Impact of short-term combined antiretroviral therapy on brain virus burden in simian immunodeficiency virus-infected and CD8+ lymphocyte-depleted rhesus macaques.
Antiretroviral drugs suppress virus burden in the cerebrospinal fluid of HIV-infected individuals; however, the direct effect of antiretrovirals on virus replication in brain parenchyma is poorly understood. We investigated the effect of short-term combined antiretroviral therapy (CART) on brain virus burden in rhesus monkeys using the CD8-depletion model of accelerated simian immunodeficiency virus (SIV) encephalitis. Four monkeys received CART (consisting of the nonpenetrating agents PMPA and RCV) for four weeks, beginning 28 days after SIV inoculation. Lower virus burdens were measured by real-time RT-PCR in four of four regions of brain from monkeys that received CART as compared with four SIV-infected, untreated controls; however, the difference was only significant for the frontal cortex (P < 0.05). In contrast, significantly lower virus burdens were measured in plasma and four of five lymphoid compartments from animals that received CART. Surprisingly, despite normalization of neuronal function in treated animals, the numbers of activated macrophages/microglia and the magnitude of TNF-alpha mRNA expression in brain were similar between treated animals and controls. These results suggest that short-term therapy with antiretrovirals that fail to penetrate the blood-cerebrospinal fluid barrier can reduce brain virus burden provided systemic virus burden is suppressed; however, longer treatment may be required to completely resolve encephalitic lesions and microglial activation, which may reflect the longer half-life of the principal target cells of HIV/SIV in the brain (macrophages) versus lymphoid tissues (T lymphocytes).
Annamalai
Lakshmanan
L
Division of Comparative Pathology, New England Primate Research Center, Harvard Medical School, Southborough, MA 01772, USA.
Bhaskar
Veena
V
Pauley
Douglas R
DR
Knight
Heather
H
Williams
Kenneth
K
Lentz
Margaret
M
Ratai
Eva
E
Westmoreland
Susan V
SV
González
R Gilberto
RG
O'Neil
Shawn P
SP
D000818:Animals; D044966:Anti-Retroviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D015683:Gene Products, gag / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008221:Lymphoid Tissue / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008253:Macaca mulatta / Q000821:virology*; D008264:Macrophages / Q000378:metabolism; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000473:pathology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects
D044966:Anti-Retroviral Agents; D015683:Gene Products, gag; D014409:Tumor Necrosis Factor-alpha