Mode of coreceptor use by R5 HIV type 1 correlates with disease stage: a study of paired plasma and cerebrospinal fluid isolates.
Through the use of chimeric CXCR4/CCR5 receptors we have previously shown that CCR5-tropic (R5) HIV-1 isolates acquire a more flexible receptor use over time, and that this links to a reduced viral susceptibility to inhibition by the CCR5 ligand RANTES. These findings may have relevance with regards to the efficacy of antiretroviral compounds that target CCR5/virus interactions. Compartmentalized discrepancies in coreceptor use may occur, which could also affect the efficacy of these compounds at specific anatomical sites, such as within the CNS. In this cross-sectional study we have used wild-type CCR5 and CXCR4 as well as chimeric CXCR4/CCR5 receptors to characterize coreceptor use by paired plasma and cerebrospinal fluid (CSF) isolates from 28 HIV-1-infected individuals. Furthermore, selected R5 isolates, with varying chimeric receptor use, were tested for sensitivity to inhibition by the CCR5 antagonist TAK-779. Discordant CSF/plasma virus coreceptor use was found in 10/28 patients. Low CD4+ T cell counts correlated strongly with a more flexible mode of R5 virus CCR5 usage, as disclosed by an increased ability to utilize chimeric CXCR4/CCR5 receptors, specifically receptor FC-2. Importantly, an elevated ability to utilize chimeric receptors correlated with a reduced susceptibility to inhibition by TAK-779. Our findings show that a discordant CSF and plasma virus coreceptor use is not uncommon. Furthermore, we provide support for an emerging paradigm, where the acquisition of a more flexible mode of CCR5 usage is a key event in R5 virus pathogenesis. This may, in turn, negatively impact the efficacy of CCR5 antagonist treatment in late stage HIV-1 disease.
Karlsson
Ulf
U
Department of Clinical Sciences, Section for Clinical and Experimental Infection Medicine, Lund University, Lund, Sweden. ulf.karlsson@med.lu.se
Antonsson
Liselotte
L
Repits
Johanna
J
Medstrand
Patrik
P
Owman
Christer
C
Kidd-Ljunggren
Karin
K
Hagberg
Lars
L
Svennerholm
Bo
B
Jansson
Marianne
M
Gisslén
Magnus
M
Ljungberg
Bengt
B
D000577:Amides / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D018791:CD4 Lymphocyte Count; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism; D003430:Cross-Sectional Studies; D015658:HIV Infections / Q000097:blood / Q000134:cerebrospinal fluid / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000187:drug effects / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000378:metabolism; D014162:Transfection; D019562:Viral Load / Q000187:drug effects
D000577:Amides; D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5; D000644:Quaternary Ammonium Compounds; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D011993:Recombinant Fusion Proteins; C119369:TAK 779