Clade B-based HIV-1 vaccines elicit cross-clade cytotoxic T lymphocyte reactivities in uninfected volunteers

Abstract

A fundamental goal of current strategies to develop an efficacious vaccine for AIDS is the elicitation of broadly reactive cytotoxic T lymphocyte (CTL) reactivities capable of destroying virally infected targets. Recent application of recombinant canarypox ALVAC/HIV-1 vectors as vaccine immunogens in HIV-1,-noninfected volunteers has produced CTL responses in a significant number of vaccinees. Using a newly developed targeting strategy, we examined the capacity of vaccine-induced CTL to lyse autologous targets infected with a diverse group of viral isolates. CTL derived from recipients of a canarypox ALVAC/HIV-1 gp160 (MN) vaccine were found capable of lysing autologous CD4+ lymphoblasts infected with the prototypic LAI strain of HIV-1. When tested against autologous targets infected with primary HIV-1 isolates representing genetically diverse viral clades, CTL from ALVAC/gp160 recipients showed both a broad pattern of cytolysis in which viruses from all clades tested were recognized as well as a highly restricted pattern in which no primary isolates, including clade B, were lysed. Differences in the HLA haplotypes of the volunteers immunized with the envelope vector might be a major determinant of the relative breadth of their CTL response. In contrast to ALVAC/gp160 vaccinees, recipients of the ALVAC/HIV-1 immunogen containing envelope as well as gag and protease genes consistently had CTL reactivities effective against a spectrum of primary isolate-infected targets. These studies demonstrate for the first time that clade B-based canarypox vaccines can elicit broad CTL reactivities capable of recognizing viruses belonging to genetically diverse HIV-1 clades. The results also reinforce the impact of viral core elements in the vaccine as well as the pattern of major histocompatibility complex class I allelic expression by the vaccine recipient in determining the relative breadth of the cellular response.

Figure 1

The percentage of HIV-1-specific lysis against vaccinia/Env- and vaccinia/Gag-infected, autologous BLCL is reported subtracting the background lysis of control vaccinia-infected targets. Results for volunteers FII, FJ2, FIL, and IRQ are reported at E/T = 40:1 and for volunteers G0B, G0C, G0H, and IG9 at E/T = 50:1. (Upper) The CTL activities are directed against env determinants only. (Lower) The CTL are directed against both env and gag determinants.

Figure 2

The percentage of HIV-1-specific lysis against vaccinia/Env-infected or vaccinia/Gag-infected, autologous BLCL targets or HIV-1_LAI-infected, autologous CD4⁺ lymphoblasts is reported subtracting the background lysis of control vaccinia-infected, autologous BLCL targets or uninfected, autologous CD4⁺ lymphoblast targets, respectively. Results for volunteers FII and FJ2 are reported at E/T = 40:1 and for volunteers G0B and G0H at E/T = 50:1.

Figure 3

The percentage of HIV-1-specific lysis against autologous CD4⁺ lymphoblasts infected with primary HIV-1 isolates representing the designated clades is reported subtracting the background lysis against uninfected, autologous CD4⁺ lymphoblast targets. Results for volunteers FII and FJ2 are reported at E/T = 40:1 and for volunteers G0B and IG9 at E/T = 50:1