Harmless virus prevents HIV variant from spreading in human tissue blocks

October 31, 2001

Human herpesvirus 6 (HHV-6), a common virus that is apparently harmless in adults, appears to prevent a form of the AIDS virus from reproducing in laboratory cultures of human tissue, according to a study published in the November issue of Nature Medicine.

The study was led by Leonid Margolis, Ph.D, of the National Institute of Child Health and Human Development (NICHD) and included Jean-Charles Grivel, Yoshinori Ito and Wendy Fitzgerald, as well as Paolo Lusso at the San Raffaele Scientific Institute in Milan, Italy and his coworkers.

Specifically, HHV-6 inhibits the HIV variants that transmit infection and are present at its early stages. Conversely, HHV-6 does not seem to significantly affect the HIV variants that are typical for the later stages of HIV infection.

"This finding provides insight into how a harmless virus might affect the immune system in a way that slows the reproduction of a lethal virus," said Duane Alexander, M.D., director of the NICHD. "Future research could lead to new drugs that can better help the immune system to fend off HIV, and may even lead to new strategies for designing a vaccine against HIV."

HHV-6 is common in the U.S. and other countries and does not appear to cause any disease in adults. Infants infected with HHV 6 may develop roseola, a mild rash that disappears within several days.

The study's senior author, Dr. Margolis, explained that both the early and late stage variants of HIV bind to target cells by means of a "receptor complex." In a process analogous to keys fitting into locks, molecules on the surface of HIV bind to molecules on the surface of immune cells. Once the molecular "unlocking" takes place, the virus fuses with the cell and infects it.

The process usually involves HIV binding to a receptor known as CD4. However, in order to fuse with a cell, HIV also needs to bind to another receptor on the cell's surface. HIV-1 variants that transmit infection and dominate the early stages of the infection bind to a molecule known as CCR5. People infected with these HIV-1 variants may not show any outward symptoms of HIV infection for a long period. As disease progresses, these viruses are often replaced with other variants, which bind to another receptor, CXCR4.

Dr. Margolis and his colleagues developed methods to maintain small blocks of living human tonsil tissue outside of the body and to infect them with HIV and HHV-6. Tonsils are part of the lymphoid system, the network of immune cells and molecules that police the body in search of disease causing organisms. They found that the HIV variants that use CCR5 do not reproduce as fast in tissue blocks that are also infected with HHV-6 as they do when maintained in tissues that are free of HHV 6. Conversely, the HIV-1 variants that use CXCR4 and are typical for the late stages of disease, reproduce slightly more rapidly in cultures containing HHV-6. These variants typically kill more immune cells than do the CCR5 variants.

The researchers also discovered the molecular mechanism by which HHV-6 affects HIV-1 reproduction. Tissues infected with HHV-6 produced large amounts of a molecule called RANTES. RANTES apparently blocks the CCR5 receptor-analogous to plugging up a lock with plumber's putty-so that HIV cannot fit its "key" into it. Therefore, by triggering RANTES production, HHV-6 deprives the early HIV variant of its binding site, which, in turn, prevents the HIV virus from entering the cell. As added proof of this mechanism, the researchers added RANTES to cultures containing only the CCR5-using HIV variant. As expected, the reproduction of these viruses was suppressed.

Dr. Margolis noted that the conclusion from these unexpected results is that a harmless herpesvirus-6 may play a profound role in the progression from initial infection to full-blown AIDS by suppressing an early type HIV variant and probably creating more favorable conditions for variants that use CXCR4.

Dr. Margolis added that another study he and his coworkers as well as Dr. Lusso's group have undertaken will seek to confirm their findings by analyzing samples from people infected with HIV. If so, researchers may try to devise strategies for manipulating HHV-6 to treat people infected with HIV. For example, trying to hinder or eliminate HHV-6 in patients with already established HIV infection may slow down or prevent the appearance of the CXCR4 variants that appear during HIV infection.

On the other hand, it may be possible that activating HHV-6 may either prevent HIV infection or slow the spread of this virus at the early stages.

"However, before these approaches could be developed and tested, any attempts to use HHV-6 to slow down HIV infection are risky and premature," Dr. Margolis said.

Recent studies of people with HIV disease show that those infected with two other microorganisms may develop AIDS more slowly than do people not infected with either of the two other microorganisms. The organisms areGB virus C, a hepatitis virus, and the bacteria that causes scrub typhus, a potentially lethal infection occurring in Asia and Australia. However, whether these two organisms do indeed slow down the progression of HIV infection to AIDS or their presence reflects other unknown factors that lead to a favorable HIV response is not yet known. The work of Dr. Margolis and his colleagues is the first demonstration that another virus can selectively affect infection by various HIV variants and for the first time showed the molecular mechanisms that another microorganism uses to suppress the AIDS virus.
The NICHD is part of the National Institutes of Health, the biomedical research arm of the Federal government. The Institute sponsors research on development before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. NICHD publications, as well as information about the Institute, are available from the NICHD website, http://www.nichd.nih.gov, or from the NICHD Clearinghouse, 1-800-370-2943; E-mail NICHDClearinghouse@mail.nih.gov.

NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development

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