New insights into the neuroimmunity of SIV infection by magnetic resonance spectroscopy.
(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.
Harvard Medical School, Boston, MA 02115, USA. rggonzalez@partners.org
R Gilberto
RG
González
Jane B
JB
Greco
Julian
J
He
Margaret R
MR
Lentz
Shawn
S
O'Neil
Sarah J
SJ
Pilkenton
Eva M
EM
Ratai
Susan
S
Westmoreland
D000818:Animals; D023241:Antiretroviral Therapy, Highly Active; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D008212:Lymphocyte Depletion; D008253:Macaca mulatta; D008264:Macrophages / Q000276:immunology; D009682:Magnetic Resonance Spectroscopy; D015213:Neuroimmunomodulation; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology*; D015302:Simian Immunodeficiency Virus