Differences in CD4 dependence for infectivity of laboratory-adapted and primary patient isolates of human immunodeficiency virus type 1.
CD4 is known to be an important receptor for human immunodeficiency virus type 1 (HIV-1) infection of T lymphocytes and macrophages. However, the limiting steps in CD4-dependent HIV-1 infections in vivo and in vitro are poorly understood. To address this issue, we produced a panel of HeLa-CD4 cell clones that express widely different amounts of CD4 and quantitatively analyzed their infection by laboratory-adapted and primary patient HIV-1 isolates. For all HIV-1 isolates, adsorption from the medium onto HeLa-CD4 cells was inefficient and appeared to be limiting for infection in the conditions of our assays. Adsorption of HIV-1 onto CD4-positive peripheral blood mononuclear cells was also inefficient. Moreover, there was a striking difference between laboratory-adapted and primary T-cell-tropic HIV-1 isolates in the infectivity titers detected on different HeLa-CD4 cells. Laboratory-adapted HIV-1 isolates infected all HeLa-CD4 cell clones with equal efficiencies regardless of the levels of CD4, whereas primary HIV-1 isolates infected these clones in direct proportion to cellular CD4 expression. Our interpretation is that for laboratory-adapted isolates, a barrier step that preceeds CD4 encounter was limiting and the subsequent CD4-dependent virus capture process was highly efficient, even at very low cell surface concentrations. In contrast, for primary HIV-1 isolates, the CD4-dependent steps appeared to be much less efficient. We conclude that primary isolates of HIV-1 infect inefficiently following contact with surfaces of CD4-positive cells, and we propose that this confers a selective disadvantage during passage in rapidly dividing leukemia cell lines. Conversely, in vivo selective pressure appears to favor HIV-1 strains that require large amounts of CD4 for infection.
Kabat
D
D
Department of Biochemistry and Molecular Biology, Oregon Health Sciences University, Portland 97201-3098.
Kozak
S L
SL
Wehrly
K
K
Chesebro
B
B
D000220:Adaptation, Biological; D000327:Adsorption; D015704:CD4 Antigens / Q000235:genetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015497:HIV-1 / Q000254:growth & development* / Q000302:isolation & purification; D006367:HeLa Cells; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000382:microbiology; D012641:Selection, Genetic; D012692:Serial Passage; D014776:Virus Cultivation / Q000379:methods; D014779:Virus Replication / Q000187:drug effects
D015704:CD4 Antigens