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

Abstract

Given the dual role of CD4 T cells as both immune effectors and targets for HIV infection, the balance of CD4 versus CD8 T cell-mediated responses induced by candidate AIDS vaccines may be critical in determining postvaccination infection outcomes. An attenuated recombinant varicella-zoster virus vaccine expressing the simian immunodeficiency virus (SIV) envelope (Env) elicited nonneutralizing Env-binding antibodies and little if any cytotoxic T lymphocyte responses in rhesus macaques (Macaca mulatta). After challenge with SIV, Env vaccinees manifested increased levels of SIV replication, more rapid CD4 depletion, and accelerated progression to AIDS compared with controls. Enhanced SIV replication correlated with increased CD4 T cell proliferation soon after SIV challenge, apparently the result of an anamnestic response to SIV antigens. Thus activation of virus-specific CD4 T cells at the time of exposure to a CD4 T cell-tropic lentivirus, in the absence of an effective CD8 response, may enhance virus replication and disease. These data suggest suggest that candidate AIDS vaccines may not simply be either efficacious or neutral; they may also have the potential to be harmful.

Fig. 1.

Vaccine-induced immune responses. (A) VZV antibody titers in six RMs preimmunization and postimmunization. (B) Anti-SIV Env antibodies detected by immunoprecipitation in rVZV-SIVenv vaccinees (RCq5, REt5, RFt5, and RGu5) but not in VZV vaccinees (RMo5 and RNn5) after three immunizations (4 mo) and after a fourth immunization 2.5 years later (33 mo). (C) Weak CTL responses to SIV and VZV antigens in chromium-release assays performed 3 weeks after the third immunization at effector:target ratios of 30:1 and 20:1, respectively.

Fig. 2.

Enhanced SIV replication (A) and CD4 cell decline (B) in rVZV-SIVenv vaccinees (dashed lines) compared to controls (solid lines).

Fig. 3.

Anamnestic antibody responses after SIV challenge of rVZV-SIVenv vaccinees. (A) Western blot analysis of SIV-specific antibodies in rVZV-SIVenv vaccinees (RGu5, REt5, RFt5, and RCq5), in rVZV vaccinees (RMo5 and RNn5), and in naive unvaccinated controls (RTh5; REe5 is not shown). For each RM, from left to right, four immunoblot strips corresponding to preimmune, day of challenge, and 2 and 4 weeks after challenge are shown. (B) SIVsmH4 NAb responses pre and post challenge.

Fig. 4.

Enhanced SIV replication correlates with early CD4 T cell proliferation. (a and b) Early changes in Ki67⁺ CD4 T cells and SIV RNA in a representative rVZV-SIVenv vaccinee (a) and a naive control (b). (c) Day 3 increase in Ki67⁺ CD4 T cells in all four rVZV-SIVenv vaccinees (dashed lines) compared with controls (solid lines). (d) Early SIV infection-induced CD4 T cell proliferation correlates with preexisting SIV antibody titers. ELISA titers are shown as the reciprocal of the log₁₀ dilution endpoint titer. Increases in Ki67⁺ CD4 T cells at day 3 are shown. (e) Correlation between increased CD4 T cell proliferation at day 3 after SIV challenge and setpoint viremia.