Objective: To examine the inter-relationship between HIV-1 infection a
nd the cell surface receptors for tumor necrosis factor (TNF)-alpha, a
n immunoregulatory cytokine that can enhance HIV-1 replication. Design
: Infected promyelocytic and promonocytic cells were examined because
they normally express both types of TNF receptors. Methods: TNF recept
or surface expression was determined by specific monoclonal antibody r
ecognition and flow cytometry, and signal transduction was detected by
gel shift analysis. HIV-1 activation and expression was quantitated b
y reverse transcriptase assay. Results: In the OM-10.1 promyelocytic m
odel of chronic infection, TNF-alpha-induced HIV-1 expression also res
ulted in a substantial increase in 75 kd TNF receptor (TR75) expressio
n although 55 kD TNF receptor (TR55) levels were not dramatically alte
red. A series of uninfected parental HL-60 subclones all reduced TR75
surface expression in response to TNF-alpha treatment. Enhanced TR75 e
xpression on OM-10.1 cells followed the same TNF-alpha-dose dependency
as that observed for HIV-1 production. An increase in TR75 expression
was also evident during the peak of an acute HIV-1 infection of HL-60
promyelocytes. Although TR55 expression was unaltered during TNF-alph
a-induced HIV activation, this receptor was still involved in the vira
l activation process. Antibody cross-linking of TR55, in the absence o
f exogenous TNF-alpha, induced maximal HIV-1 expression, an up-modulat
ion of surface TR75, and nuclear NF-kappaB activity in OM-10.1 culture
s. Surprisingly, this was the case even when an antagonistic anti-TR55
antibody was used. Anti-TR55 antibody cross-linking in chronically in
fected U1 promonocytic cultures could only partially substitute for TN
F-alpha-induced HIV-1 expression. Conclusions: Our results demonstrate
d that HIV-1 infection can selectively influence the surface expressio
n of TNF receptors, potentially influencing its own expression and alt
ering normal immunoregulatory signal transduction.