Simian immunodeficiency virus-infected macaques treated with highly active antiretroviral therapy have reduced central nervous system viral replication and inflammation but persistence of viral DNA.
BACKGROUND
During the era of highly active antiretroviral therapy (HAART), the prevalence of HIV-associated central nervous system (CNS) disease has increased despite suppression of plasma viremia.


METHODS
In a simian immunodeficiency virus (SIV) model system in which all animals develop AIDS and 90% develop CNS disease by 3 months after inoculation, pigtailed macaques were treated with a regimen of tenofovir disoproxil fumarate, saquinavir, atazanavir, and an integrase inhibitor starting at 12 days after inoculation and were euthanized at approximately 175 days after inoculation.


RESULTS
Plasma and cerebrospinal fluid (CSF) viral loads declined rapidly after the initiation of HAART. Brain viral RNA was undetectable at necropsy, but viral DNA levels were not different from those in untreated SIV-infected macaques. CNS inflammation was significantly reduced, with decreased brain expression of major histocompatibility complex class II and glial fibrillary acidic protein and reduced levels of CSF CCL2 and interleukin 6. Brain from treated macaques had significantly lower levels of interferon beta, type 1 interferon-inducible gene myxovirus (influenza) resistance A, and indolamine 2,3-dioxygenase messenger RNA, suggesting that immune hyperactivation was suppressed, and fewer CD4(+) and CD8(+) T cells, suggesting that trafficking of T cells from peripheral blood was reduced. Brain levels of CD68 protein and tumor necrosis factor alpha and interferon gamma RNA were reduced but were not significantly lower, indicating continued CNS inflammation.


CONCLUSIONS
These data, generated in a rigorous, high-viral-load SIV-infected macaque model, showed that HAART provided benefits with respect to CNS viral replication and inflammation but that no change in the level of viral DNA and continued CNS inflammation occurred in some macaques.
Zink
M Christine
MC
Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. mczink@jhmi.edu
Brice
Angela K
AK
Kelly
Kathleen M
KM
Queen
Suzanne E
SE
Gama
Lucio
L
Li
Ming
M
Adams
Robert J
RJ
Bartizal
Christopher
C
Varrone
John
J
Rabi
S Alireza
SA
Graham
David R
DR
Tarwater
Patrick M
PM
Mankowski
Joseph L
JL
Clements
Janice E
JE
D056704:Adaptive Immunity; D000818:Animals; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D015415:Biomarkers; D002493:Central Nervous System Diseases / Q000188:drug therapy* / Q000821:virology; D016207:Cytokines / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism; D004279:DNA, Viral; D007113:Immunity, Innate; D007249:Inflammation / Q000188:drug therapy / Q000821:virology*; D008253:Macaca mulatta; D016097:Simian Acquired Immunodeficiency Syndrome / Q000150:complications / Q000188:drug therapy*; D015302:Simian Immunodeficiency Virus; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects*
D019380:Anti-HIV Agents; D015415:Biomarkers; D016207:Cytokines; D004279:DNA, Viral