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Evolution of Broadly Neutralizing Anti-HIV Antibodies and Vaccine Development
Human immunodeficiency virus (HIV) causes a chronic infection of a type of immune cell, called CD4+ T cells. Vaccines against HIV have so far been elusive, due mainly to the fact that HIV is a retrovirus. A retrovirus is a type of virus that contains a ribonucleic acid (RNA genome). The RNA is reverse-transcribed into deoxyribonucleic acid (DNA), which is then inserted into the host cell’s genome. In most organisms, DNA is the molecule of choice for storage of genetic information. DNA is then converted to RNA, which then directs the cell to produce protein.

Retroviral infections are difficult to prevent and treat for several reasons. First, the reverse-transcriptase, the enzyme that converts RNA to DNA, is very error-prone. It constantly makes mistakes, which causes a large number of mutations in the virus. These mutations can change viral proteins enough to make them unrecognizable by the immune system. The high mutation rate is also responsible for the large number of different strains of HIV-1 that are found in patients. Also, because the viral genome integrates into the host genome, the virus is difficult to remove completely from the host. As the host cell replicates, the viral genome is also replicated. Even if all HIV particles are removed from the bloodstream, some may remain quietly integrated in a host cell genome, waiting to be reactivated.

The high mutation rate of HIV has made vaccine development very difficult. The biggest hope for a successful vaccine lies in the development of broadly neutralizing antibodies. An antibody is a protein produced by the immune system that helps target a cell or virus for destruction to prevent and control infections. Broadly neutralizing antibodies recognize HIV viral proteins, such as the HIV envelope protein, that are involved in binding to the CD4+ T cell. These proteins are less likely to mutate significantly, and tend to be similar even in different strains of virus, as they are necessary for the infection process. A small percentage of HIV-infected patients, termed elite controllers, are able to produce these broadly-neutralizing antibodies. Because of these antibodies, elite controllers maintain low-to-undetectable levels of virus in their blood for extended periods, without the use of anti-retroviral therapy.

This week, researchers published information in the journal Nature following the development of broadly neutralizing antibodies in an HIV-infected patient. Generally, early on during an infection, a host is primarily infected with a founder strain that eventually evolves many changes due to the high mutability of the virus. The researchers followed the evolution of both the virus as it collected mutations, and the antibodies produced in response to the virus. By learning how broadly neutralizing antibodies are naturally developed within the host, scientists can rationally design vaccines to mimic the natural production of these antibodies. Studying the evolution of the virus within the host can also aid in vaccine design, by showing researchers which proteins mutate the most rapidly, and which the most slowly. Amazingly, the antibodies produced were able to neutralize over half of the HIV-1 strains tested by the researchers. This is also an important concept for vaccine design, as one vaccine could protect against multiple strains of HIV, and even provide protection as the virus mutates within the host.

The production of an effective, highly versatile anti-HIV vaccine is of the utmost importance to defeating the virus and stopping the world-wide pandemic. As mentioned above, because HIV integrates into the host cell genome, it may never completely be removed from the host, even by the most advanced retroviral therapies. Even when viral proteins are undetectable in the plasma of a host, it is still possible that virus is lurking in the genome of CD4+ T cells. The most likely way to stop transmission of the virus is to prevent infection in the first place, by the use of a vaccine. A vaccine that elicits broadly neutralizing antibodies would be able to prevent the virus from getting a strong hold in the host. Even patients who have already been infected with HIV could benefit from vaccination. If the immune response has not yet been severely impacted by the virus, the host could potentially develop broadly neutralizing antibodies that prevent further reproduction and growth of the virus.

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