Serpin A1 and CD91 as host instruments against HIV-1 infection: Are extracellular antiviral peptides acting as intracellular messengers?

Serpin A1 (α1-antitrypsin, α1-proteinase inhibitor) has been shown to be a non-cytolytic antiviral factor present in blood and effective against HIV infection. The best known physiological role of serpin A1 is to inhibit neutrophil elastase, a proteinase which is secreted by neutrophils at sites of infection and inflammation. Decreased HIV-infectivity is associated with decreased density of membrane-associated elastase. The enzyme may facilitate binding of the HIV membrane protein gp120 to host cells, and it specifically cleaves SDF-1, the physiological ligand of the HIV-1 co-receptor CXCR4. It has been suggested that one of the actions of serpin A1 as antiviral agent is to reduce HIV infectivity, and this property could be due to elastase inhibition. However, the most dramatic effect of serpin A1 is inhibition of HIV production. In vitro experiments indicate that the C-terminal peptide of serpin A1, produced during the formation of the complex of serpin with serine proteinases, may be responsible for the inhibition of HIV-1 expression in infected cells. This peptide, an integral part of the serpin–enzyme complex, is internalized by several scavenger receptors. Peptides corresponding to the C-terminal section of serpin A1 inhibit HIV-1 long-terminal-repeat-driven transcription and interact with nuclear proteins, such as α1-fetoprotein transcription factor. LDL-receptor-related protein 1 (LRP1/CD91), the best known receptor for serpin–enzyme complexes, is up-regulated in monocytes of HIV-1-infected true non-progressors. CD91 could be one of the major players in host resistance against HIV-1. It has the capacity of internalizing antiviral peptides such as serpin C-terminal fragments and α-defensins, and is at the same time the receptor for heat-shock proteins in antigen-presenting cells, in which chaperoned viral peptides could lead to the induction of cytotoxic T-cell responses.