title: Treatment intensification with maraviroc (CCR5 antagonist) leads to declines in CD16-expressing monocytes in cART-suppressed chronic HIV-infected subjects and is associated with improvements in neurocognitive test performance: implications for HIV-associated neurocognitive disease (HAND).
abstract: HIV-associated neurocognitive disorders (HAND) continues to be prevalent (30-50%) despite plasma HIV-RNA suppression with combination antiretroviral therapy (cART). There is no proven therapy for individuals on suppressive cART with HAND. We have shown that the degree of HIV reservoir burden (HIV DNA) in monocytes appear to be linked to cognitive outcomes. HIV infection of monocytes may therefore be critical in the pathogenesis of HAND. A single arm, open-labeled trial was conducted to examine the effect of maraviroc (MVC) intensification on monocyte inflammation and neuropsychological (NP) performance in 15 HIV subjects on stable 6-month cART with undetectable plasma HIV RNA (<48 copies/ml) and detectable monocyte HIV DNA (>10 copies/10(6) cells). MVC was added to their existing cART regimen for 24 weeks. Post-intensification change in monocytes was assessed using multiparametric flow cytometry, monocyte HIV DNA content by PCR, soluble CD163 (sCD163) by an ELISA, and NP performance over 24 weeks. In 12 evaluable subjects, MVC intensification resulted in a decreased proportion of circulating intermediate (median; 3.06% (1.93, 6.45) to 1.05% (0.77, 2.26)) and nonclassical (5.2% (3.8, 7.9) to 3.2% (1.8, 4.8)) CD16-expressing monocytes, a reduction in monocyte HIV DNA content to zero log10 copies/10(6) cells and in levels of sCD163 of 43% by 24 weeks. This was associated with significant improvement in NP performance among six subjects who entered the study with evidence of mild to moderate cognitive impairment. The results of this study suggest that antiretroviral therapy with potency against monocytes may have efficacy against HAND.
authors.affiliation: Hawaii Center for AIDS, University of Hawai'i, 651 Ilalo St, BSB 325C, Honolulu, HI, 96815, USA, lndhlovu@hawaii.edu.
authors.forename: Lishomwa C
authors.initials: LC
authors.lastname: Ndhlovu
authors.forename: Tracie
authors.initials: T
authors.lastname: Umaki
authors.forename: Glen M
authors.initials: GM
authors.lastname: Chew
authors.forename: Dominic C
authors.initials: DC
authors.lastname: Chow
authors.forename: Melissa
authors.initials: M
authors.lastname: Agsalda
authors.forename: Kalpana J
authors.initials: KJ
authors.lastname: Kallianpur
authors.forename: Robert
authors.initials: R
authors.lastname: Paul
authors.forename: Guangxiang
authors.initials: G
authors.lastname: Zhang
authors.forename: Erika
authors.initials: E
authors.lastname: Ho
authors.forename: Nancy
authors.initials: N
authors.lastname: Hanks
authors.forename: Beau
authors.initials: B
authors.lastname: Nakamoto
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Shiramizu
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Shikuma
mesh_terms: D015526:AIDS Dementia Complex / Q000188:drug therapy* / Q000503:physiopathology / Q000821:virology; D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000503:physiopathology / Q000821:virology; D000368:Aged; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D003071:Cognition / Q000187:drug effects*; D003510:Cyclohexanes / Q000627:therapeutic use*; D019468:Disease Management; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D000077592:Maraviroc; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000473:pathology / Q000821:virology; D009483:Neuropsychological Tests; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000627:therapeutic use*; D019562:Viral Load / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; C584933:CCR5 protein, human; D003510:Cyclohexanes; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D019713:Receptors, CCR5; D017452:Receptors, IgG; D014230:Triazoles; D000077592:Maraviroc