The efficacy of potent anti-retroviral drug combinations tested in a murine model of HIV-1 encephalitis.
Development of anti-retroviral regimens with enhanced efficacy against brain HIV-1 is essential if viral eradication is to be achieved. To address this, a severe combined immune deficiency mouse model of HIV-1 encephalitis was used to assay the effect of protease-containing and protease-sparing drug regimens on viral replication in brain macrophages. Here, HIV-1-infected human monocyte-derived macrophages (MDM) are inoculated into basal ganglia, causing a multinucleated giant cell encephalitis reminiscent of human disease. Drugs were administered at the time of MDM inoculation and continued until sacrifice. Immunohistochemical tests evaluated ongoing viral replication, glial immunity, and neuronal survival. Treatment with ddI/d4T decreased the numbers of infected cells by 75%, while ddI/d4T/amprenavir or ZDV/3TC/ABC diminished infection by 98%. Triple drug regimens decreased astrogliosis by > or = 25%. This small-animal model may be used to screen drug regimens that affect ongoing HIV-1 replication within its brain sanctuary.
Limoges
J
J
Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198-5215, USA.
Poluektova
L
L
Ratanasuwan
W
W
Rasmussen
J
J
Zelivyanskaya
M
M
McClernon
D R
DR
Lanier
E R
ER
Gendelman
H E
HE
Persidsky
Y
Y
D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D001479:Basal Ganglia / Q000473:pathology / Q000821:virology; D001812:Blood-Brain Barrier; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D018792:Encephalitis, Viral / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D008264:Macrophages / Q000637:transplantation / Q000648:ultrastructure / Q000821:virology; D051379:Mice; D016513:Mice, SCID; D008854:Microscopy, Electron; D009457:Neuroglia / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure / Q000821:virology; D009474:Neurons / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology / Q000821:virology; D014463:Ultrasonography; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents