Part of the C-terminal tail of the envelope gp41 transmembrane glycoprotein of human immunodeficiency virus type 1 is exposed on the surface of infected cells and is involved in virus-mediated cell fusion.

The C-terminal tail of the gp41 transmembrane glycoprotein of the human immunodeficiency virus type 1 (HIV-1) virion is usually thought to be inside the virion, but it has been shown recently that part of the tail is exposed on the virion exterior. Here, using a panel of antibodies, it was demonstrated that the same part of the tail is exposed on the surface of HIV-1-infected C8166 lymphoblastoid cells and HeLa cells infected with a gp41-expressing vaccinia virus recombinant. Both types of infected cell failed to react with p17 matrix protein-specific IgGs until permeabilized with saponin, confirming the integrity of the plasma membrane. Cell-surface exposure of the gp41 tail was independently demonstrated by inhibition of HIV-1-mediated cell-cell fusion by one of the gp41 tail-specific antibodies. These data also implicate the exposed region of the gp41 C-terminal tail either directly or indirectly in the viral fusion process. Its surface exposure suggests that the gp41 C-terminal tail may be a candidate for immune intervention or chemotherapy of infection.

Interfering vaccine: a novel antiviral that converts a potentially virulent infection into one that is subclinical and immunizing.

Infection with human influenza A virus can reach cataclysmic levels, with 40 or more million deaths arising from the 1918 pandemic. Preventative and therapeutic measures have improved since that time, but new approaches are needed. Here, we describe one such new approach--the interfering vaccine, which has two activities--it prophylactically prevents influenza, and at the same time converts an otherwise lethal infection into one that is avirulent and immunizing. Mice treated in this way develop a solid immunity that protects them against a subsequent challenge with homologous virus, and to a lesser extent from challenge with heterologous influenza A viruses. The interfering vaccine comprises non-infectious, defective interfering (DI) influenza A virus. Prophylaxis is mediated directly by DI RNA, and results from interference with the replication of the infecting virus. However, interference is incomplete, and there is sufficient wild-type virus multiplication to stimulate a virus-specific natural immunity. As the replication mechanism is common to all influenza A viruses, an interfering vaccine should protect from, and permit immunity to be developed to all influenza A viruses. Indeed, we demonstrate protection against two viruses with antigenically unrelated HA and NA proteins. Thus an interfering vaccine, unlike the conventional vaccine, is independent of the antigenicity of the infecting virus. In principle, interfering vaccines derived from other virus systems could also be developed.

A region of the C-terminal tail of the gp41 envelope glycoprotein of human immunodeficiency virus type 1 contains a neutralizing epitope: evidence for its exposure on the surface of the virion.

The approximately 150 amino acid C-terminal tail of the gp41 transmembrane glycoprotein of human immunodeficiency virus type 1 (HIV-1) is generally thought to be located inside the virion. However, we show here that both monoclonal IgG and polyclonal epitope-purified IgG specific for the (746)ERDRD(750) epitope that lies within the C-terminal tail neutralized infectious virus. IgG was mapped to the C-terminal tail by its failure to neutralize tail-deleted virus, and by sequencing of antibody-escape mutants. The fact that antibody does not cross lipid membranes, and infectious virus is by definition intact, suggested that ERDRD was exposed on the surface of the virion. This was confirmed by reacting virus and IgG, separating virus and unbound IgG by centrifugation, and showing that virus was neutralized to essentially the same extent as virus that had been in constant contact with antibody. Epitope exposure on virions was independent of temperature and therefore constitutive. Monoclonal antibodies specific to epitopes PDRPEG and IEEE, upstream of ERDRD, also bound to virions, suggesting that they too were located externally. Protease digestion destroyed the ERDRD and PDRPEG epitopes, consistent with their proposed external location. Altogether these data are consistent with part of the C-terminal tail of gp41 being exposed on the outside of the virion. Possible models of the structure of the gp41 tail, taking these observations into account, are discussed.