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
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
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.
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.