CXCR4 mediates entry and productive infection of syncytia-inducing (X4) HIV-1 strains in primary macrophages.
CCR5 and CXCR4 are the main coreceptors for non-syncytia-inducing (NSI) and syncytia-inducing (SI) HIV-1 strains, respectively. NSI HIV-1 isolates do not infect either human lymphoid or monocytoid cell lines, and this inability correlates with the absence of CCR5 expression in these cell types. The ability of SI HIV-1 isolates to infect human primary macrophages has been disputed. Here, we report that CXCR4 is expressed in primary blood-derived human mononuclear phagocytes at all stages of differentiation, although the maturation process correlates with downregulation of CXCR4 mRNA. Infection experiments with the SI molecular clone NL4-3 tagged with a mutant of the green fluorescent protein established that both monocytes and attached macrophages are susceptible to infection with CXCR4-restricted HIV-1 strains. NL4-3 entry into primary macrophages could be blocked by SDF-1alpha in a dose-dependent manner, or by the anti-CXCR4 monoclonal antibody 12G5. HIV-1 entry led to productive infection. No evidence of postentry defects or nuclear import delay for CXCR4-restricted HIV-1 strains was detected using a quantitative real-time PCR assay measuring HIV-1 DNA entry into the nucleus. Macrophages infected by HIV-1 and expressing virus were maintained in culture for long periods of time (up to 5 months). These results demonstrate that CXCR4 is the main HIV-1 SI coreceptor in human primary macrophages and underline the importance of the macrophage as a long-living viral reservoir for HIV-1.
Valentin
A
A
Human Retrovirus Section ABL-Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland, 21702-1201, USA.
Trivedi
H
H
Lu
W
W
Kostrikis
L G
LG
Pavlakis
G N
GN
D002478:Cells, Cultured; D003001:Cloning, Molecular; D005434:Flow Cytometry; D015497:HIV-1 / Q000472:pathogenicity; D006801:Humans; D008264:Macrophages / Q000821:virology*; D016133:Polymerase Chain Reaction; D019718:Receptors, CXCR4 / Q000502:physiology*; D012260:Ribonucleases / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology
D019718:Receptors, CXCR4; D012260:Ribonucleases