Background Vaccination with inactivated (killed) whole-virus particles has been used to prevent a wide range of viral diseases. However, for an HIV vaccine this approach has been largely negated due to inherent safety concerns, despite the ability of killed whole-virus vaccines to generate a strong, predominantly antibody-mediated immune response in vivo. HIV-1 Clade B NL4-3 was genetically modified by deleting the nef and vpu genes and substituting the coding sequence for the Env signal peptide with that of honeybee melittin signal peptide to produce a less virulent and more replication efficient virus. This genetically modified virus (gmHIV-1NL4-3) was inactivated and formulated as a killed whole-HIV vaccine, and then used for a Phase I human clinical trial (Trial Registration: Clinical Trials NCT01546818). The gmHIV-1NL4-3 was propagated in the A3.01 human T cell line followed by virus purification and inactivation with aldrithiol-2 and γ-irradiation. Thirty-three HIV-1 positive volunteers receiving cART were recruited for this observer-blinded, placebo-controlled Phase I human clinical trial to assess the safety and immunogenicity.Results Genetically modified and killed whole-HIV-1 vaccine, SAV001, was well tolerated with no serious adverse events. HIV-1NL4-3-specific PCR showed neither evidence of vaccine virus replication in the vaccine virus-infected human T lymphocytes in vitro nor in the participating volunteers receiving SAV001 vaccine. Furthermore, SAV001 with adjuvant significantly increased the pre-existing antibody response to HIV-1 proteins. Antibodies in the plasma of vaccinees were also found to recognize HIV-1 envelope protein on the surface of infected cells as well as showing an enhancement of broadly neutralizing antibodies inhibiting tier I and II of HIV-1 B, D, and A subtypes.ConclusionThe killed whole-HIV vaccine, SAV001, is safe and triggers anti-HIV immune responses. It remains to be determined through an appropriate trial whether this immune response prevents HIV infection.

The loss of CD4(+) T-cells in human immunodeficiency virus-infected individuals has been attributed not only to dysregulation of immune cell function but also direct and indirect killing mechanisms of both infected and bystander cells. This process proceeds through both necrotic and programmed cell death pathways. Several human immunodeficiency virus type 1 (HIV-1) gene products have been linked to the induction of cell death and apoptosis associated with virus infection. These include the Nef, Tat, Vpr, and Vpu proteins as well as the viral envelope glycoprotein. Our results now indicate that the signal peptide of HIV-1 is also involved in the induction of cytopathic effects leading to cell death. We have shown here that expression of HIV-1 gp120 or vesicular stomatitis virus G glycoprotein with the HIV-1 Env signal peptide resulted in a rapid induction of cytopathicity and cell death in S. frugiperda cells, whereas removal or replacement of the signal peptide ameliorated those effects. Further, our results show that cell death is induced, at least in part, through apoptotic pathways as characterized by evidence of nuclear condensation and DNA fragmentation, as well as by the activation of host-cell caspase activity. Our results indicate that the signal peptide of HIV-1 Env itself thus has a direct role in cellular cytotoxicity and the triggering of cell death pathways.