Genetic Variation in HIV
AIDS is a single disease throughout the world. At the beginning of the epidemic, HIV was most likely limited to Africa. HIV, like any other virus, underwent mutation to create distinct subtypes. People infected with a single subtype of HIV then exported their infection to other places, with different subtypes becoming predominant in different geographical areas. Subsequently, HIV underwent further mutation to create individual strains of each subtype.
Although the potential genetic variation in HIV might appear limitless, only a small number of mutations confer advantage to the virus. As a result, there are a limited number of deadly viral subtypes and strains. We believe these fall into particular patterns providing a logical basis to formulating a vaccine for HIV. We also believe that the major subtypes of gp120 have been identified. Although minor subtypes are identified periodically, no new major subtypes have been identified in the last 15 years.
SUBTYPES. There are five major subtypes of HIV. These are labeled “A” through “E,” according to their order of discovery. The major difference between each subtype is a genetic variation in a region of the gp120 protein known as the chemokine-binding site.
The major subtypes of HIV tend to be distributed along geographical lines. This is consistent with the general understanding of how HIV has spread throughout the world. Virtually all HIV in the Americas, Europe, the Caribbean and Australia is subtype B. The vast majority of HIV in Thailand and in the Pacific Rim countries is subtype E. Subtype C virus has emerged as the most rapidly expanding HIV in Africa, China and India. The remaining subtypes A and D occur primarily in Africa and in limited areas around the world.
STRAINS. Each subtype of HIV is further subdivided into strains. Four strains arise from two mutations in specific regions of the gp120 protein: a sub-region in the chemokine-binding site and a sub-region in the CD4-binding site. These strains are of key importance in that they have different patterns of infection and they each react with different antibodies.
- Chemokine-binding site. HIV has mutated at the chemokine-binding site to yield two distinct strains, known as T-tropic and M-tropic. Each of these strains binds to a chemokine receptor on a target cell. In the T-tropic strains, the gp120 protein binds to a chemokine receptor on T cells. In the M-tropic strains, the gp120 protein binds to a chemokine receptor found on macrophages, as well as on T cells.
- CD4-binding site. HIV has also mutated at the CD4-binding site to yield two additional strains: CD4a and CD4b. Each of these strains binds with slight differences to the CD4 receptor, which occurs on human T cells.
SUBTYPE/STRAIN COMBINATIONS. In summary, there are five major worldwide subtypes of HIV: A through E. Each subtype has two different strains that bind to chemokine receptors on T cells and macrophages. These strains are further subdivided by two variations in the CD4-binding site on gp120. Each of these strains requires different antibodies for neutralization.
To construct a successful vaccine, we need to consider the entire range of variation in gp120 and assure that we cover each of the sites on the gp120 protein that are open to attack by antibodies. Fortunately, as described above, most of the variable sites on gp120 have only one or two principal forms. By careful examination, we have been able to identify pairs of HIV viruses whose gp120 proteins, when combined together in a vaccine, enhance the overall antibody response. We believe this antibody response covers virtually the entire range of HIV genetic variations currently known in North America and in countries of South Asia and the Pacific Rim.