An alteration of human immunodeficiency virus gp41 leads to reduced CCR5 dependence and CD4 independence.
Human immunodeficiency virus (HIV) type 1 infection requires functional interactions of the viral surface (gp120) glycoprotein with cell surface CD4 and a chemokine coreceptor (usually CCR5 or CXCR4) and of the viral transmembrane (gp41) glycoprotein with the target cell membrane. Extensive genetic variability, generally in gp120 and the gp41 ectodomain, can result in altered coreceptor use, fusion kinetics, and neutralization sensitivity. Here we describe an R5 HIV variant that, in contrast to its parental virus, infects T-cell lines expressing low levels of cell surface CCR5. This correlated with an ability to infect cells in the absence of CD4, increased sensitivity to a neutralizing antibody recognizing the coreceptor binding site of gp120, and increased resistance to the fusion inhibitor T-20. Surprisingly, these properties were determined by alterations in gp41, including the cytoplasmic tail, a region not previously shown to influence coreceptor use. These data indicate that HIV infection of cells with limiting levels of cell surface CCR5 can be facilitated by gp41 sequences that are not exposed on the envelope ectodomain yet induce allosteric changes in gp120 that facilitate exposure of the CCR5 binding site.
Taylor
Brian M
BM
Institute of Human Virology, School of Medicine, and Department of Microbiology and Immunology, University of Maryland Baltimore, 725 W. Lombard St., Baltimore, Maryland 21201, USA.
Foulke
J Scott
JS
Flinko
Robin
R
Heredia
Alonso
A
DeVico
Anthony
A
Reitz
Marvin
M
D000595:Amino Acid Sequence; D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002522:Chlorocebus aethiops; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*; D012680:Sensitivity and Specificity; D016415:Sequence Alignment; D013601:T-Lymphocytes / Q000378:metabolism; D014771:Virion / Q000235:genetics / Q000378:metabolism
D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D019713:Receptors, CCR5; C514793:gp120 protein, Human immunodeficiency virus 1