The Physiological Relevance of CD4 Receptor Down-Modulation During HIV Infection

Abstract

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.

HIV dynamics with multiple infections of target cells

“…1, we present a schematic of how a cell infected singly at time t ϭ 0 is multiply infected at later times. In general, ␦ will depend on the multiplicity of infection, i. Accumulation of unintegrated DNA, seen by the host cell as DNA damage, and the expression of toxic viral gene products induce apoptotic and͞or cytotoxic effects, which are expected to increase ␦ with i (22)(23)(24). In contrast, greater down-modulation of CD4 and MHC class I molecules may promote immune evasion and decrease ␦ at higher i (25)(26)(27).…”

“…4 quantifies the reduced susceptibility of the cell to infection at time due to CD4 down-modulation (22,28,29), which appears to proceed exponentially with a characteristic timescale, t d , after the first infection of the cell (17,29) (see Supporting Text and Fig. 6, which are published as supporting information on the PNAS web site).…”

Resistance to superinfection by a vigorously replicating, uncloned stock of simian immunodeficiency virus (SIVmac251) stimulates replication of a live attenuated virus vaccine (SIVmacC8)

“…Alternatively, the presence of the vaccine could elicit retroviral interference mechanisms. Interference between retroviruses that share the same cellular receptor, mediated by the envelope protein, is recognized as a method by which superinfection with a second retrovirus may be prevented at the cellular level (Lama, 2003). It remains unclear as to how this could apply to attenuated SIV vaccines, when the frequency of SIV-infected cells would appear to be a very small proportion of the total number of susceptible cells.…”

210 Low Post-Seroconversion CD4 Count and Rapid Decrease of CD4 Density Identify HIV+ Fast Progressors

“…[15][16][17][18] The well-known CD4 down-regulation by HIV in vitro is mediated by the viral proteins Nef, Env, and Vpu. 19 explanations have been proposed for why CD4 downmodulation favors HIV, including attenuation of CD4 signaling that might decrease viral transcription, prevention of superinfection, and enhancement of virion release. 19 Thus, the role of CD4 expression in HIV infection appears paradoxical.…”