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Adaptation of a CCR5-Using, Primary Human Immunodeficiency Virus Type 1 Isolate for CD4-Independent Replication

1999; American Society for Microbiology; Volume: 73; Issue: 10 Linguagem: Inglês

10.1128/jvi.73.10.8120-8126.1999

1098-5514

Peter Kolchinsky, Tajib A. Mirzabekov, Michael Farzan, Enko Kiprilov, Mark J. Cayabyab, Larissa J. Mooney, Hyeryun Choe, Joseph Sodroski,

HIV/AIDS drug development and treatment

ABSTRACT The gp120 envelope glycoprotein of the human immunodeficiency virus type 1 (HIV-1) promotes virus entry by sequentially binding CD4 and chemokine receptors on the target cell. Primary, clinical HIV-1 isolates require interaction with CD4 to allow gp120 to bind the CCR5 chemokine receptor efficiently. We adapted a primary HIV-1 isolate, ADA, to replicate in CD4-negative canine cells expressing human CCR5. The gp120 changes responsible for the adaptation were limited to alteration of glycosylation addition sites in the V2 loop–V1-V2 stem. The gp120 glycoproteins of the adapted viruses bound CCR5 directly, without prior interaction with CD4. Thus, a major function of CD4 binding in the entry of primary HIV-1 isolates can be bypassed by changes in the gp120 V1-V2 elements, which allow the envelope glycoproteins to assume a conformation competent for CCR5 binding.