Suppression of HIV-1 infection in linomide-treated SCID-hu-PBL mice.
BACKGROUND
Proinflammatory cytokine overproduction, as well as synthesis of the inducible form of nitric oxide synthase (iNOS), are known to play a major role in HIV-1-triggered disease. AIDS patients show increased serum tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma levels, which synergize with HIV-1-produced nitric oxide (NO) to augment viral replication. Linomide has strong immunomodulatory effects in animals and humans, yielding promising clinical benefits in several pathological disorders including septic shock and autoimmune disease, processes largely mediated by overproduction of these cytokines. In peripheral T cells, linomide also prevents apoptosis triggered by a variety of stimuli, including superantigens, dexamethasone and vaccinia virus.


METHODS
Linomide inhibits production of proinflammatory cytokines such as TNF-alpha, interleukin-1 beta and IFN-gamma, as well as iNOS synthesis. The SCID-hu-PBL mouse model was used to analyse the effect of linomide on HIV-1 infection. T-cell frequency was characterized in reconstituted animals, and the frequency of infected mice and viral load of infected animals were studied.


RESULTS
Linomide promotes an increase in human CD4+ T-cell counts in the peritoneal cavity of HIV-1-infected, linomide-treated mice. Linomide also prevents human TNF-alpha and IFN-gamma production, as well as iNOS expression and affects the viral load, promoting potent suppression of HIV-1 infectivity as detected in peritoneal cavity and spleen.


CONCLUSIONS
The combination of linomide's properties, namely, blockage of proinflammatory cytokine and NO production, as well as prevention of apoptosis, is of paramount interest, making linomide a potential candidate for combating HIV-1 infection or preventing some of its associated pathological manifestations.
del Real
G
G
Department of Immunology and Oncology, Centro Nacional de Biotecnología, Universidad Autónoma, Cantoblanco, Madrid, Spain.
Llorente
M
M
Boscá
L
L
Hortelano
S
S
Serrano
A
A
Lucas
P
P
Gómez
L
L
Torán
J L
JL
Redondo
C
C
Martínez
C
C
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D017252:CD3 Complex / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D015699:HIV Envelope Protein gp120 / Q000032:analysis; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification / Q000502:physiology; D006801:Humans; D006912:Hydroxyquinolines / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000821:virology; D051379:Mice; D016513:Mice, SCID; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D010529:Peritoneal Cavity / Q000166:cytology / Q000821:virology; D013154:Spleen / Q000276:immunology / Q000821:virology; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects
D000276:Adjuvants, Immunologic; D019380:Anti-HIV Agents; D017252:CD3 Complex; D016207:Cytokines; D015699:HIV Envelope Protein gp120; D006912:Hydroxyquinolines; C045282:roquinimex; D007371:Interferon-gamma; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse