Complexity in human immunodeficiency virus type 1 (HIV-1) co-receptor usage: roles of CCR3 and CCR5 in HIV-1 infection of monocyte-derived macrophages and brain microglia.
CCR3 has been implicated as a co-receptor for human immunodeficiency virus type 1 (HIV-1), particularly in brain microglia cells. We sought to clarify the comparative roles of CCR3 and CCR5 in the central nervous system (CNS) HIV-1 infection and the potential utility of CCR3 as a target for manipulation via gene transfer. To target CCR3, we developed a single-chain antibody (SFv) and an interfering RNA (RNAi), R3-526. Coding sequences for both were cloned into Tag-deleted SV40-dervied vectors, as these vectors transduce brain microglia and monocyte-derived macrophages (MDM) highly efficiently. These anti-CCR3 transgenes were compared to SFv-CCR5, an SFv against CCR5, and RNAi-R5, an RNAi that targets CCR5, for the ability to protect primary human brain microglia and MDM from infection with peripheral and neurotropic strains of HIV-1. Downregulation of CCR3 and CCR5 by these transgenes was independent from one another. Confocal microscopy showed that CCR3 and CCR5 co-localized at the plasma membrane with each other and with CD4. Targeting either CCR5 or CCR3 largely protected both microglia and MDM from infection by many strains of HIV-1. That is, some HIV-1 strains, isolated from either the CNS or periphery, required both CCR3 and CCR5 for optimal productive infection of microglia and MDM. Some HIV-1 strains were relatively purely CCR5-tropic. None was purely CCR3-tropic. Thus, some CNS-tropic strains of HIV-1 utilize CCR5 as a co-receptor but do not need CCR3, while for other isolates both CCR3 and CCR5 may be required.
Agrawal
Lokesh
L
Department of Pathology and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Maxwell
Christina R
CR
Department of Pathology and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Peters
Paul J
PJ
Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Clapham
Paul R
PR
Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Liu
Sue M
SM
Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW 2010, Australia.
Mackay
Charles R
CR
Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW 2010, Australia.
Strayer
David S
DS
Department of Pathology and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
D000818:Animals; D000906:Antibodies / Q000276:immunology; D001921:Brain / Q000166:cytology / Q000821:virology*; D015497:HIV-1 / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D008264:Macrophages / Q000821:virology*; D051379:Mice; D017628:Microglia / Q000821:virology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D054397:Receptors, CCR3 / Q000235:genetics / Q000378:metabolism*; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*; D015728:Receptors, HIV / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
D000906:Antibodies; D034741:RNA, Small Interfering; D054397:Receptors, CCR3; D019713:Receptors, CCR5; D015728:Receptors, HIV