Highly active antiretroviral therapy and human immunodeficiency virus encephalitis

Abstract

The ability of highly active antiretroviral therapy (HAART) to prevent the onset of HIV-associated dementia and to prevent or reduce the neuropathological features of HIV encephalitis (HIVE) remains unclear. Using a severe combined immunodeficient (SCID) mouse model of HIVE, we determined the effects of regular HAART treatment on HIVE. Before studying HAART in infected SCID mice, nonmanipulated SCID mice were treated with a single injection of the HAART cocktail (consisting of zidovudine, lamivudine, and indinavir) to determine optimum dosage and sampling time and to measure antiretroviral levels in the brain. After these preliminary studies, SCID mice that were inoculated with either HIV-infected or uninfected human monocytes were given intraperitoneal (IP) injections of HAART three times daily over a 1- and 2-week period. All three drugs were detected in the brain using a novel drug extraction technique and a modified high-performance liquid chromatography method. HAART significantly decreased the amount of astrogliosis and viral load in treated mice compared with mice that received vehicle injections. These studies offer insight into the ability of HAART to treat HIV infection of the brain.

Chronic cocaine exposure in the SCID mouse model of HIV encephalitis

“…Brains of mice inoculated with uninfected cells also showed presence of human macrophages (p24 negative); however, in comparison to the HIV-infected group, fewer multinucleated giant cells were observed. Although seen in greatest quantity around the injection track, these cells frequently spread to adjacent brain parenchyma as previously reported (Avgeropoulos et al, 1998b;Cook et al, 2005;Griffin et al, 2004). Finally, as expected, the numbers of HIV-infected cells (positive for p24 staining) were equivalent for cocaine treated vs vehicle HIV-infected mice indicating that the numbers of cells in the xenografts were similar.…”

“…The neuropathology was evaluated by WRT who was blinded to the animals' treatment history. Pathological analysis revealed the presence of human macrophages (EBM/ 11; DAKO; 1:50), p24+ human macrophages (DAKO; 1:50), and multinucleated giant cells in HIV-infected mice as previously reported (Avgeropoulos et al, 1998b;Cook et al, 2005;Griffin et al, 2004). Brains of mice inoculated with uninfected cells also showed presence of human macrophages (p24 negative); however, in comparison to the HIV-infected group, fewer multinucleated giant cells were observed.…”

“…To control for the effects of human macrophages themselves, a separate group of mice were inoculated with uninfected macrophages. The cell culture and inoculation procedures for the current study were identical to recent reports (Avgeropoulos et al, 1998b;Cook et al, 2005;Griffin et al, 2004). Briefly, 10 8 purified primary human macrophages were cultured in the presence of monocyte colony stimulating factor (M-CSF).…”

“…After snap freezing, brains were sectioned at 5 microns and the tissue sections were stained according to our previously published protocols (Avgeropoulos et al, 1998b;Cook et al, 2005;. The neuropathology was evaluated by WRT who was blinded to the animals' treatment history.…”

“…Astrogliosis (anti-GFAP; Chemicon; 1:750) and microgliosis (F4/80; Caltag; 1:20) were graded according to a 4-point scale (Cook et al, 2005;Griffin et al, 2004). The section with the highest score from each mouse was used for the data summarized in Fig.…”