The physiological relevance of CD4 receptor down-modulation during HIV infection.
Upon binding to the CD4 receptor the HIV envelope protein undergoes conformational changes that culminate in the fusion of the viral and cellular membranes. A few hours later, a sophisticated set of processes is initiated to ensure the down-modulation of the viral receptor. Three viral proteins participate in this process: Nef, Env, and Vpu, suggesting that this function is critical for virus replication. The mechanisms of action of these proteins have been extensively characterized. However, the physiological relevance of the virus-induced CD4 down-modulation remains a focus of controversy, and the impact of this function on the viral life cycle has been underestimated. This review summarizes current hypotheses explaining why HIV needs to reduce expression of its own receptor, and discusses the experimental evidence supporting them. Recent findings indicate that efficient CD4 down-modulation is essential for the production of infectious particles, and highlight the importance of this function in HIV pathogenesis in vivo. Progression to disease correlates with enhanced viral induced CD4 down-modulation, and a subset of long-term nonprogressors carry viruses defective in this function. To date, the HIV-induced CD4 down-modulation has not been targeted for therapeutic intervention. Addressing the reasons why this function is so critical and understanding the interplay between viral and host factors governing surface expression of CD4 may provide clues for the development of new antiviral strategies.
Lama
Juan
J
Department of Medicine and UCSD Cancer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0665, USA. jlama@ucsd.edu
D015536:Down-Regulation; D015686:Gene Products, env / Q000502:physiology*; D015693:Gene Products, nef / Q000502:physiology*; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D054298:Human Immunodeficiency Virus Proteins; D006801:Humans; D016167:Integrin alphaXbeta2 / Q000378:metabolism / Q000502:physiology*; D015728:Receptors, HIV / Q000502:physiology*; D015398:Signal Transduction; D054334:Viral Regulatory and Accessory Proteins / Q000502:physiology*; D054311:nef Gene Products, Human Immunodeficiency Virus; D000086082:Viroporin Proteins
D015686:Gene Products, env; D015693:Gene Products, nef; D054298:Human Immunodeficiency Virus Proteins; D016167:Integrin alphaXbeta2; D015728:Receptors, HIV; D054334:Viral Regulatory and Accessory Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins