How does HIV cause AIDS?
Although there are still a few people who deny that human immunodeficiency virus (HIV) infection causes AIDS, they no longer have any scientific credibility. The best way to avoid AIDS is not to become infected with HIV, but that’s not much help to the 39 million people worldwide who already are infected with the virus. If we are to find a cure for AIDS, we need to understand the mechanisms by which the virus causes the disease. Although the basic biology of HIV is well understood (Basics of the virology of HIV-1 and its replication. J Clin Virol. 2005 34: 233-244), and there have been many theories about how HIV infection may result in AIDS, scientists have never had a complete understanding of the processes by which CD4+ T helper cells are depleted in HIV infection, and therefore have never been able to fully explain why HIV destroys the body’s supply of these vital cells.
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AIDS is defined as the presence of HIV infection, plus one or both of the following:
- A helper T cell count of less than 200 cells per mL of blood (the normal count is 600 to 1,000 per mL)
- Development of an opportunistic infection that occurs when the immune system is not working correctly, such as Pneumocystis carinii pneumonia (PCP), certain eye diseases, encephalitis, and some specific tumours such as Kaposi’s sarcoma.
Soon after HIV was discovered in the 1980s it was shown that the virus could kill CD4+ cells in culture. Early experiments suggested there might not be enough virus present in AIDS patients to account for all the damage seen. More recently, sensitive techniques such as PCR suggest that with the amount of virus now known to be present in infected individuals, the CD4+ cell count should in fact decline much faster and AIDS develop much earlier than it does after HIV infection. A paper recently published in PLoS Medicine addresses this important question (Understanding the Slow Depletion of Memory CD4+ T Cells in HIV Infection. 2007 PLoS Medicine 4, 5, e177).
For over a decade, researchers have used a “tap and drain” analogy to describe CD4+ cell loss in HIV infection. In this description, CD4+ cells (like water in a sink) are constantly being eliminated by HIV (the drain), while the body is constantly replacing them with new ones (the tap). Over time, the tap cannot keep up with the drain, and CD4 counts begin to drop, leaving the body susceptible to the infections that define AIDS. CD4+ cells that are activated in response to invading microbes (including HIV itself) are highly susceptible to infection with the virus, and following infection these cells may produce many new copies of HIV before dying. A popular explanation for CD4+ cell loss is the “runaway” hypothesis, in which CD4+ cells infected by HIV produce more virus particles, which activate more CD4+ cells that in turn become infected, leading to a positive feedback cycle of CD4+ cell activation, infection, HIV production, and cell destruction.
Using a mathematical model containing a series of equations to describe the processes by which CD4+ cells are produced and eliminated, the authors showed that if the “runaway” hypothesis was correct, then CD4+ cells in HIV infected individuals would fall to low levels over a few months, not over several years as usually happens. Therefore they conclude that the “runaway” hypothesis cannot explain the slow pace of CD4+ cell depletion in HIV infection.
Of course that leaves open the question of what exactly is going on between the time someone becomes infected with HIV and the time that they develop AIDS. Although they have no definitive answer, the paper does summarize some alternative mechanisms by which the CD4+ T cells might slowly diminish. While virus adaptation (antigenic variation) is important in the biology of HIV, this alone cannot explain the whole story. This study highlights how understanding CD4+ T cell dynamics in chronic HIV infection requires a quantitative description of T cell maintenance in health, as well as understanding how HIV infection affects the turnover and differentiation of T cell subsets.
I spent ten years of my scientific career trying to find out how HIV causes AIDS, and the ongoing debate shows that we still don’t completely understand this vital issue. Until we do, the prospects for curing AIDS remain bleak.
Related:
- HIV infection is due to the sins of the fathers
- How HIV Infects Cells – The Entry Claw (Video)
- The role of PD-1 in HIV Pathogenesis
