The goal of this project is to test if rhesus cytomegalovirus-based SIV vaccines (RhCMV/SIV) can be improved via IL-10 pathway modulation to obtain significantly over 50% protective efficacy. We found that second-generation RhCMVdIL10/SIV vaccines lacking the viral IL-10 gene protect non-human primate infants, while first-generation (IL-10 intact) RhCMV/SIV vaccines do not. First-generation vaccines have been proven effective only in wild-type RhCMV-seropositive macaques having neutralizing antibodies to viral IL-10. The significance of this work is that if successful it will provide (i) new candidate HIV vaccines with greater efficacy in some or all segments of the population, (ii) a coherent, mechanistic explanation for previously obscure patterns of RhCMV/SIV vaccine protectiveness, (iii) new pharmacologic tools for control over IL-10 signaling, and (iv) immunologic insight into consequences of cellular and viral IL-10 pathway modulation. Our preliminary data show that rhesus macaques infected by wild-type rhesus cytomegalovirus (wtRhCMV) mount immune responses to viral interleukin-10 (vIL-10), which in most cases leads to generation of neutralizing antibodies. RhCMV/SIV vaccine stringently protects ~50% of such wtRhCMV+ but not wtRhCMV- seronegative monkeys against SIV challenge. A second-generation RhCMV/SIV vaccine lacking the viral IL-10 gene, however, can protect seronegative macaques. We hypothesize that RhCMV/SIV vaccination in the context of inhibited host IL-10 signaling will achieve superior efficacy (>50%) in infant and adult macaques.
Our specific aims are:
Aim 1. Define the transcriptomic and immunologic signatures of increased or decreased IL-10 signaling using previously collected samples. Here we determine the true transcriptomic signature of host IL-10 signaling using samples from animals receiving anti-IL-10 antibody or with forced IL-10 expression. We then evaluate host responses to RhCMV/SIV vaccination in the presence of varying levels of viral IL-10 neutralization to determine how such neutralization affects (i) host IL-10 signaling, (ii) likelihood of generating a transcriptomic signature associated with protection, and (iii) vaccine efficacy.
Aim 2. Test if cellular IL-10 inhibition augments vaccine efficacy in infant (RhCMV-negative) macaques. Since viral IL-10 deletion presumably interferes with the host IL-10 response, we reason that further interference (via administration of neutralizing anti-IL-10 antibody) will further augment vaccine efficacy. In this aim we therefore administer RhCMVdIL10/SIVgag alone or in the presence of neutralizing anti-cIL-10 antibody.
Aim 3. Test if cellular and/or viral IL-10 inhibition augment vaccine efficacy in adult (RhCMV-positive) macaques. Here we test if complete inhibition of viral and/or cellular IL-10 can substantially increase efficacy. Together these studies will provide clear understanding of the role of IL-10 signaling in RhCMV/SIV vaccine efficacy and may point the way to new vaccine regimens that are 85-100% effective.
We are seeking an effective vaccine against the human immunodeficiency virus (HIV), which has killed about 35 million people. The most effective current vaccine candidate is carried by another virus, cytomegalovirus, and is approximately 50% effective. In this work we will test if an immunomodulatory antibody can increase vaccine efficacy significantly, making this vaccine regimen a likely tool for fighting the HIV epidemic worldwide.
