HIV has a new crime to answer for on its rap sheet.

The AIDS virus's previous indictment reads: Homes in on and murders T lymphocytes, which it singles out by the CD4 antigens decorating their surface, and onto which it locks. Before inflicting its death blow, the HIV particle forces entry into the CD4 T cell, where it multiplies -- sending out new hordes of virus to attack more CD4-positive T cells.

Actually, that invasion triggers a one-two punch. Besides hijacking the T cell's own genome to promote the viral proliferation, HIV, by killing off those T cells, cripples its victim's immune defenses, for which its battalions of T lymphocytes provide the strongest resistance.

That's why AIDS is commonly known as a disease of CD4-positive T cell decline.

It now turns out that a better alias would be "a disease of CD4+-cum-CD8+ T cell decline."

An article in today's Proceedings of the National Academy of Sciences (PNAS), dated March 17, 1998, reports this unexpected finding. Its title: "Activation of CD8+ T lymphocytes through the T cell receptor turns on CD4 gene expression: Implications for HIV pathogenesis."

CD8 T cells, a.k.a. killer T cells, have been regarded as uninfectable by HIV, and even capable of destroying HIV-infected cells and suppressing viral replication. They do so by attacking such cells as "foreign."

The PNAS paper's senior author is virologist Robert Gallo, a pioneer of AIDS research who is now director of The Institute of Human Virology at the University of Maryland, in Baltimore. He reports that, contrary to received wisdom, the AIDS virus can and does infect CD8 T cells. And adding insult to that injury, it does so by siccing its original targets, the CD4 surface antigens, onto the CD8s.

Workers in the field, Gallo told BioWorld Today, have assumed CD8 T cells to be infection-proof because "in order for HIV to gain entry into the cell, it has to interact with certain chemokine receptors." (See BioWorld Today, Dec. 7, 1995, p. 1)

Whenever researchers or clinicians encountered CD8 T cells in a patient's blood, or in in vitro cultures, Gallo observed, "they thought it to be a kind of artifact, or maybe some CD4 cells contaminating the CD8 T cell population. Basically, when you try to infect a CD8 cell in the lab, it doesn't get infected. When you look in vivo, you don't see the bulk of CD8 cells infected."

Was CD8 Infection For Real?

But then virologist Louis Flamand, a Canadian post-doctoral fellow in Gallo's lab, thought he was finding some double-positive CD-4-cum-CD8 antigens on the surface of CD8 cells.

"He was doing some experiments for lymphocyte activation," Gallo recalled. "When he didn't activate, he didn't see these double-positive cells. And he asked himself, 'Is this real? Am I seeing T cells that are actually CD8-positive turning on CD4 — which I don't see until I activate?'"

Flamand, the PNAS paper's lead author, "repeated his experiments," Gallo recounted, "and lo and behold, he observed that when he activated a goodly number of the CD8 cells, they transiently expressed CD4. At this point, he asked: 'Can I infect them now when they couldn't be infected before?' He could, and did."

This contrarian finding led Gallo and his team to consider its therapeutic potential. "First of all," he pointed out, "HIV-infected people are treated with CD-positive T cells today. Adoptive immunotherapy takes them from their body when they are symptom-free, and reinfuses them back when they're in trouble.

"We know that that trouble begins in late-stage AIDS, when CD4 counts decline. We have good reasons for that, but why in late-stage disease do you see the CD8s also decline?

"In view of our observations," Gallo went on, "we were thinking that before immune suppression sets in, patients are not getting a lot of other infections. The only foreign antigen they're seeing is HIV. And while that infection is under control, CD8 T cells are not being activated at all."

Gallo continued: "But once you start getting immune impairment from the final depletion of CD4, you catch a lot of other opportunistic infections. Then the CD8 cells start to become activated in significant numbers and become susceptible to HIV invasion. That may be the main reason they decline in late-stage AIDS.

"Turning on the CD4," he said, "is what allows those cells to get infected. That's what our PNAS paper, our data, would say."

Wanted: A Gene To Turn Off CD4

This pivotal conclusion led Gallo and his team into conjectures as to possible clinical treatment. "The scientific clinicians doing adoptive therapy with CD8 T cells for HIV late infection," Gallo observed, "might want to consider ways, before reinfusing the stockpiled cells, to have those cells in a state wherein CD4 cannot be turned on. One strategy might be the gene therapy approach."

He depicted a scenario: "You have the cells in the freezer. If I'm infected and you're the doctor, you say to me, 'Hey, I'm going to take your CD8 cells, little by little, this year and next year, for possible use later in the disease.'

"Then I say to the doctor, 'Would you please find a way to put a gene in with the reinfused CD8 T cells, which would suppress the turning on of CD4, because otherwise my CD8 cells are going to get activated and killed by HIV.'"

Gallo asked rhetorically, "Do I have a program in development to do that? The answer is no. Could it be done? The answer is yes.

"Somebody will be thinking about that," he concluded, "and the arguments will go as to whether that therapeutic strategy should become routine or not. The answer will be based partly, but not totally, on these PNAS results." *

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