HIV: out of sight but not inactive.
"The new findings demonstrate that significant viral activity occurs even during the prolonged period of apparent disease quiescence," says Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases in Bethesda, Md. A report by Fauci's team, one by Ashely T. Haase and his co-workers, and a related editorial on the HIV situation appear in the March 25 NATURE.
It is well known that HIV can be found in lymphoid tissues. However, this is the first time researchers have shown the extent and significance of HIV's presence in lymphoid tissues, which include the spongy lymph nodes, the spleen, the tonsils, and adenoids.
In the first report, Fauci and his colleagues collected lymphoid tissue from 12 people with HIV infection. Some of those people had the virus but showed no outward sign of their infection and appeared healthy. Others had progressed to AIDS. Fauci's team used a powerful viral detector called polymerase chain reaction and other techniques in their study.
As expected, asymptomatic people showed little evidence of HIV in the bloodstream. However, lymphoid tissue removed from the same people showed high amounts of HIV as well as evidence of HIV replication.
That finding suggests that HIV not only hides out in the lymphoid tissues but actively replicates there, creating a dangerous reservoir of virus at a time when the person appears outwardly healthy, Fauci says.
Virologists know that soon after HIV infection, HIV begins to replicate, causing flu-like symptoms in many people. After that initial illness, the disease seems to go into hiding. During this time, the so-called follicular dendritic cells in the lymphoid tissues begin to trap the HIV circulating in the bloodstream. This immune mechanism clears most HIV from the blood, Fauci says. During this early, asymptomatic period, CD4 T-lymphocytes (T-cells) migrate to the lymph nodes and become infected with the deadly virus. These T-cells are the major target of HIV.
As the disease progresses, more and more follicular dendritic cells die or become damaged. The lymphoid tissue's ability to ensnare HIV becomes limited, and the virus begins to spill out into the bloodstream, Fauci says. This is the period during which the number of T-cells begins to drop precipitously and people with HIV infection start to suffer from bouts of life-threatening infection.
The second paper adds to that view of HIV's progress. Haase, who is at the University of Minnesota in Minneapolis, and his colleagues obtained lymph node tissue from four HIV-infected people, including three who were asymptomatic. Using polymerase chain reaction and other techniques, Haase's team horned in on T-cells that had migrated to the lymph nodes. They showed that an extraordinarily large number of the cells had been infected with HIV. Indeed, Haase estimates that during the early stages of HIV infection, about 100 billion T-cells carry H IV but show no signs of viral replication. At the same time, approximately 1 billion T-cells contain actively replicating HIV.
The notion that HIV continues to reproduce even during the relatively symptom-free period of AIDS has led Haase and Fauci to conclude that a true state of latency in the disease does not exist. "I liken it to a constantly exploding volcano," Haase says. Even though the patient appears healthy, the virus never goes through a true period of total quiescence, he says.
Such findings may prompt AIDS experts to reconsider the policy of treating HIV-infected people only when some sign of deterioration appears. At present, clinicians give HIV-infected people antiviral drug therapy when their T-cell concentrations fall below 500 T-cells per cubic millimeter of blood, a point at which opportunistic infections begin to emerge.
The new findings suggest that treatment started right after infection might stand a better chance of stopping HIV's progress, says Dani P. Bolognesi at the Duke University Medical Center in Durham, N.C., who coauthored an editorial accompanying the reports.
Fauci warns that early treatment with available AIDS drugs could lead to resistance later on, a problem that could prove deadly if the virus outwits the first assault. Clinical trials must be done to prove that early treatment will benefit those with HIV infection, he adds.