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M94A2876.TXT
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1994-10-25
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Document 2876
DOCN M94A2876
TI Use of N-(4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]-1- glutamic
acid (methotrexate) (MT) in inhibiting replication of human
immunodeficiency virus-1(HIV-1) in vitro.
DT 9412
AU Kumar S; Clinical Regional Laboratory, Flossmoor, IL 60422.
SO Int Conf AIDS. 1994 Aug 7-12;10(1):204 (abstract no. PB0246). Unique
Identifier : AIDSLINE ICA10/94369699
AB OBJECTIVE: To study the possible effects of different drugs on the
activity and growth and on controlling, delaying, or preventing the
replication of the AIDS virus (HIV-1) in humans, we have used peripheral
blood lymphocytes from untreated AIDS-positive patients and studied the
effect of MT, a drug used for the treatment of various types of
carcinomas, acute lymphocytic leukemia, meningeal leukemia, etc. on the
growth of HIV in culture. METHODS: Phytohaemagglutin (PHA)-stimulated
peripheral blood lymphocytes (PHABL) were infected with isolates of
HIV-1 from five untreated patients and grown in a serum-free, synthetic,
completely chemically defined tissue culture medium containing varying
concentrations of MT. The cells were cultured at an initial
concentration of 1 x 10(6) per milliliter in 5 ml of culture media.
Appropriate concentrations of MT (0.01, 0.02, 0.04, 0.08 and 0.12
microM) were added to the cultures with no MT added to control cultures
containing cells from AIDS-positive blood samples. Cells were passaged
every 3 days and MT added so that the original drug level was
maintained. The cultures were monitored for 30 days. Fresh PHABL from
uninfected donors were added every week to replenish aged cultures.
RESULTS: Activity of supernate viral reverse transcriptase (RT)
(measured as an indicator of HIV replication) increased 2 to 5 times in
cultures that contained no MT or 0.01 uM/L of MT. No viral cells, viral
enzyme (RT) activity or HIV-1 p24 antigen production was detected in
cultures containing 0.12 uM/L of MT by day 15. No cell toxicity at
concentrations used in our experiments was observed. DISCUSSIONS AND
CONCLUSIONS: Results of our study indicate that MT inhibits the
replication of HIV-1 in culture. Virus breakthrough suppression and
complete inhibition of HIV-1 RT by MT, should prevent emergence of the
virus, once inactivated, in humans. Complete inhibition of HIV-1
replication indicates that MT therapy may be beneficial in the treatment
of HIV-1 infections and possibly, in post-exposure prophylaxis. To our
knowledge, this is the first time that a drug has been shown to inhibit
HIV-1 replication and inactivate the virus completely. While our results
strongly suggest use of MT as a drug to control replication of HIV-1,
extrapolation of in vitro experiments to clinical therapy will require
further work to determine a direct relationship on the effect of MT and
the level of HIV-1 in patients with HIV-induced persistent generalized
lymphadenopathy. Experiments are presently being performed to determine
if MT will affect the progression of viral infection, in vivo, in
animals infected with HIV.
DE Antiviral Agents/*PHARMACOLOGY Cells, Cultured Culture Media,
Conditioned/CHEMISTRY Human HIV Core Protein p24/ANALYSIS HIV-1/*DRUG
EFFECTS Lymphocytes/MICROBIOLOGY Methotrexate/*PHARMACOLOGY Reverse
Transcriptase/ANALYSIS Virus Replication/*DRUG EFFECTS MEETING
ABSTRACT
SOURCE: National Library of Medicine. NOTICE: This material may be
protected by Copyright Law (Title 17, U.S.Code).