(1)H magnetic resonance spectroscopy (MRS) was employed to noninvasively monitor neuronal injury in eight rhesus macaques infected with simian immunodeficiency virus (SIV), whose immune system was compromised by CD8 T lymphocyte depletion and treated with
highly active antiretroviral therapy (
HAART). SIV
infection and CD8 depletion resulted in a rapid decline in cerebral
N-acetylaspartate (NAA) levels, a sensitive marker of neuronal health. Within 3 months of SIV
infection and CD8 depletion, four animals developed
AIDS and severe SIV
encephalitis. The other four macaques underwent daily doses of
HAART beginning 4 weeks after
infection/CD8 depletion.
HAART involved drugs that do not penetrate the central nervous system (CNS) including 9-[2(R)-(phosphonomethoxy)propyl]
adenine and a racemic mixture of D: -L: -enantiomers of 2',3'-dideoxy-5-fluoro-3'thiacytidine.
HAART resulted in reversal of NAA/Cr decline after 4 weeks of
therapy, and no virus or
encephalitis was found in brain samples analyzed. These results indicate that the CNS injury in
AIDS is entirely dependent on events involving the peripheral immune system mediated by trafficking of SIV-infected monocytes into the brain. The rapid decline in NAA/Cr with SIV
infection/CD8 depletion and its rapid recovery with
HAART suggest that: (1) infected monocyte turnover in the CNS is rapid, occurring in days to weeks; (2) there are endogenous mechanisms that reverse neuronal injury; and (3) a threshold level of infected monocytes/macrophages in the CNS is required to overcome the neuronal recovery processes. These observations explain the clinical success of antiretroviral
therapy in reducing the incidence of HIV-associated
dementia and minor cognitive/motor disorder and suggest novel targets for
drug development.