Oscillation of the human immunodeficiency virus surface receptor is regulated by the state of viral activation in a CD4+ cell model of chronic infection.
We have developed a unique physiologic model of chronic human immunodeficiency virus type 1 (HIV-1) infection, OM-10.1, clonally derived from infected HL-60 promyelocytes and harboring a single integrated provirus. Unlike other models of chronic infection, OM-10.1 cultures remain CD4+ under normal culture conditions, during which less than 10% of the cells constitutively express HIV-1 proteins. However, when treated with tumor necrosis factor alpha (TNF-alpha), OM-10.1 cultures dramatically increased (greater than 35-fold) HIV-1 expression and rapidly down-modulated surface CD4, as greater than 95% of the cells became HIV-1+. The complete loss of surface CD4 following viral activation was neither associated with apparent cytopathicity nor due to a decline of available CD4 mRNA. There was, however, a temporal association between CD4 down-modulation and the accumulation of intracellular HIV-1 gp 160/120; in addition, intracellular CD4-gp 160 complexes were identifiable in OM-10.1 cell lysates at time points following TNF-alpha induction after surface CD4 was no longer detectable. Surface CD4 expression by OM-10.1 cells returned once viral activation ceased and could be repeatedly oscillated upon HIV-1 reactivation. Furthermore, inhibition of protein kinase activity following maximal TNF-alpha stimulation of OM-10.1 cells quickly returned activated HIV-1 to a state of latency, as evidenced by an accelerated return of surface CD4. These results with the new OM-10.1 cell line demonstrate that CD4 surface expression can be maintained during chronic infection and is critically dependent on the state of viral activation, that CD4-gp 160 intracellular complexing is involved in CD4 down-modulation, and that protein kinase pathways not only function in the primary induction of latent HIV-1 but also are required for maintaining the state of viral activation.
Butera
S T
ST
Retrovirus Diseases Branch, Centers for Disease Control, Atlanta, Georgia 30333.
Perez
V L
VL
Wu
B Y
BY
Nabel
G J
GJ
Folks
T M
TM
D015139:Blotting, Southern; D015704:CD4 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000382:microbiology*; D002460:Cell Line; D004279:DNA, Viral / Q000032:analysis; D015536:Down-Regulation; D015967:Gene Expression Regulation, Viral; D015686:Gene Products, env / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D019302:HIV Envelope Protein gp160; D015658:HIV Infections / Q000382:microbiology*; D015497:HIV-1 / Q000254:growth & development*; D006801:Humans; D066298:In Vitro Techniques; D011498:Protein Precursors / Q000378:metabolism; D011991:Receptors, Virus / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D015704:CD4 Antigens; D004279:DNA, Viral; D015686:Gene Products, env; D015699:HIV Envelope Protein gp120; D019302:HIV Envelope Protein gp160; D011498:Protein Precursors; D011991:Receptors, Virus; D014409:Tumor Necrosis Factor-alpha