Tumor necrosis factor-alpha and nitric oxide in vertically HIV-1-infected children: implications for pathogenesis.
We performed a cross-sectional study to investigate the plasma TNF-alpha and nitric oxide (NO) production in 44 vertically HIV-1-infected children, and the relationship with immunological status and viral replication. As a control group, 36 healthy, uninfected children were studied. Plasma TNF-alpha and NO levels were determined by ELISA. Viral load was quantified using standard assays. Cell proliferation, apoptosis and viral replication were evaluated in vitro by incorporation of (3H)-thymidine, flow cytometry and p24 antigen, respectively. Higher plasma TNF-alpha and NO levels were observed in HIV-1-infected children compared with healthy controls. We found a very strong correlation between plasma TNF-alpha and NO levels in HIV-1-infected children (r = 0.98; p < 0.001). Moreover, HIV-1-infected children with higher viral load (> 4.7 log10) showed higher TNF-alpha and NO levels than those with viral load below this threshold. Interestingly, we detected inducible nitric oxide synthase (iNOS) mRNA in T-lymphocytes from HIV-1-infected children. To address their possible patho-physiological significance, we tested the in vitro effects of NO and TNF-alpha in HIV-1 replication. Addition of TNF-alpha and NO donors to mitogen-activated, HIV-1-infected PBMC cultures produced a significant increase in viral replication. Moreover, HIV-1 replication in mitogen-stimulated, PBMC cultures was partially inhibited by iNOS specific inhibitors, and a neutralising, anti-TNF-alpha monoclonal antibody. Our results indicate that TNF-alpha and NO correlated with high viral load in HIV-1-infected children and favoured HIV-1 in vitro replication. These data suggest a detrimental role of NO in HIV-1 infection, and that NOS inhibitors may have some therapeutic benefit in HIV-1-infection.
González-Nicolás
J
J
Departamento de Inmunología, Hospital General Universitario "Gregorio Marañón", C/ Doctor Esquerdo 46, 28007 Madrid, Spain.
Resino
S
S
Jiménez
J L
JL
Alvarez
S
S
Fresno
M
M
Muñoz-Fernández
M A
MA
D002478:Cells, Cultured; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D004305:Dose-Response Relationship, Drug; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D015658:HIV Infections / Q000276:immunology* / Q000635:transmission / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology / Q000472:pathogenicity*; D006801:Humans; D018445:Infectious Disease Transmission, Vertical; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis / Q000097:blood* / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects / Q000276:immunology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D014409:Tumor Necrosis Factor-alpha; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase