Evaluation of antiretroviral drug efficacy for HIV-1 encephalitis in SCID mice

Objectives: To compare the efficacy of the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, zidovudine (AZT), lamivudine (3TC), didanosin e (ddI), and stavudine (d4T) to inhibit viral replication in brain macropha ges. A severe combined immunodeficiency (SCID) mouse model of HIV-1 encepha litis (HIVE) was used to monitor spreading viral infection in the CNS. Back ground: The development of antiretroviral therapies with CNS efficacy again st 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) wer e inoculated into the caudate and putamen of SCID mice. This resulted in th e spreading of viral infection with a concomitant multinucleated giant cell encephalitis (astrogliosis, microglial activation, and neuronal injury). N RTIs were administered to animals at the time of intracerebral MDM inoculat ions and continued until the time of sacrifice. Antiretroviral effects were assessed by viral load and percentages of infected MDMs. Results: In brain s 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 similar to 1 log. Zidovudine, didanosine, and stavudine showed vari able effects. Conclusions: Abacavir and lamivudine showed significant antir etroviral activity in SCID mice with HIVE when compared with other NRTIs. T he extrapolation of these results to humans with HIV-1 dementia awaits futu re investigations.