Evaluation of antiretroviral drug efficacy for HIV-1 encephalitis in SCID mice.
OBJECTIVE
To compare the efficacy of the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, zidovudine (AZT), lamivudine (3TC), didanosine (ddI), and stavudine (d4T) to inhibit viral replication in brain macrophages. A severe combined immunodeficiency (SCID) mouse model of HIV-1 encephalitis (HIVE) was used to monitor spreading viral infection in the CNS.


BACKGROUND
The development of antiretroviral therapies with CNS efficacy against neuroinvasive virus is important if eradication of HIV-1 can be achieved within critical "hidden reservoirs."


METHODS
HIV-1-infected human monocyte-derived macrophages (MDMs) (after a single round of viral replication) were inoculated into the caudate and putamen of SCID mice. This resulted in the spreading of viral infection with a concomitant multinucleated giant cell encephalitis (astrogliosis, microglial activation, and neuronal injury). NRTIs were administered to animals at the time of intracerebral MDM inoculations and continued until the time of sacrifice. Antiretroviral effects were assessed by viral load and percentages of infected MDMs.


RESULTS
In brains of SCID mice with HIVE, abacavir and lamivudine reduced HIV-1 p24 antigen-positive cells by 80% and 95%, respectively, whereas both decreased viral load by approximately 1 log. Zidovudine, didanosine, and stavudine showed variable effects.


CONCLUSIONS
Abacavir and lamivudine showed significant antiretroviral activity in SCID mice with HIVE when compared with other NRTIs. The extrapolation of these results to humans with HIV-1 dementia awaits future investigations.
Limoges
J
J
Department of Internal Medicine, University of Nebraska Medical Center, Omaha 68198-5215, USA.
Persidsky
Y
Y
Poluektova
L
L
Rasmussen
J
J
Ratanasuwan
W
W
Zelivyanskaya
M
M
McClernon
D R
DR
Lanier
E R
ER
Gendelman
H E
HE
D015526:AIDS Dementia Complex / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D016049:Didanosine / Q000494:pharmacology; D015224:Dideoxynucleosides / Q000494:pharmacology*; D004195:Disease Models, Animal; D015497:HIV-1; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009000:Monocytes / Q000166:cytology / Q000821:virology; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D018119:Stavudine / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000494:pharmacology; D000099227:Abacavir
D016049:Didanosine; D015224:Dideoxynucleosides; D019259:Lamivudine; D018894:Reverse Transcriptase Inhibitors; D018119:Stavudine; D015215:Zidovudine; D000099227:Abacavir