Hurricane Muremba raising awareness of HIV/AIDS

Sometime in the last century, the HIV virus, which apparently resided harmlessly in chimpanzees, made a big jump to infect a human. Actually, many viruses make such cross-species leaps, but very few survive and propagate in the new host to create a new epidemic. There is one virus that we are all familiar with that crosses successfully from pigs and birds every year—yes, it’s the influenza virus.

What’s common to the influenza virus and HIV? In a word, mutability. They both contain several regions on their protein envelope that mutate at an incredible rate. And that allows them to readily adapt to the new host. And that’s not all, the very fact that they change so fast makes the creation of a vaccine that targets those “hot spots” a frustrating undertaking. This is why we need to get immunized to influenza every year; the vaccine of the previous year will no longer be effective against the new strain.

Now, we are ready to understand the problem in getting an effective HIV vaccine.

 

The HIV virus

The HIV virus looks more or less like a ball covered with spikes. One of these spikes contains a region called GP120 that plays a crucial role in the infectivity of the virus. GP120 binds to a receptor, called CD4, that appears on the surface of white blood cells. Once the virus latches on to the CD4 receptor via GP120, the whole complex (CD4 plus virus) is internalized into the cell. The reason why HIV is so much more deadly than the influenza virus is that it attacks immune cells. Hence the immune deficiency in patients infected with HIV.

 

What happens when a person is infected with HIV?

The immune response jumps into action. One form of lymphocytes, NK (for Natural Killer) cells, recognizes infected cells and kills them. Another type of lymphocytes (B cells) makes antibodies that bind to the virus. The fact that an antibody binds to the HIV virus does not mean that it neutralizes it. In order to be effective, antibodies should be directed to GP120 in order to prevent the virus’s entry into cells. Unfortunately, the vast majority of the antibodies manufactured by the infected persons are directed to regions on the virus envelope other than CD4. Even the ones that do interact with CD4, bind so feebly as to be ineffective in preventing the virus from entering into the cell—they simply come off too easily.

But!

Clinicians have noticed since the early days of the AIDS epidemic that some individuals, although few and far between, have been infected with HIV but failed to progress to AIDS. Something was different with their immune response that inhibited the further progression of the disease. Several of these patients were tested for inhibitory antibodies. Almost invariably, the ones that showed inhibitory activity were specific to the strain that had elicited them in the first place. Given that there are over 100 strains of the virus, inhibiting one or a few related strains is not very useful for creating a vaccine that would inhibit close to 100% of the strains… Last year, following a trial in Thailand, results of the first HIV vaccine to show any efficacy were announced. But that vaccine reduced the chances of infection only by about 30%. What is needed are broadly neutralizing antibodies.

In the latest development, in two papers in the online edition of the journal Science (July 9, 2010), U.S. government scientists say they have discovered three powerful antibodies, the strongest of which neutralizes 91% of HIV strains, more than any AIDS antibody yet discovered. This discovery is important for obvious reasons. But how they did it deserves accolades.

 

Two technical breakthroughs

The HIV antibodies were discovered in the cells of a 60-year-old African-American gay man, known in the scientific literature as Donor 45, whose body made the antibodies naturally. Donor 45’s antibodies didn’t protect him from contracting HIV. That is likely because the virus had already taken hold before his body produced the antibodies. He is still alive, and when his blood was drawn, he had been living with HIV for 20 years.

Two new techniques made it possible. First, the investigators used an imaging technique (X-ray crystallography) to determine the exact structure of the part of CD4 that binds to the viral GP120. Second, they used this structure as a probe (basically a bait) to fish out antibodies that bound to it. Sounds simple? Consider the fact that they had to screen 25 million of his cells to find 12 that produced the antibodies. Furthermore, until recently, it was practically impossible to detect the minute amount of antibodies generated by one cell. And it was just as difficult to analyze and determine the structure of such a minute amount. The convergence of all these new techniques made this remarkable feat possible.

 

What now?

Several things will still have to be accomplished before this discovery can rise to the level of a potential vaccine:

  1. An exact replica of the same antibody will have to be manufactured in commercial quantities. These identical replicas are called monoclonal antibodies. The technique to manufacture them is already in widespread use. The problem is the cost. They are extremely costly to manufacture and, therefore, are simply not practical for long-term chronic use.
  2. The alternative is to coax the body to manufacture its own antibodies that would be identical to the ones isolated from patient 45. The approach to be taken is to immunize the patients with the fragment of CD4 that had been used to fish out the antibodies made by patient 45. The hope is that antibodies would be elicited to bind in a manner that would neutralize the virus. This is a tall order, but not insurmountable. Such a vaccine should not cost much more than the ordinary pediatric vaccines. We are talking tens of dollars, as opposed to monoclonal antibodies that would cost tens of thousands of dollars.
  3. Antibodies, such as these, administered after the diagnosis is made, are not curative. They will only halt the progression of the disease. A cure could only be effected either by vaccination before the infection (thus requiring some kind of preventative program) or a the vaccine would need to be used in combination with antiviral drugs.

More than 33 million people were living with HIV at the end of 2008, and about 2.7 million contracted the virus that year, according to United Nations estimates. This is an enormous burden in human and economic terms. Hopefully, science will once again ride again to the rescue.

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.