Molecular basis for cell tropism of CXCR4-dependent human immunodeficiency virus type 1 isolates.
Laboratory isolates of human immunodeficiency virus type 1 (HIV-1) that utilize CXCR4 as a coreceptor infect primary human macrophages inefficiently even though these express a low but detectable level of cell surface CXCR4. In contrast, infection of primary macrophages by primary CXCR4-tropic HIV-1 isolates is readily detectable. Here, we provide evidence suggesting that this difference in cell tropism results from a higher requirement for cell surface CXCR4 for infection by laboratory HIV-1 isolates. Transfected COS7 cells that express a high level of CD4 but a low level of CXCR4 were infected significantly more efficiently by two primary CXCR4-tropic HIV-1 isolates compared to the prototypic laboratory HIV-1 isolate IIIB. More importantly, overexpression of either wild-type or signaling-defective CXCR4 on primary macrophages dramatically enhanced the efficiency of infection by the laboratory HIV-1 isolate yet only modestly enhanced infection by either primary CXCR4-tropic virus. Overexpression of CD4 had, in contrast, only a limited effect on macrophage infection by the laboratory HIV-1, although infection by the primary isolates was markedly enhanced. We therefore conclude that the laboratory CXCR4-tropic HIV-1 isolate exhibits a significantly higher CXCR4 requirement for efficient infection than do the primary CXCR4-tropic isolates and that this difference can explain the poor ability of the laboratory HIV-1 isolate to replicate in primary macrophages. More generally, we propose that the cell tropisms displayed by different strains of HIV-1 in culture can largely be explained on the basis of differential requirements for cell surface CD4 and/or coreceptor expression levels.
Tokunaga
K
K
Department of Genetics, Duke University Medical Center, Durham, North Carolina 27710, USA.
Greenberg
M L
ML
Morse
M A
MA
Cumming
R I
RI
Lyerly
H K
HK
Cullen
B R
BR
D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism; D019556:COS Cells; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D015870:Gene Expression; D015497:HIV-1 / Q000302:isolation & purification / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000821:virology; D016296:Mutagenesis; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D018523:Tropism
D015704:CD4 Antigens; D019718:Receptors, CXCR4