Viruses play a deadly game of hide-and-seek. But it's really more like blind man's buff.

Take the simple cold sore, or fever blister. It comes without warning, and goes away as a rule in 10 days or so. Then it returns, again and again. In between attacks, the Herpes labialis virus hides out inaccessibly in the trigeminal ganglion of the facial nerve.

Or consider the varicella-zoster virus, which causes chickenpox in young children, and decades later, shingles, a more serious infection, in adults. During all those years of latency, the virus hibernates out of sight in nerve ganglions of the torso.

Then, of course, there's HIV, the human immunodeficiency virus, perpetrator of AIDS.

The current two-plus-one triple drug therapy against HIV infection — two retroviral blockers plus one protease inhibitor — can reduce a body's viral load almost to the vanishing point. Almost, but not quite. Somewhere in its still unknown sanctuary, HIV lies low, ready to flare up if the triple drug regimen's guard is lowered.

Today's Nature and tomorrow's Science report three pivotal patient studies that track the AIDS virus in its onslaught from bloodstream to lymphoid tissues, under siege by the triple-drug regimen. All three papers ask if and when it will ever be possible to extirpate the very last HIV infective virion, and leave the individual 100 percent virus-free.

Virologist Ashley Haase, who chairs microbiology at the University of Minnesota in Minneapolis, reports his finding in Friday's Science, dated May 9, 1997. The paper, of which he is senior author, bears the title: "Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection."

He and his co-authors found that the three-drug treatment, over a period of six months, eradicated 99.9 percent of the estimated 100 billion HIVs infecting an individual's lymphoid tissues — from thymus, spleen and lymph nodes to tonsils. Those tissues, rich in T cells, B cells, and macrophages, which man the immune defense battlements, are vast, compared to the bloodstream, into which the virus makes its entry.

One percent of a human body's weight consists of lymphoid tissue. It contains all of the immune system's cells except one to two percent in the bloodstream.

"Even though that drug-induced 99.9 percent HIV wipe-out leaves only a very small fraction, 0.1 percent, of sequestered virus," Haase told BioWorld Today, "it's a fraction of a very big number; it's 100 million viruses. We're still left with that pool of follicular dendritic cells [FDC]."

FDCs, Haase explained, "are like antigen depots. Any antigen, whether virus and other particles, pollen or whatever, is stored on the surface of these cells." Then, the FDCs are "presented" to components of the immune system, triggering its action to remove the intruder.

The rub is that the immune system itself is the primary target of attack by HIV. In the ding-dong battle that follows the first viral infection of T cells in the bloodstream, immune defenses grow weaker as the proliferating virus grows stronger.

"The drug therapy, which vastly decreases the amount of virus in the system," Haase observed, "opens a window of opportunity for the immune system to recover. Most clinicians who are using these drug therapies," he added, "are seeing clinical benefit, in the sense that there are fewer hospitalizations, and patients are not developing the same opportunistic infections. But recovery of the immune system is relatively slow, so there is still a substantive risk."

Haase and his co-authors studied ten HIV-positive adults just as they began the triple-drug regimen. They measured the virus in fingernail-size tonsil tissue biopsies from these subjects, and found that at the outset of their anti-HIV treatment, half of the infected CD4-positive T cells that were producing virus disappeared in less than a day. And it took only 1.7 days to clear half the virus particles from FDCs. At six months, 99.9 percent of the virus had been eliminated. "Though the impact of treatment on the major tissue reservoir is quite gratifying," Haase said, "it still looks as if this is still a persistent infection, which will require chronic therapy, perhaps for life."

He compared this outlook to that confronting a cancer patient in remission induced by chemotherapy. "There's some kind of maintenance or consolidation treatment, and you're in for the long term. The real question is: How long is long?"

Cutting Off HIV Invasion At Bloodstream Pass

Today's Nature, dated May 8, 1997, explores this question from the perspective of HIV infection in the bloodstream, rather than lymphoid tissues.

In a paper titled "Decay characteristics of HIV-infected compartments during combination therapy," retrovirologist David Ho of the Aaron Diamond AIDS Research Center in New York, reported that eight HIV-positive patients had viral-load decreases of 93 to 99 percent in their blood during the first two weeks of triple-drug treatment.

This brisk initial rate of viremia decay slowed down in subsequent weeks, perhaps reflecting the elimination of cells such as macrophages, infected before the therapy began.

Employing mathematical analytical algorithms, Ho and his co-authors concluded that "known compartments of virus could be completely eliminated after 2.3 to 3.1 years of treatment with a 100-percent inhibitory antiretroviral regimen. However, to eradicate HIV-1 completely from an infected person, treatment may need to be administered for a longer period, because of the possible existence of small, undetected...sanctuary sites (such as the brain) which are impenetrable by some or all of the retroviral drugs."

A companion paper in today's Nature, by Robert Siliciano of Johns Hopkins University, in Baltimore, reports on "Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection."

It concludes: "[A]lthough latently infected CD4-positive T cells are present at low frequency, the importance of this small reservoir should not be underestimated, because memory CD4-positive T cells can survive for months and possibly years. Defining the rate of turnover of this reservoir will be an important next step."

"What I think we can tell HIV-positive patients," Haase suggested, "is: 'This triple-drug regimen is the best opportunity we have seen for you to feel better, and your immune system to get back on the road to health. We don't know how long you're going to have to hang in there with this, but it's important that you do, because in the interim there's going to be — hopefully — progress in simplifying the regimens and side effects.'" *