Pentoxifylline inhibits acute HIV-1 replication in human T cells by a mechanism not involving inhibition of tumour necrosis factor synthesis or nuclear factor-kappa B activation.
OBJECTIVE
To study the in vitro activity of pentoxifylline (PTX), which may be of benefit in AIDS, on cell proliferation, tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma (a type 1 cytokine) and interleukin (IL)-10 (a type 2 cytokine) production, viral replication and CD4+ depletion in acutely HIV-1-infected human T cells.


METHODS
T cells were stimulated with anti-CD3 antibody or phytohaemagglutinin (PHA) and infected with HIV-1 in presence or absence of PTX. Cell proliferation, CD4+ cell number, nuclear factor (NF)-kappa B activation, p24 antigen release or lymphokine content of the supernatants were evaluated by [3H]-thymidine incorporation, cytofluorimetry, electrophoretic mobility shift assays and specific enzyme-linked immunosorbent assay, respectively.


RESULTS
In HIV-1-infected T cells, PTX inhibited cell proliferation and p24 release and prevented CD4+ depletion associated with HIV replication. Moreover, PTX reduced TNF-alpha, IFN-gamma and IL-10 production and NF-kappa B activation. PTX inhibited with similar potency IFN-gamma, TNF-alpha and cell proliferation. However, the inhibition of p24 release and specially of IL-10 production required significantly lower doses of PTX. Exogenous addition of IL-2 or TNF-alpha in presence of PTX restore T-cell proliferation and NF-kappa B activation respectively, but did not affect p24 inhibition.


CONCLUSIONS
Our data suggest that the inhibitory effect of PTX on HIV replication cannot be satisfactorily explained by the inhibition of NF-kappa B or TNF-alpha. Moreover, PTX cannot be primarily considered as a TNF-alpha inhibitor and has several immunomodulatory and antiviral properties which could be of benefit against HIV-1 at various levels.
Navarro
J
J
Department of Immunology, Gregorio Marañón Universitary Hospital, Universidad Autonoma de Madrid, Spain.
Punzón
M C
MC
Pizarro
A
A
Fernández-Cruz
E
E
Fresno
M
M
Muñoz-Fernández
M A
MA
D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D018791:CD4 Lymphocyte Count; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D016655:HIV Core Protein p24 / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D010431:Pentoxifylline / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000821:virology*; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D016207:Cytokines; D016655:HIV Core Protein p24; D007376:Interleukin-2; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D010431:Pentoxifylline