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Abstract
The suppression of viral loads and identification of selection signatures in non-human primates after challenge are indicators for effective human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) vaccines. To mimic the protective immunity elicited by attenuated SIV vaccines, we developed an integration-defective SIV (idSIV) vaccine by inactivating integrase, mutating sequence motifs critical for integration, and inserting the cytomegalovirus (CMV) promoter for more efficient expression in the SIVmac239 genome. Chinese rhesus macaques were immunized with idSIV DNA and idSIV particles, and the cellular and humoral immune responses were measured. After the intravenous SIVmac239 challenge, viral loads were monitored and selection signatures in viral genomes from vaccinated monkeys were identified by single genome sequencing. T cell responses, heterologous neutralization against tier-1 viruses, and antibody-dependent cellular cytotoxicity (ADCC) were detected in idSIV-vaccinated macaques post immunization. After challenge, the median peak viral load in the vaccine group was significantly lower than that in the control group. However, this initial viral control did not last as viral set-points were similar between vaccinated and control animals. Selection signatures were identified in Nef, Gag, and Env proteins in vaccinated and control macaques, but these signatures were different, suggesting selection pressure on viruses from vaccine-induced immunity in the vaccinated animals. Our results showed that the idSIV vaccine exerted some pressure on the virus population early during the infection but future modifications are needed in order to induce more potent immune responses.
Highlights
After over three decades of research, an efficient human immunodeficiency virus type 1(HIV-1) vaccine is still elusive [1,2]
To generate a safe vaccine that can elicit protective immune responses with pan-viral proteins as in attenuated simian immunodeficiency virus (SIV) vaccines, we constructed an integration-defective SIV (idSIV) by introducing a number of modifications into the SIVmac239 genome to avoid the risks due to integration and by enhancing the expression of viral proteins under a potent CMV promoter (Figure 1A)
We developed a new idSIV vaccine which expressed pan-viral proteins, elicited cellular and humoral immune responses, and reduced the peak viremia after the vigorous intravenous SIVmac239 challenge
Summary
After over three decades of research, an efficient human immunodeficiency virus type 1(HIV-1) vaccine is still elusive [1,2]. Attenuated simian immunodeficiency virus (SIV) vaccines induce effective protection from SIV challenge in non-human primates (NHPs) [3,4,5]. Attenuated SIV vaccines are usually engineered by inactivating non-essential regulatory genes to reduce viral replication capacity and pathogenicity. Recent studies using a replication-competent cytomegalovirus (CMV) vector that can persistently express SIV genes showed a 50% protection efficacy in vaccinated macaques against the infection of a pathogenic autologous SIVmac239 challenge through non-classical CD8+ T immune responses [7,8]. The results from attenuated SIV vaccines and replication-competent CMV vector vaccines indicate that viral vector-based vaccines that can stimulate the immune system with all viral proteins without integration of the viral genome into host chromosomes may induce desirable protective immune responses
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