Neuroprotective maraviroc monotherapy in simian immunodeficiency virus-infected macaques: reduced replicating and latent SIV in the brain.
OBJECTIVE
HIV-associated neurocognitive deficits remain a challenge despite suppressive combined antiretroviral therapy. Given the association between HIV-induced central nervous system (CNS) disease and replication of HIV in immune-activated macrophages, CCR5 antagonists may attenuate CNS disease by modulating inflammatory signaling and by limiting viral replication.


METHODS
To establish whether initiating CCR5 inhibition during early infection altered CNS disease progression, outcomes were compared between simian immunodeficiency virus (SIV)-infected macaques treated with maraviroc (MVC) versus untreated SIV-infected macaques.


METHODS
Six SIV-infected rhesus macaques were treated with MVC monotherapy for 5 months beginning 24 days postinoculation; 22 SIV-infected animals served as untreated controls. SIV RNA levels in plasma, cerobrospinal fluid, and brain, and CNS expression of TNFα and CCL2 were measured by qRT-PCR. Immunostaining for CD68 and amyloid precursor protein in the brain was measured by image analysis. Plasma sCD163 was measured by ELISA.


RESULTS
SIV RNA and proviral DNA levels in brain were markedly lower with MVC treatment, demonstrating CCR5 inhibition reduces CNS replication of SIV and may reduce the CNS latent viral reservoir. MVC treatment also lowered monocyte and macrophage activation, represented by CNS CD68 immunostaining and plasma sCD163 levels, and reduced both TNFα and CCL2 RNA expression in brain. Treatment also reduced axonal amyloid precursor protein immunostaining to levels present in uninfected animals, consistent with neuroprotection.


CONCLUSIONS
CCR5 inhibitors may prevent neurologic disorders in HIV-infected individuals by reducing inflammation and by limiting viral replication in the brain. Furthermore, CCR5 inhibitors may reduce the latent viral reservoir in the CNS. Adding CCR5 inhibitors to combined antiretroviral regimens may offer multiple neuroprotective benefits.
aDepartment of Molecular and Comparative Pathobiology bDepartment of Pharmacology and Molecular Sciences cDivision of Clinical Pharmacology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland dDepartment of Biostatistics, Texas Tech University School of Medicine, El Paso Texas eDepartment of Neurology fDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Kathleen M
KM
Kelly
Sarah E
SE
Beck
Kelly A
KA
Metcalf Pate
Suzanne E
SE
Queen
Jamie L
JL
Dorsey
Robert J
RJ
Adams
Lindsay B
LB
Avery
Walter
W
Hubbard
Patrick M
PM
Tarwater
Joseph L
JL
Mankowski
D000818:Animals; D015703:Antigens, CD / Q000032:analysis / Q000097:blood; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis / Q000097:blood; D001921:Brain / Q000473:pathology / Q000821:virology*; D065100:CCR5 Receptor Antagonists / Q000627:therapeutic use*; D018932:Chemokine CCL2 / Q000134:cerebrospinal fluid; D003510:Cyclohexanes / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D008253:Macaca mulatta; D000077592:Maraviroc; D010949:Plasma / Q000821:virology; D012367:RNA, Viral / Q000097:blood / Q000134:cerebrospinal fluid; D060888:Real-Time Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000097:blood; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000302:isolation & purification*; D014230:Triazoles / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000134:cerebrospinal fluid; D019562:Viral Load; D000098902:CD163 Antigen; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D065100:CCR5 Receptor Antagonists; D018932:Chemokine CCL2; D003510:Cyclohexanes; D000077592:Maraviroc; D012367:RNA, Viral; D011956:Receptors, Cell Surface; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; D000098902:CD163 Antigen; C067980:CD68 antigen, human; D000097382:CD68 Molecule