Retroviral superinfection resistance - PubMed (original) (raw)

Review

Retroviral superinfection resistance

Micha Nethe et al. Retrovirology. 2005.

Abstract

The retroviral phenomenon of superinfection resistance (SIR) defines an interference mechanism that is established after primary infection, preventing the infected cell from being superinfected by a similar type of virus. This review describes our present understanding of the underlying mechanisms of SIR established by three characteristic retroviruses: Murine Leukaemia Virus (MuLV), Foamy Virus (FV), and Human Immunodeficiency Virus (HIV). In addition, SIR is discussed with respect to HIV superinfection of humans. MuLV resistant mice exhibit two genetic resistance traits related to SIR. The cellular Fv4 gene expresses an Env related protein that establishes resistance against MuLV infection. Another mouse gene (Fv1) mediates MuLV resistance by expression of a sequence that is distantly related to Gag and that blocks the viral infection after the reverse transcription step. FVs induce two distinct mechanisms of superinfection resistance. First, expression of the Env protein results in SIR, probably by occupancy of the cellular receptors for FV entry. Second, an increase in the concentration of the viral Bet (Between-env-and-LTR-1-and-2) protein reduces proviral FV gene expression by inhibition of the transcriptional activator protein Tas (Transactivator of spumaviruses). In contrast to SIR in FV and MuLV infection, the underlying mechanism of SIR in HIV-infected cells is poorly understood. CD4 receptor down-modulation, a major characteristic of HIV-infected cells, has been proposed to be the main mechanism of SIR against HIV, but data have been contradictory. Several recent studies report the occurrence of HIV superinfection in humans; an event associated with the generation of recombinant HIV strains and possibly with increased disease progression. The role of SIR in protecting patients from HIV superinfection has not been studied so far. The phenomenon of SIR may also be important in the protection of primates that are vaccinated with live attenuated simian immunodeficiency virus (SIV) against pathogenic SIV variants. As primate models of SIV infection closely resemble HIV infection, a better knowledge of SIR-induced mechanisms could contribute to the development of an HIV vaccine or other antiviral strategies.

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Figures

Figure 1

Figure 1

Schematic of three possible interference mechanisms mediated by Fv1 expression. Although the mechanism of Fv1 interference is still poorly understood and firm experimental evidence is lacking, several likely routes can be envisaged. Route A depicts the binding of Fv1 to CA, thereby restricting CA participation in the integration of the pre-integration complex (PIC) of MuLV DNA. In favour of this model, crystallographic studies recently suggested that a potential Fv1 binding domain exists in the MuLV CA [18]. Alternatively, if yet undetermined CA helper factors (CAhf) are needed during CA mediated integration of the PIC; binding of Fv1 to CAhf would prevent CAhf to assist CA during integration of the PIC (route B). A third possible route would involve direct binding of Fv1 to the PIC, thereby changing its conformation, and restricting it from further processing during CA-mediated integration (route C).

Figure 2

Figure 2

Schematic of Fv4 mediated interference of MuLV infection. Fv4 expression results in sustained levels of Fv4 Env proteins in the cytoplasm. Binding of the mCAT1 receptor by Fv4 Env proteins, either in the cytoplasm or at the cell surface (the exact location of interaction is unresolved, which is represented by question marks), prevents MuLV Env to interact with mCAT1, as either the receptor is already occupied by Fv4, or it cannot reach the cell surface when bound to Fv4 in the cytoplasm.

Figure 3

Figure 3

Expression of Bet and Tas in FV susceptible and restricted cell lines. FV susceptible cell lines containing abundant concentrations of Bet and low concentrations of Tas are still able to enhance the LTR and internal promoter (IP) (panel A). Restricted FV cell lines are associated with reduced LTR and IP activity (panel B). Bet-mediated inhibition of IP activation results in reduced concentrations of Tas and consequently further inhibition of IP activity. The underlying mechanism of Bet-mediated inhibition of IP could be a negative control on transcription or translation of the Tas gene as indicated by a question mark.

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