AIDS Vaccination Studies Using an Ex Vivo Feline Immunodeficiency Virus Model: Failure To Protect and Possible Enhancement of Challenge Infection by Four Cell-Based Vaccines Prepared with Autologous Lymphoblasts

Abstract

Immunogenicity and protective activity of four cell-based feline immunodeficiency virus (FIV) vaccines prepared with autologous lymphoblasts were investigated. One vaccine was composed of FIV-infected cells that were paraformaldehyde fixed at the peak of viral expression. The other vaccines were attempts to maximize the expression of protective epitopes that might become exposed as a result of virion binding to cells and essentially consisted of cells mildly fixed after saturation of their surface with adsorbed, internally inactivated FIV particles. The levels of FIV-specific lymphoproliferation exhibited by the vaccinees were comparable to the ones previously observed in vaccine-protected cats, but antibodies were largely directed to cell-derived constituents rather than to truly viral epitopes and had very poor FIV-neutralizing activity. Moreover, under one condition of testing, some vaccine sera enhanced FIV replication in vitro. As a further limit, the vaccines proved inefficient at priming animals for anamnestic immune responses. Two months after completion of primary immunization, the animals were challenged with a low dose of homologous ex vivo FIV. Collectively, 8 of 20 vaccinees developed infection versus one of nine animals mock immunized with fixed uninfected autologous lymphoblasts. After a boosting and rechallenge with a higher virus dose, all remaining animals became infected, thus confirming their lack of protection.

Enhanced SIV replication and accelerated progression to AIDS in macaques primed to mount a CD4 T cell response to the SIV envelope protein

“…Several precedents exist for vaccines to shift the host-pathogen interaction in harmful ways upon subsequent exposure to live virus (26)(27)(28)(29), including examples of vaccinemediated enhancement of lentivirus infections (30)(31)(32). Because lentiviral vaccine-mediated enhancement does not always involve enhancing antibodies (31), a mechanism of lymphocyte activation-mediated enhancement of virus replication has been proposed (33); data consistent with such a mechanism were reported in one feline immunodeficiency virus (FIV) vaccine study (34).…”

Antiviral Activity and Conformational Features of an Octapeptide Derived from the Membrane-Proximal Ectodomain of the Feline Immunodeficiency Virus Transmembrane Glycoprotein

“…The FIV particles used in this study were rendered noninfectious by the internal inactivating agent AT2 (24). This agent has previously been shown to inactivate HIV and SIV without affecting Env structure and functions, including cell entry (2, 58).…”

“…d FIV inactivated with AT2 (5 g of protein) and incubated with MBM cells (5 ϫ 10 5 ) at 4°C for 1 h before C8 addition, to permit virus adsorption but not entry (24).…”

“…Titration of the viral stocks was carried out in MBM cells and, depending on experiment design, included or did not include washout of unadsorbed virus after 5 h at 37°C to reproduce the conditions used in the FIV inhibition assay (see below). Internal inactivation of the viruses used in peptide binding experiments was carried out with 2,2Ј-dithiodipyridine (also known as aldrithiol-2 [AT2]) as previously described (24). In brief, viral stocks were incubated with 300 M AT2 at 4°C for 2 h, pelleted in the cold at 20,000 ϫ g for 90 min, and resuspended at 1 mg/ml in phosphatebuffered saline.…”

Antibodies specific for hypervariable regions 3 to 5 of the feline immunodeficiency virus envelope glycoprotein are not solely responsible for vaccine-induced acceleration of challenge infection in cats

“…The accelerated virus replication correlated with the presence of envelope-specific antibodies at the time of challenge in some studies 3Present address: UMC Utrecht, Department of Immunology, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. (Lombardi et al, 1994;Siebelink et al, 1995c;Karlas et al, 1999;Giannecchini et al, 2002), but not in others (Hosie et al, 1992;Richardson et al, 1997Richardson et al, , 2002. Hence, the mechanism underlying this enhancement phenomenon has not been fully elucidated.…”