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Effect of Combined ART on Brain and Lymphoid Tissue Virus Burden in An Accelerated Model of SIV Encephalitis in Rhesus Macaques
Lakshmanan Annamalai*1, S Westmoreland1, D Pauley2, K Williams3, E Ratai4, M Lentz4, R Schinazi5, N Bischofberger6, G Gonzalez4, and S O'Neil1
1New England Primate Res Ctr, Harvard Med Sch, Southborough, MA, US; 2New England Primate Res Ctr, Harvard Med Sch, Southborough, MA, US; 3Boston Univ, MA, US; 4AA Martinos Ctr for Biomed Imaging, Massachusetts Gen Hosp, Charlestown, US; 5Emory Univ Sch of Med and VAMC, Atlanta, GA, US; and 6Gilead Sci, Foster City, CA, US
Background: Like lymphoid tissues, brain serves as
an important anatomical reservoir for HIV. HAART has been shown to reduce the
prevalence of HIV-associated dementia; however, the direct effect of HAART on
brain virus burden in relation to peripheral lymphoid tissue virus burden
remains unknown.
Methods: We used the CD8-depletion model of simian
immunodeficiency virus (SIV) encephalitis (SIVE) to investigate the effect of
short-term combined antiretroviral therapy (cART) on virus burden in brain and
peripheral lymphoid tissues of 8 rhesus monkeys inoculated with SIVmac251
and depleted of CD8+ T cells: 4 monkeys received cART (consisting
of daily subcutaneous injections of racivir and tenofovir) for 28 days,
beginning 28 days post-inoculation, while the remaining 4 animals served as
untreated controls. Brain specimens (frontal cortex, putamen, hippocampus, and
brainstem) and lymphoid tissues (spleen, bone marrow, and mesenteric, axillary,
and inguinal lymph nodes) were collected during necropsy and the tissue virus
burdens were measured by real time polymerase chain reaction (RT-PCR). In
addition, the extent of viral replication in tissues was evaluated by computer
image analysis on tissue sections subjected to in situ hybridization for
SIV RNA.
Results: Tissue virus burdens were lower in all
compartments of brain and lymphoid tissues from animals that received cART;
however, the differences were statistically significant only in frontal cortex,
inguinal lymph node, mesenteric lymph node, spleen, and bone marrow (p
<0.03). Productively infected cells were localized by in situ hybridization
in the brain parenchyma of both treated and untreated macaques; however,
significantly fewer SIV+ cells were observed in frontal cortex and
brainstem from animals that received cART as compared to untreated controls.
Surprisingly, we were unable to localize viral RNA by in situ hybridization
in many of the brain lesions that were present in treated animals.
Conclusions: Although virus burdens were lower in
both brain and lymphoid tissues from monkeys that received short-term cART as
compared to untreated controls, statistically significant differences were
measured in only 1 of 4 regions of brain parenchyma as opposed to 4 of 5
lymphoid organs. This suggests that longer periods of therapy may be required
to reduce brain virus burden than lymphoid virus burden, which may reflect the
longer half-life of the principal target cells in the brain (macrophages)
versus lymphoid tissues (T lymphocytes).
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