenuated SIV vaccine was shown to regain virulence in some animals. So attenuated HIV was also abandoned.
Recall, about HIV and viruses in general, that when they replicate inside the cell, the cell will display proteins or peptides derived from the virus on its surface. So a virus infected cell appears foreign to the host immune system. On the other hand, some viruses, and particularly HIV, fight back by developing many ways to evade the host immune system. Before we proceed to talk about how newer vaccine candidates were made, let's quickly review how they might work. So let's remind ourselves about the virus biology. It's important to keep in mind a couple of aspects of virus biology in thinking about immune mechanisms that might protect against HIV. First, HIV, like all viruses, replicates inside of cells, co-opting the cell's machinery to make new viruses. Viral proteins, we'll be mostly talking, in this lecture, about envelope, which is a surface protein that attaches to cells so HIV can enter and infect them, Gag, a structural protein, and polymerase, which is shorthand called pol, P-O-L, which codes for several key enzymes. Portions of these proteins, which are called peptides, become attached to major histocompatibility engines that then go to the surface of cells. This makes the cell look foreign into the immune system and induces immune responses to these peptides or, as we call the smallest units recognized by the immune system, epitopes. HIV has many mechanisms to escape immune recognition. One is the extreme rapidity of its variation. And there are several structural aspects that make it hard for the immune system to gain access to critical epitopes.

HIV vaccine development

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