Yesterday I attended a seminar by Dr. Ronald Veazy, a scientist in the Pathology Department at Tulane National Primate Research Center. His research focuses on the effects of HIV infection on the gut. His lab works with the animal model of HIV, which is SIV infection of Asian macaques.
For a little background on this model, HIV originated from an SIV (simian immunodeficiency virus) that naturally infects chimpanzees (though now there is some debate on how "natural" this infection is. more on this later...). SIV doesn't result in the same disease course in chimps because they have had some time to adapt to the virus. So while they are not able to get rid of the infection, they are able to control the virus to some extent and death from SIV in chimps seems to be pretty rare.
However, Asian primates are not naturally infected with SIV and when infected display a disease course much like AIDS in humans. This was discovered when a captive rhesus macaque was accidentally infected with an SIV from a sooty mangabee (SIVsm), which gave rise to the virus that is currently used in the animal model, which we now call SIVmac.
Now back to Dr. Veazey's work. Following the discovery of HIV/AIDS, it was thought that the pathogenesis of the virus was predominantly a result of depletion of immune cells called CD4 positive T cells or helper T cells in the blood (from now on CD4+ cells). These cells play a central role in the immune response to invaders and are the target cells of HIV/SIV. The virus uses the CD4 molecule on the surface of these cells (along with a co-receptor) to enter the cells and turn them into little virus factories. These cells can be isolated from the blood and counted to determine the state of the immune system during HIV infection. However, these cells are also found in large numbers in the gut, in what we call gut-associated lymphoid tissue or GALT. The depletion of these cells in the gut was not appreciated as a source of pathogenesis until around 1998 when a group of scientists, including Dr. Veazey, discovered that in macaques these cells are quickly depleted following infection and, unlike the cells in the circulation, these populations of CD4+ cells do not recover after this initial depletion. Tracking these populations in humans was difficult (gut biopsies had to be taken, which is something to avoid in people with impaired immune systems). So there was no evidence of this in humans and it was thought to be a peculiarity of the macaque model until 2004 when it was shown to occur in humans with HIV as well. In the mean time, the co-receptor for HIV was discovered (a molecule called CCR5) and was shown to have high expression in CD4+ cells in the gut. So we now know that T cell depletion in the gut plays a central role in HIV pathogenesis, though the exact mechanism is still under some debate. It was initially assumed that the decrease in CD4+ T cells itself directly leads to immunodeficiency. However, it now seems that the depletion of CD4+ cells in the gut leads to gut "leakiness" that in turn results in systemic inflammation at levels too high to sustain, thus exhausting the immune system and leading to immunodeficiency. Regardless of whether this depletion is the key to disease progression or is just one of many factors that leads to AIDS, Dr. Veazey's research has been incredibly important in the discovery of an important factor in HIV/AIDS pathogenesis.
