Two papers appearing back-to-back in today's issue of Naturedemonstrate that HIV is capable of killing immature T cells whilethey are still resident in the thymus, their organ of origin.

If these results eventually translate from experimental murinesystems to humans, they would indicate that the virus is capable notonly of destroying mature, circulating disease-fighting white bloodcells, but is able to attack them at their site of origin, thus ensuringthe immune system's inability to replenish itself after a viral attack.

Both research teams -- one headed by J. Mike McCune of SyStemixInc. (NASDAQ:STMX) and the other by Jerome Zack of the UCLASchool of Medicine -- have used the SCID-hu mouse as an animalmodel for HIV infection.

The mouse, developed by McCune and a team of scientists atStanford University, is a rodent with severe combined immunedeficiency that has been surgically implanted with human fetaltissue -- in this case thymus and liver -- to provide humanhematopoietic stem cells and the microenvironment in which T cellsnormally mature. Researchers have already demonstrated that suchmice are capable of producing differentiated, phenotypically normaland functionally competent human T cells.

But McCune and his associates have found that if they infect thesemice with HIV by direct intrathymic injection, the virus can replicatein the thymus implants and there is a progressive loss of CD4+ T cells.These effects were specific to HIV infection.

The researchers followed viral replication by assaying the p24 viralantigen from thymocyte suspensions of graft tissue. They found thatthe p24 level peaked at day 23 post-infection, and then fell off. Andimmunohistochemical analyses of infected tissues demonstrated thepresence of infected cells throughout the thymus by four weeks,along with a change in the distribution of CD4+ and CD8+ thymocytes,leading to a rapid depletion of those cells.

These events could be mediated in part by programmed cell death,according to the researchers. "Our working hypothesis is that HIVfacilitates the normal mechanism of programmed cell death,"SyStemix's McCune told BioWorld. "The morphological indications aresimilar."

And Zack's group at UCLA, which also used SCID-hu mice implantedwith human fetal liver and thymus tissue, has observed severedepletion of CD4+ cells within a few weeks after the mice wereinfected with HIV by direct injection into the implants. Via flowcytometry, Zack and his collaborators determined that the immaturethymocytes (CD4+/CD8+) are depleted first, followed by CD4+/CD8-cells. Finally, the CD4-/CD8+ cells succumb.

As well, the researchers found that the implants' viral load increasedduring this time (as measured by polymerase chain reaction), risingrapidly during the first two to three weeks after infection. Again, theobserved effects were specific to HIV; infection of the implants withhuman cytomegalovirus, for instance, does not result in thymocytedepletion.

And histologically, the infected implants were depleted ofthymocytes; in fact "the entire organ appeared to be atrophic andhypocellular," the researchers reported.

Overall, the UCLA results "complement ours," said SyStemix'sMcCune. For one, since SyStemix transferred the SCID-hu mousesystem to the UCLA labs (as well as to Anthony Fauci's lab at theNational Institutes of Health), the two groups started with the sameexperimental system. "Our approach was the same, the questionswere the same, but the methods for analysis differed," McCuneexplained.

The bottom line, however, is that the SCID-hu model system forstudying HIV pathogenesis has evolved to the point where it isuseful not only for making observations, but also for testinghypotheses, McCune told BioWorld. And that could lead eventually togene therapy protocols for combating HIV. In fact, "the model in theNature paper is the fulcrum of preclinical analysis of different genetherapies for HIV disease," said McCune.

"We hope to understand the mechanisms by which HIV causesthymocyte depletion," he said. "Then we would have a betterunderstanding of which genes to use."

-- Jennifer Van Brunt Senior Editor

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