One of the cruelest aspects of AIDS is that clinical symptoms typically do not begin to develop until long after infection by the HIV virus, generally eight to ten years after the initial exposure to HIV. During this long interval, carriers of HIV have no clinical symptoms but are apparently fully infectious, which makes the spread of HIV very difficult to control. The reason why HIV remains hidden for so long has puzzled researchers for some time. The most widely-held view has been that the virus “hides,” inserting itself into the host cell’s chromosomes, much as the herpes virus that causes fever blisters does. The supposition was that HIV, like herpes, remains inactive in its chromosomal hiding place until some stressful event causes the virus to exit the chromosome and resume activity. Data uncovered this year cast serious doubt on this view. It now looks like the HIV infection cycle continues throughout the long eight to ten year latent period, without doing serious harm to the infected person. Then events transpire that allow the virus to quickly overcome the immune defense, starting AIDS.
When HIV is introduced into the human bloodstream, the virus particle circulates throughout the entire body but will only infect certain cells, ones called macrophages (Latin, “big eaters”). Macrophages are the garbage collectors of the body, taking up and recycling fragments of ruptured cells and other bits of organic debris. That HIV specializes in this one kind of cell is not surprisingmost other animal viruses are similarly narrow in their requirements. Polio virus infects only certain spinal nerves, hepatitis virus infects only liver cells, and rabies virus only the brain.
How does a virus such as HIV recognize a specific kind of target cell such as a macrophage? Every kind of cell in the human body has a specific array of cell-surface “dogtags” that serve to identify them to other, similar cells. These ID markers are made of protein, usually with a sugar attached. HIV viruses recognize macrophage cells because they are able to recognize the macrophage ID marker. Studding the surface of each HIV virus are spikes that bang into any cell the virus encounters. Each spike is composed of a protein called gp120. Only when gp120 happens on a cell ID marker that matches its shape does the HIV virus adhere to an animal cell and infect it. It turns out that gp120 precisely fits a cell-surface ID protein called CD4, and that CD4 occurs on the surfaces of macrophages.
The cells of the immune system, called lymphocytes, also possess CD4 ID markers. Why are they not infected right away, as macrophages are? This is the key question underlying the mystery of the long AIDS latent period. When lymphocytes become infected and killed, AIDS commences. So what holds off lymphocyte infection so long?
Researchers have recently learned that after docking onto the CD4 receptor of a macrophage, the HIV virus requires a second receptor protein, called CCR5, to pull itself across the cell membrane. After gp120 binds to CD4, its shape becomes twisted (a chemist would say it goes through a conformational change) into a new form that fits the CCR5 coreceptor molecule. Investigators speculate that after the conformational change, the coreceptor CCR5 passes the gp120-CD4 complex through the cell membrane by triggering endocytosis (that is, the cell’s membrane folds inward to form a deep cavity around the virus, and eventually closes over it, literally folding the virus into the cell interior). Once inside the macrophage cell, the HIV virus particle sheds its protective coat. This leaves the virus nucleic acid (RNA in this case) floating in the cell’s cytoplasm, along with a virus enzyme that was also within the virus shell. This enzyme, called reverse transcriptase, binds to the tip of the virus RNA and slides down it, synthesizing a double strand of DNA that matches the information contained in the virus RNA. Like using a blueprint to recreate an engineer’s drawing, this process translates the RNA language of the virus’s genes into the DNA language of the cell, so it can be used by the cell’s machinery to direct the production of new viruses.
Importantly, the HIV reverse transcriptase enzyme doesn’t do its job very accurately. It often makes mistakes in reading the HIV RNA, and so creates many new mutations. The mistake-ridden double-stranded DNA that it produces then takes over the host cell’s machinery, directing it to produce many copies of the virus.
In all of this process, no lasting damage is done to the host cell. HIV does not rupture and kill the macrophage cells it infects. Instead, the new viruses are released from the cell by exocytosis, being folded out in much the same way that HIV initially gained entry into the cell at the start of the infection.
This, then, is the basis of the long latency period characteristic of AIDS. The HIV virus cycles through macrophages over a period of years, multiplying powerfully but doing little apparent damage to the body.
All during this long latent period, HIV is constantly replicating and mutating as it cycles through successive generations of macrophages. Eventually, by chance, HIV alters the gene for gp120 in a way that causes the gp120 protein to change its coreceptor allegiance. This new form of gp120 protein prefers to bind instead to a different coreceptor, CXCR4, a receptor that occurs on the surface of T lymphocyte CD4+ cells. Soon the body’s T lymphocytes become infected with HIV.
This has deadly consequences, as new viruses exit the cell not by harmless exocytosis, but by bursting through the cell membrane, rupturing the cell. Like puncturing a water balloon, this destroys the cell’s physical integrity, effectively killing the infected T cell. As the released viruses infect nearby T lymphocytes, they in turn are ruptured, in a widening circle of cell death. Soon, the shift to the CXCR4 second receptor produces a steep drop in the number of living T cells. It is this destruction of the body’s T cell lymphocytes that blocks the body’s immune response and leads directly to the onset of AIDS, with cancers and opportunistic infections free to invade the defenseless body.
Identification of a shift in coreceptor allegiance as the key event triggering AIDS has excited researchers. Any therapy that blocks the CXCR4 coreceptor might prevent the development of full-blown AIDS in HIV-infected individuals.
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