ZIA BC 011126 (ZIA) | |||
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Title | Preventive Vaccines for HIV | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Franchini, Genoveffa | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $4,538,987 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) | N/A | ||
Research Type | |||
Vaccines Resources and Infrastructure Related to Prevention |
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Abstract | |||
The recombinant vaccine containing Aventis Pasteur's Canarypox vector clade A/B/E (ALVAC)-HIV and gp120 alum, first pioneered 20 years ago, decreased the risk of HIV acquisition by 31.2% in the RV144 HIV vaccine trial in Thailand, and it did so despite negligible CD8+ cytotoxic T cells and neutralizing antibody titers against primary HIV strains. The result of this trial defied expectations in the field that it would fail since this vaccine platform was not considered sufficiently immunogenic. Some investigators have been invigorated by this unexpected positive result, as RV144 may indicate that a vaccine for HIV may be feasible through the elicitation of non-canonical immune responses. Others continue to believe that the key to HIV prevention lies in preventive antiretroviral therapy or the life-long administration of broadly neutralizing antibodies. HIV is a formidable pathogen that has evolved a variety of mechanisms to hijack every arm of the human immune system. Given that variables as diverse as population genetics, nutrition, age, sex, and co-infecting agents might affect the efficacy of any intervention, the development of different approaches is a strategic necessity to prevent infection and eradicate this virus. Having confirmed the results of RV144 and adapted them into the macaque model, our work has identified a novel correlate in monocyte innate memory responses that involves the metabolic and epigenetic reprogramming of myeloid cells. This response is persistent and it has been shown to be effective against infectious agents and some forms of cancer. In addition, our work has uniquely demonstrated several correlates of both decreased and increased risk of SIVmac251 acquisition, suggesting mechanistic insights and possible remedies. Increased risk of SIVmac251 acquisition: Cellular immunity: Activated gut-homing CD4+ T cells, mucosal IFN-? producing NKG2Anegative NKp44negative cells, and CD16+ monocytes. Cytokines: Plasma IL-6 and IL-8 in old macaques. Humoral: Antibodies to V1. Systems biology: STAT3 activation. Decreased risk of SIVmac251 acquisition: Cellular immunity: CD14+ monocytes (innate memory), gut-homing CCR5negative Th2 cells, and gut mucosal NKp44+ cells. Humoral: Antibodies to V2. Systems biology: RAS, inflammasome, and hypoxia. We have gained mechanistic insights into the efficacy of the DNA/ALVAC/gp120/alum vaccine regimen (see accompanying manuscript by Vaccari et al., Nat Med 2018). Firstly, the intramuscular priming with the Gag and Envelope DNAs (a productive collaboration with Dr. Felber and Dr. Pavlakis) and boosting with ALVAC-SIV, both able to express SIV pseudo-virions, focuses the antibody response to conformational V2 epitopes. Secondly, the DNA prime collaborates with the ALVAC and alum adjuvants to activate the inflammasome and release IL-1b in CD14+ cells. Consistent with the model proposed in, ALVAC has a tropism for CD14+ monocytes and its cytosolic DNA activates the inflammasome through the engagement of cGAS, IF116, and AIM2, key components of the inflammasome. We have shown that within 24 hours of immunization, ALVAC causes more than 50-fold higher plasma levels of IL-1b, a cytokine tightly regulated by inflammasome activation, than do the Ad26, MVA, or NYVAC primes. Similarly, the DNA vaccine activates cGAS IF116 via cross-presentation. AIM2 knockout mice experiments demonstrated the essential role of the inflammasome in DNA vaccination and alum alhydrogel is likewise a strong activator of the inflammasome. IL-1b expression is associated with emergency myelopoiesis and induces differentiation of hematopoietic stem and progenitor cells via the PU.1 transcription program. Indeed, we have found a correlation with CXCR4+ premonocytes (cells recently released from the bone marrow) and a decreased risk of virus acquisition as well as a decrease in the number of transmitted virus variants in the animals that become infected. However, our data suggest that while necessary, the early IL |