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Neurokinin-1 Receptor Antagonist Inhibits Drug-resistant HIV-1 Infection of Monocyte-derived Macrophages in vitro
Xu Wang*1,2, S Douglas1,2, J P Lai1,2, P Tebas2, J Lathey3, and W Z Ho1,2
1Children's Hosp of Philadelphia, PA, US; 2Univ of Pennsylvania, Philadelphia, US; and 3SeraCare BioSvcs, Gaithersburg, MD, US
Background:
In spite of the
success of ART in maintaining control of HIV viral replication, treatment
failure occurs in >50% of the individuals on treatment. Cellular
targets are attractive because it might be more difficult for HIV to develop
resistance. We have shown that the
neurokinin-1 receptor (NK-1R) antagonist (CP-96,345) inhibits HIV-1 infection
of monocyte-derived macrophages (MDM) in vitro by down-regulating CCR5
expression. We have now investigated the effects of other NK-1R antagonists on
HIV infection of MDM. Among NK-1R antagonists examined in these preliminary
assays, aprepitant (an FDA-approved NK-1R antagonist, antiemetic)
had the greatest inhibitory effect on HIV Bal infection of MDM (aprepitant
>L733060 >CP-96,345 >CJ-12,255 >RP-67,580).
Methods: MDM cultured for 7 days
derived from CCR5 expressing healthy donors were treated in the presence or
absence of aprepitant (10-6
M) for 2 hours, and then
infected with drug-resistant strains
of HIV for 2 hours.
Untreated and HIV-infected MDM were used as controls. Culture supernatants were
harvested for p24 ELISA or HIV reverse transcriptase (RT) activity at different
time points after infection. R5X4
tropic, zidovudine (AZT)-resistant virus (A012:
D67N, K70R, V118I, Q207E, R211K, F214L, T215F, K219Q) (A018:
V60I, D67N, K70R, I178L, H208Y, R211K, T215Y, K219Q, L228H) and R5 tropic, RT inhibitor-resistant
virus (TC60: K65R, K101E, V106M, V108IV)
were used for infection.
Results: Aprepitant
inhibited infection of MDM with the AZT-resistant viruses (A018, A012) by 0.7 log10. Aprepitant
also suppressed infection of MDM with another RT inhibitor-resistant virus (TC
60) by 0.5 log10. Further, aprepitant significantly enhanced the
anti-HIV activity of ART (AZT, efavirenz, and indinavir). Aprepitant, in a dose-dependent manner,
inhibited infection of MDM with HIV-1 Bal, R5 strain, but had little effect on X4 strain (UG024) infection. Aprepitant
inhibited CCR5 expression on MDM, ranging from 50.5% to 29.6%. Of note,
however, we observe donor heterogeneity in both antiviral and CCR5 responses.
Conclusions: Aprepitant is active against certain HIV drug-resistant
isolates and can enhance the anti-HIV activity of certain antiretrovirals.
Aprepitant down-regulates CCR5 expression on MDM. NK-1R antagonists merit
further investigation as potential HIV therapeutic and immunomodulatory agents.
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