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Vpr -- A Viral Protein is Found to Activate HIV




 

AIDS TREATMENT NEWS Issue #212, December 03, 1994

Vpr, a protein produced by HIV and found in the bloodstream of persons with HIV disease, has been found to activate HIV at low concentrations -- lower than those often found in patients' blood. A recent paper, by four University of Pennsylvania researchers, presented considerable evidence that Vpr may be involved in the development of HIV disease, stimulating latently infected cells to become productively infected when the body loses the ability to produce enough of the right antibodies to keep Vpr activity in check. Vpr also affects many kinds of human cells, so it could contribute to the damage cause by HIV, in addition to stimulating the virus itself. This is important because Vpr might easily be a target for antiviral therapy, for example by administering anti-Vpr antibodies.

The evidence that Vpr may contribute to HIV disease appears in "Serum Vpr Regulates Productive Infection and Latency of Human Immunodeficiency Virus Type 1," by David N. Levy, Yoseph Rafaeli, Rob Roy MacGregor, and David B. Weiner, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, U.S.A., November 1994.

The researchers tested the blood of eight persons with AIDS, and eight others with asymptomatic HIV infection, and found that Vpr was present in each. The levels found were correlated with the levels of p24, another protein produced by HIV. And in three patients, who had frozen blood serum collected before and after the development of late-stage disease, the Vpr increased greatly (about ten fold), comparable to the increase in p24. HIV negative blood was tested as a control, and no Vpr was found.

Vpr was also found in the cerebrospinal fluid of five HIV- positive patients with neurological disease; the levels were about the same as in the blood.

In laboratory cultures, Vpr greatly activated expression of HIV. The amount of the effect was dose dependent, with some activity found at concentrations as low as 50 times less than concentrations found in the blood. [The blood concentrations included Vpr which was bound to antibodies, and therefore would not stimulate HIV. These antibodies may be helping the body establish control of the virus after the initial primary infection, and keep control during the period of clinical latency of the illness. As immune-system damage accumulates, however, the ability to continue controlling Vpr may be lost.] Blood serum from rabbits immunized with Vpr greatly inhibited the activation of HIV by Vpr, in laboratory tests. Similarly prepared serum from non-immunized rabbits had no effect. As an additional control, in another experiment, another substance (PMA) -- not Vpr -- was used to activate HIV; in this case, the serum from the immunized rabbits had no effect. These experiments together show that the viral activation did result from the Vpr.

Another test showed that Vpr produced somewhat more and longer-lasting viral activation than either PMA or PHA, two substances often used in laboratory tests to activate HIV.

The authors mentioned the possibility that Vpr might particularly increase HIV activity in localized areas, such as the germinal centers of lymph nodes, where many infected cells are close to each other and, as a result, the level of Vpr may be high.

A November 8 article in the PHILADELPHIA INQUIRER, based on an interview with Assistant Professor David Weiner, who headed the study, suggested that Vpr and antibodies to it might be part of a "regulatory loop" that is a major determinant of HIV disease progression. Dr. Weiner suggested that either antibodies or drugs could be used to block the action of Vpr.

Comment The obvious way to find out whether this research lead has immediate practical value would be to prepare anti-Vpr antibodies and inject them into persons with HIV, to see if the viral load is decreased. Viral load -- plasma HIV RNA -- can now be measured with a simple, commercially-available blood test (either quantitative PCR, or branched DNA). Anti- Vpr drugs might take a longer time to discover and develop.

A trial could use monoclonal antibodies, which are made by genetically-engineered cells. This approach has the disadvantage that it would first be necessary to find out exactly what antibodies are needed, and then engineer them. And the lack of money for producing new monoclonal antibodies has been a serious barrier to AIDS research in other projects.

It might also be possible to obtain the antibodies from the serum of immunized animals -- a familiar, low-tech approach which has long been used in medicine.



 


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Information in this article was accurate in December 3, 1994. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.