It takes guts for an AIDS virus to infect a T cell.
At first, virologists looked in the blood of infected individuals for the HIV particles that hijacked T cells flying the flag of CD4 receptors. Then they hunted down those doomed CD4-positive T lymphocytes in the lymphatic circulation, which ferries white blood cells around the body. Now, they're turning their attention to the intestinal tract.
Pathologist Andrew Lackner, of Harvard Medical School, in Boston, tells why:
"The virus wants to replicate," he explained, "so it seeks out its optimal target, the activated T cell, which has the appropriate CD4 receptor on its surface. And it just so happens," Lackner went on, "much to the detriment of the body, that those CD4-positive lymphocytes have an extremely significant role in controlling the immune system. Without those T cells, you're in trouble."
Lackner is senior author of a paper appearing in today's Science, dated April 17, 1998, and titled: "Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection."
"Some of the understanding of how the AIDS virus works, with its preference for activated cells," Lackner told BioWorld Today, "led us to think: 'Hey, if this virus really likes these activated cells, where are they?'"
Pursuing the Willie Sutton principle (he robbed banks because "that's where the money was"), Lackner and his co-authors followed the T cell trail to the human intestinal tract.
This coiled, elongated food-processor harbors anywhere from 40 to 80 percent of all the T lymphocytes in the body.
"In a normal human being," Lackner pointed out, "you can show fairly convincingly by flow cytometry that a much larger percentage of the cells in the intestine are activated than are activated in peripheral blood or lymph nodes.
"The gut is constantly bombarded by foreign antigens," he said, "so it's a tremendous task for the immune system to sort out which of these things are innocuous — as in breakfast — and which are potential pathogens. So it needs an awful lot of activated T cells in self-defense.
"That's why we decided we should look there," he recalled, "and we hypothesized that this intestinal site might be a key target for HIV infection. But the kinds of studies we had in mind," he continued, "would be extraordinarily difficult to do in a human, for obvious reasons."
Gut Out-Targets Blood
Lackner is head of comparative pathology at the Harvard University-affiliated New England Regional Primate Center, in Southborough, Mass. Thus, the answer to his predicament was within arm's reach. He and his co-authors recruited a contingent of macaque (rhesus) monkeys, which normally contract the symptomatic equivalent of human AIDS from simian immunodeficiency virus (SIV) — the counterpart of HIV.
His team inoculated groups of the animals intravenously with pathogenic strains of SIV. One, two, three and seven weeks later, they harvested T cells from the monkeys' large and small intestines, lymph nodes and peripheral blood, looking for signs of infection.
They found "rapid and profound depletion of CD4+ cells exclusively in the lamina propria" (a concentric layer of tissue supporting the epithelial cells that line the gut's tubular inner space). "This is consistent," the Science paper reported," with the recent finding that CD4 depletion in the intestine of HIV-infected patients selectively occurs in the lamina propria."
The low point of T cell survival in the macaques' intestines occurred as early as two to three weeks after the initial infection.
"In marked contrast," Science noted, "there were minimal changes in the percentages of CD4+ lymphocytes in the blood, spleen and lymph nodes from these same animals at the same time points."
"The key point of our findings from this experiment," Lackner observed, "would be that the intestinal tract and the lymphocytes within it are the initial and primary target for HIV infection and destruction of the CD4 cells.
"I think the important thing," he continued, "is that this initial target may result in a tremendous amplification of the amounts of virus and their seeding of the peripheral lymphoid organs. And it would appear that the intestine is the primary site of that viral amplification."
Lifting Lid On AIDS Vaccine Development
Lackner pointed to "important implications for understanding the pathogenesis of AIDS, because this large lymphoid mucosal compartment, the gut, has been poorly studied thus far. And it also has implications for future vaccine development. We have work ongoing with vaccines," he added, "looking at the intestinal tract."
He pointed out, "Many of the opportunistic infections that arise in AIDS — such as candidiasis and pneumocystis pneumonia — occur at mucosal surfaces. That doesn't say this is causative, but it is very strong circumstantial evidence."
How the viral particles get across intact mucous membranes from their initial point of entry in the body, Lackner allowed, "is an area of intense research interest."
He continued: "Obviously, for an intravenous drug abuser, the mucosa's not a barrier, because he's putting it straight into the blood. "As for heterosexual or homosexual transmission, in an individual who's already infected, the virus is shed in body secretions, including semen. In such exposures, virus in the excretions get placed onto the mucosal surfaces — vagina or rectum, or even the oral mucosa."
He concluded: "Because if — as I think we have shown — the intestines are a major site of early viral replication, you have to be able to stop the virus as early as possible, and that would appear to mean stopping it in the intestinal mucosa." *