Abstract
HIV vaccine development has been hampered by issues such as undefined correlates of protection and extensive diversity of HIV. We addressed these issues using a previously established SIV-macaque model in which SIV mutants with deletions of multiple gp120 N-glycans function as potent live attenuated vaccines to induce near-sterile immunity against the parental pathogenic SIVmac239. In this study, we investigated the protective efficacy of these mutants against a highly pathogenic heterologous SIVsmE543-3 delivered intravenously to rhesus macaques with diverse MHC genotypes. All 11 vaccinated macaques contained the acute-phase infection with blood viral loads below the level of detection between 4 and 10 weeks postchallenge (pc), following a transient but marginal peak of viral replication at 2 weeks in only half of the challenged animals. In the chronic phase, seven vaccinees contained viral replication for over 80 weeks pc, while four did not. Neutralizing antibodies against challenge virus were not detected. Although overall levels of SIV specific T cell responses did not correlate with containment of acute and chronic viral replication, a critical role of cellular responses in the containment of viral replication was suggested. Emergence of viruses with altered fitness due to recombination between the vaccine and challenge viruses and increased gp120 glycosylation was linked to the failure to control SIV. These results demonstrate the induction of effective protective immune responses in a significant number of animals against heterologous virus by infection with deglycosylated attenuated SIV mutants in macaques with highly diverse MHC background. These findings suggest that broad HIV cross clade protection is possible, even in hosts with diverse genetic backgrounds. In summary, results of this study indicate that deglycosylated live-attenuated vaccines may provide a platform for the elucidation of correlates of protection needed for a successful HIV vaccine against diverse isolates.
Highlights
Molecular epidemiological studies have revealed the existence of an extensive degree of diversity of HIV-1 isolates [1]
The heterologous challenge virus used in this study is the molecularly cloned pathogenic strain SIVsmE543-3 that belongs to lineage 1
We examined whether reduction of glycosylation on viral spikes would allow for more ready access for host immune responses and provide for a new type of live attenuated vaccine, which would induce more robust anti-viral immune response and protect outbred rhesus macaques, against heterologous virus challenge
Summary
Molecular epidemiological studies have revealed the existence of an extensive degree of diversity of HIV-1 isolates [1]. Group M represents the predominant HIV-1 circulating through the world and has been divided into more than 10 subtypes (clades) as well as increasing number of circulating recombinant forms (CRF) primarily due to error-prone viral reverse transcriptase and the occurrence of super-infections. This diversity is continuously expanding worldwide and is a major obstacle for the successful development of an AIDS vaccine. The failure and dismal success of HIV-1 vaccine trials that have been conducted so far has prompted a re-emphasis for more basic studies concerning vaccine design against heterologous challenge viruses, which can at present only be addressed in a macaque model. One of the pre-conditions for the objective assessment of the protective efficacy against a heterologous strain would be that the macaque model used should have the capacity to confer sterile or near-sterile immunity against the homologous virus challenge
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