title: Impact of short-term combined antiretroviral therapy on brain virus burden in simian immunodeficiency virus-infected and CD8+ lymphocyte-depleted rhesus macaques.
abstract: 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).
authors.affiliation: Division of Comparative Pathology, New England Primate Research Center, Harvard Medical School, Southborough, MA 01772, USA.
authors.forename: Lakshmanan
authors.initials: L
authors.lastname: Annamalai
authors.forename: Veena
authors.initials: V
authors.lastname: Bhaskar
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Pauley
authors.forename: Heather
authors.initials: H
authors.lastname: Knight
authors.forename: Kenneth
authors.initials: K
authors.lastname: Williams
authors.forename: Margaret
authors.initials: M
authors.lastname: Lentz
authors.forename: Eva
authors.initials: E
authors.lastname: Ratai
authors.forename: Susan V
authors.initials: SV
authors.lastname: Westmoreland
authors.forename: R Gilberto
authors.initials: RG
authors.lastname: González
authors.forename: Shawn P
authors.initials: SP
authors.lastname: O'Neil
mesh_terms: 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
chemical_list: D044966:Anti-Retroviral Agents; D015683:Gene Products, gag; D014409:Tumor Necrosis Factor-alpha