title: A novel chemokine-receptor-5 (CCR5) blocker, SCH532706, has differential effects on CCR5+CD4+ and CCR5+CD8+ T cell numbers in chronic HIV infection.
abstract: HIV treatment with CCR5 receptor blockers may impact CCR5(+) cell distribution. T cell subsets, plasmacytoid dendritic cells (PDC), and antigen-specific [Mycobacteria tuberculosis/avium (M.TB/MAI), cytomegalovirus (CMV), Herpes simplex (HSV), HIV-Gag] CD4(+) T cells were measured in untreated R5-tropic-HIV-infected adults receiving 10 days of SCH532706 (Phase 1), 15 days no therapy, then 10 days of cART (without SCH532706) (Phase 2). Ten males were enrolled with median cells/microl (range) of CD4(+) 310 (92-848), CCR5(+)CD4(+) 57 (17-118), CD8(+) 895 (459-1666), and CCR5(+)CD8(+) 392 (250-983), and median plasma HIV RNA of 4.6 log(10) copies/ml. At baseline, proportions of M.TB, MAI, CMV, HSV, and HIV-Gag-specific CD4(+) T cells were 0.3%, 3.0%, 6.0%, 2.0%, and 1.6%, respectively. Median log(10) HIV RNA copies/ml declines were 1.5 (Phase 1) and 1.75 (Phase 2) (p = 0.7). Median CD4(+) and CD8(+) changes, respectively, during Phases 1 (+16; +91) and 2 (+28; -71) were similar (p = 0.7 both). However, CCR5(+)CD8(+) T cell fluctuations were significantly different (p = 0.02) during Phase 1 (+147 cells) vs. Phase 2 (-35 cells). PDC increased significantly more during Phase 1 (p = 0.04). Declines in antigen-specific cells were similar except for M. avium, which declined significantly during Phase 2 (p = 0.04). Similar declines in activation and proliferation of T cell subsets were observed during both treatment phases. For equivalent HIV RNA declines, CCR5-receptor blockade differentially increased CD8(+) T cell and PDC numbers in the circulation. These results confirm that cell surface CCR5 expression on these cells constantly directs trafficking during HIV infection. The persistence and clinical meaning of these immunological changes during long-term exposure to this class of anti-HIV drugs are unknown, but may have implications for immunosurveillance of inflammation.
authors.affiliation: HIV, Immunology and Infectious Diseases Clinical Services Unit, St. Vincent's Hospital, Sydney, Australia. spett@nchecr.unsw.edu.au
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Pett
authors.forename: John
authors.initials: J
authors.lastname: Zaunders
authors.forename: Michelle
authors.initials: M
authors.lastname: Bailey
authors.forename: John
authors.initials: J
authors.lastname: Murray
authors.forename: Karen
authors.initials: K
authors.lastname: MacRae
authors.forename: Sean
authors.initials: S
authors.lastname: Emery
authors.forename: David A
authors.initials: DA
authors.lastname: Cooper
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Kelleher
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D065100:CCR5 Receptor Antagonists; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects*; D003587:Cytomegalovirus / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy*; D018259:Herpesvirus 1, Human / Q000276:immunology; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects*; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists