Susceptibility of HIV type 1 to the fusion inhibitor T-20 is reduced on insertion of host intercellular adhesion molecule 1 in the virus membrane.
BACKGROUND
T-20 is a synthetic peptide that targets and blocks the entry of human immunodeficiency virus (HIV)-1 inside target cells. Data from clinical studies have shown that primary HIV-1 variants display a broad range of susceptibilities to T-20 that are mainly caused by mutations in the N-terminal heptad repeat of gp41 and by other determinants, such as envelope and coreceptor affinity, coreceptor specificity, and receptor density. We investigated whether sensitivity to this drug is affected by the incorporation of intercellular adhesion molecule (ICAM)-1 in HIV-1.


METHODS
We used laboratory isolates of HIV-1 (X4- and R5-tropic) either lacking or bearing ICAM-1 and clinical variants.


RESULTS
We demonstrate that ICAM-1-bearing virions are more resistant to T-20 than are isogenic HIV-1 particles without it. This effect is lost when ICAM-1/leukocyte function antigen-1 interactions are blocked by antibody. The mechanism through which virus-anchored host ICAM-1 is acting seems to be a reduction of the kinetic window during which the viral envelope is sensitive to T-20.


CONCLUSIONS
Altogether, these results demonstrate that the insertion of host-derived ICAM-1 into HIV-1 represents another factor that affects virus sensitivity to the entry inhibitor. These findings have potential implications for the therapeutic use of T-20.
Beauséjour
Yannick
Y
Research Center in Infectious Diseases, CHUL Research Center, Laval University, Quebec, Canada.
Tremblay
Michel J
MJ
D002460:Cell Line; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology*; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism / Q000472:pathogenicity; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000821:virology; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008561:Membrane Fusion / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology*; D014771:Virion / Q000378:metabolism*
D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D016169:Lymphocyte Function-Associated Antigen-1; D010446:Peptide Fragments; D018799:Intercellular Adhesion Molecule-1; D000077560:Enfuvirtide