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Blocking of HIV-1 Infection by Targeting CD4 to Nonraft Membrane Domains

Gustavo del Real, Sonia Jiménez-Baranda, Rosa Ana Lacalle, Emilia Mira, Pilar Lucas, Concepción Gómez-Moutón, Ana C. Carrera, Carlos Martínez-A. and Santos Mañes

Department of Immunology and Oncology, Centro Nacional de Biotecnología/Spanish Council for Scientific Research (CSIC), E-28049 Madrid, Spain

Address correspondence to Santos Mañes, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, UAM Campus de Cantoblanco, E-28049 Madrid, Spain. Phone: 34-91-585-4660; Fax: 34-91-372-0493; E-mail: smanes{at}cnb.uam.es

Human immunodeficiency virus (HIV)-1 infection depends on multiple lateral interactions between the viral envelope and host cell receptors. Previous studies have suggested that these interactions are possible because HIV-1 receptors CD4, CXCR4, and CCR5 partition in cholesterol-enriched membrane raft domains. We generated CD4 partitioning mutants by substituting or deleting CD4 transmembrane and cytoplasmic domains and the CD4 ectodomain was unaltered. We report that all CD4 mutants that retain raft partitioning mediate HIV-1 entry and CD4-induced Lck activation independently of their transmembrane and cytoplasmic domains. Conversely, CD4 ectodomain targeting to a nonraft membrane fraction results in a CD4 receptor with severely diminished capacity to mediate Lck activation or HIV-1 entry, although this mutant binds gp120 as well as CD4wt. In addition, the nonraft CD4 mutant inhibits HIV-1 X4 and R5 entry in a CD4⁺ cell line. These results not only indicate that HIV-1 exploits host membrane raft domains as cell entry sites, but also suggest new strategies for preventing HIV-1 infection.

Key Words: CD4 • lipid rafts • HIV-1 • Lck • infection inhibition

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