N-acetyl-cysteine and L-2-oxothiazolidine-4-carboxylic acid enhance contact-dependent growth of HIV in resting peripheral blood mononuclear cells (PBMC) in vitro and increase recovery of HIV from human-PBMC SCID mice.
OBJECTIVE
To ascertain the effects of N-acetyl-cysteine (NAC) and L-2-oxothiazolidine-4-carboxylic acid (OTC) on HIV replication in resting T lymphocytes mixed with chronically infected U1 promonocytic cells; examine the phenotypes of NAC- and OTC-treated cells; and monitor HIV recovery from hu-PBMC SCID mice (SCID mice infected with HIV-1BaL reconstituted with human peripheral blood mononuclear cells) treated with oral OTC.


METHODS
Unstimulated PBMC from uninfected donors preincubated for 2 days with pH-adjusted NAC or OTC were cultured at a concentration of 1 x 10(6) cells/ml with 100 U1 cells that were chronically infected with HIV-1IIIB. HI-1 production in the presence or absence of zidovudine was measured by p24 assay at 1-3 weeks, and results were compared with values from the same cell cultures maintained without NAC or OTC exposure. In some experiments U1 cells were separated from PBMC by a 0.4 micron membrane. NAC-treated and -untreated cells were subjected to FACS analysis of multiple-cell-surface adhesion and activation molecules and the results were compared. Hu-PBMC SCID mice were fed OTC for 3 days prior to infection with HIV-1BaL and for the next 3 weeks. Mice were then sacrificed and peritoneal lavage cells were cultured for virus analysis.


RESULTS
Unstimulated, non-dividing PBMC supported high levels of HIV replication when in direct contact with U1 cells in the presence of NAC or OTC; CD2 and CD54 (I-CAM1) were down-regulated on NAC-treated PBMC; and OTC-treated mice produced significantly higher yields of HIV-1 from peritoneal cells than did untreated mice.


CONCLUSIONS
At concentrations < or = 5 mM, NAC and OTC potentiate HIV growth in unstimulated PBMC in vitro and in SCID mice. Caution in the use of these agents as antiviral monotherapies is advisable.
Chen
P
P
Department of Molecular Microbiology and Immunology, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA.
Bauer
G
G
Mitchell
J
J
Factor
R
R
Markham
R
R
Schwartz
D H
DH
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D018801:CD2 Antigens / Q000032:analysis; D002455:Cell Division; D002478:Cells, Cultured; D018920:Coculture Techniques; D015536:Down-Regulation; D005260:Female; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D007963:Leukocytes, Mononuclear / Q000821:virology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009000:Monocytes / Q000166:cytology / Q000821:virology; D010529:Peritoneal Cavity / Q000166:cytology / Q000821:virology; D011761:Pyrrolidonecarboxylic Acid; D013844:Thiazoles / Q000494:pharmacology*; D053778:Thiazolidines; D014779:Virus Replication / Q000187:drug effects*; D015215:Zidovudine / Q000494:pharmacology
D019380:Anti-HIV Agents; D018801:CD2 Antigens; D013844:Thiazoles; D053778:Thiazolidines; D018799:Intercellular Adhesion Molecule-1; D015215:Zidovudine; D011761:Pyrrolidonecarboxylic Acid; D000111:Acetylcysteine; C029536:2-oxothiazolidine-4-carboxylic acid