Feline research may help address thymic problems
AZT did not stop FIV damage to thymus
Researchers who have been working with the feline immunodeficiency virus (FIV) for years have recently concluded that while AZT will stop the virus from multiplying, it does not protect the thymus from physical damage.
"With FIV-infected cats and young humans, the thymus is one of the major target organs for infection, a massive depletion of lymphoid elements and inflammatory response that damages the thymus," says Lawrence Mathes, PhD, professor of immunology at The Ohio State University in Columbus and co-author of a recent study on FIV and thymic activity.1
Earlier research conducted by Mathes and other investigators has shown that the feline leukemia virus could be effectively stopped with the administration of AZT. If cats were treated fairly early in their infection, they could be cured. "We called the effect drug-induced vaccination,’" Mathes says. "With HIV, the feeling was that early in the infection, the immune response was suppressing the virus because the viral load rises to a peak and then drops back down, but it wasn’t actually clearing the infection," he adds. "The virus was getting around the normal way to clear the infection."
Then, when felines or humans are given antiviral drugs, the medications suppress their natural immune response. "The toxicity you see is a suppression of the bone marrow’s rapidly dividing cells, due to the biochemistry of the drug," Mathes says. "So if you suppress the replenishing of bone marrow cells, you’ll see a drop in blood cell numbers and anemia develops."
Investigators found a dose of AZT that would induce the vaccine effect in cats with leukemia without suppressing the immune response to the point of anemia. Finding the right dose of AZT to use in FIV-infected cats was more difficult because the virus itself suppresses the immune system and the thymus undergoes a more rapid involution with FIV. The researchers used AZT with the felines because most of the other antiretrovirals would not work with cats.
When the FIV-infected felines were given AZT treatment, the thymus sometimes was damaged to the point of becoming dysfunctional and unable to produce new cells. The cats received AZT daily for 12 weeks, with treatment beginning two days before the cats were infected with the virus. Investigators compared the levels of T-cells in the infected and uninfected groups.
Felines receiving AZT treatment had a 75%-85% reduction in the levels of FIV in their blood and a 74% reduction in virus in their thymus. But they also had physical damage and inflammation in their thymuses similar to that of the untreated felines. Investigators concluded that the extent of inflammation, once initiated by FIV infection, was independent of thymus virus load. The threshold virus load needed to turn on the inflammatory response in the thymus was not determined in this study, but was predicted to be below the reduced virus load achieved by AZT monotherapy.
Mathes says the same effect could occur in human infants who are HIV-infected and are treated with AZT. Infants and children have fewer lymphocytes than do adults, meaning they have yet to develop the T-cells that defend their bodies against infection and disease. Thus, there are far worse health implications for a child’s thymus to be damaged and unable to produce lymphocytes than for an adult’s.
"It makes children more susceptible to opportunistic infections and major infections," he says. "We have to be aware that the immune system is a two-edged sword, because on the one hand it can clear infection, and on the other hand it can cause collateral damage through inflammation," he adds. This type of research may lead to ways to help HIV-infected children retain a healthy thymus despite antiretroviral treatment, Mathes says.
Reference
1. Hayes KA, et al. Antiviral therapy reduces viral burden but does not prevent thymic involution in young cats infected with feline immunodeficiency virus. Antimicrob Agents Chemother 2000; 44:2399-2405.
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