Vaccine-induced immune responses against both Gag and Env improve control of simian immunodeficiency virus replication in rectally challenged rhesus macaques

Abstract

The ability to control lentivirus replication may be determined, in part, by the extent to which individual viral proteins are targeted by the immune system. Consequently, defining the antigens that elicit the most protective immune responses may facilitate the design of effective HIV-1 vaccines. Here we vaccinated four groups of rhesus macaques with a heterologous vector prime/boost/boost/boost (PBBB) regimen expressing the following simian immunodeficiency virus (SIV) genes: env, gag, vif, rev, tat, and nef (Group 1); env, vif, rev, tat, and nef (Group 2); gag, vif, rev, tat, and nef (Group 3); or vif, rev, tat, and nef (Group 4). Following repeated intrarectal challenges with a marginal dose of the neutralization-resistant SIVmac239 clone, vaccinees in Groups 1–3 became infected at similar rates compared to control animals. Unexpectedly, vaccinees in Group 4 became infected at a slower pace than the other animals, although this difference was not statistically significant. Group 1 exhibited the best post-acquisition virologic control of SIV infection, with significant reductions in both peak and chronic phase viremia. Indeed, 5/8 Group 1 vaccinees had viral loads of less than 2,000 vRNA copies/mL of plasma in the chronic phase. Vaccine regimens that did not contain gag (Group 2), env (Group 3), or both of these inserts (Group 4) were largely ineffective at decreasing viremia. Thus, vaccine-induced immune responses against both Gag and Env appeared to maximize control of immunodeficiency virus replication. Collectively, these findings are relevant for HIV-1 vaccine design as they provide additional insights into which of the lentiviral proteins might serve as the best vaccine immunogens.

Mamu-B*17 + Rhesus Macaques Vaccinated with env , vif , and nef Manifest Early Control of SIVmac239 Replication

“…gp140-binding Abs in group 2 was 4,800 ( Fig. 4B), a value that was twice as high as that induced by an EP rDNA/rAd5/rVSV/rRRV vaccine regimen recently tested by our group (27). However, these responses were still about 100-fold lower than those generated by live attenuated SIV vaccination (Fig.…”

“…As a reference, these values were plotted alongside the endpoint titers of gp140-binding Abs in four RMs that had been infected with SIVmac239Δnef for 28 weeks as part of a previous experiment (70). The endpoint titers of gp140-binding Abs in macaques vaccinated with an EP rDNA/rAd5/rVSV/rRRV regimen encoding env, gag, vif, tat, rev, and nef are also shown (27). (C) Ab-dependent cellular cytotoxicity (ADCC) activity was screened against SIVmac239-infected target cells using plasma collected from the group 2 vaccinees at the time of the first i.r.…”

“…(A) In trial 1, 24 RMs were vaccinated with env, gag, vif, rev, tat, and nef delivered by either rRRV alone or rRRV followed by two boosts with rAd5 and rVSV. (27). Briefly, 32 RMs were vaccinated with an EP rDNA/rAd5/rVSV/rRRV regimen encoding four different sets of SIV inserts.…”

Gag and env conserved element CE DNA vaccines elicit broad cytotoxic T cell responses targeting subdominant epitopes of HIV and SIV Able to recognize virus-infected cells in macaques

“…The inability of Gag-specific T cells alone to control virus acquisition has been shown in other studies. 88–91 Martins et al 88 reported that vaccine regimens that did not contain Gag, or Env or a combination of both were largely inefficient in reducing viremia, suggesting that the synergy between Gag-specific T cell responses and antibodies targeting Env were an important requirement in the effective control of the virus, an observation also supported by others. 92 , 93 Roederer et al 89 reported that vaccination with mosaic Gag DNA as prime followed by rAd5 as a booster immunization did not protect from infection but showed reduction of viremia.…”

The Frequency of Vaccine-Induced T-Cell Responses Does Not Predict the Rate of Acquisition after Repeated Intrarectal SIVmac239 Challenges in Mamu-B*08 + Rhesus Macaques

“…Sixteen RMs expressing the Mamu-B*08 MHC-I allele were used. The details regarding animal welfare described herein are either similar or identical to those published in one of our previous experiments (18). The Indian-origin RMs (Macaca mulatta) utilized in this study were housed at the Wisconsin National Primate Research Center (WNPRC).…”