Date Published: September 12, 2017
Publisher: BioMed Central
Author(s): Jean-Pierre Routy, Vikram Mehraj.
The quest for an effective HIV-1 vaccine began as soon as the virus causing AIDS was identified. After several disappointing attempts, results of the Phase-III RV144 trial in Thailand were a beacon of hope for the field demonstrating correlation between protection and immunological markers. In order to optimize vaccine response, we underline results from yellow fever and hepatitis B vaccines, where protective responses were predicted by the pre-vaccination level of immune activation in healthy individuals. Such findings support the assessment and reduction of pre-vaccine immune activation in order to optimize vaccine response. Immune activation in healthy individuals can be influenced by age, presence of CMV infection, gut dysbiosis and microbial translocation. We speculate that the level of immune activation should therefore be assessed to better select participants in vaccine trials, and interventions to reduce inflammation should be used to increase protective HIV vaccine response.
Despite tremendous effort to develop a successful human immunodeficiency virus (HIV) vaccine, the quest for a safe and effective HIV vaccine seems to be remarkably long and winding. Most licensed vaccines against viral and bacterial infections demonstrate efficacy in inducing antibodies . In addition to the induction of specific antibodies, vaccines also induce protective immunity by eliciting a combination of innate and acquired cellular responses . However, specific immune responses following administration of licensed vaccines is not well-understood, but have recently been shown to be associated with pre-vaccine level of immune activation . In contrast to the clearance of childhood viral infections like smallpox and measles, vaccine development against HIV remains challenging as the virus inexorably causes a chronic infection that cannot be naturally cleared by the host. Furthermore, there is little guidance in vaccine design when considering the determinants of host response, due to the absence of spontaneous clearance of HIV infection. Development of an HIV vaccine is even more difficult considering the unparalleled capacity of HIV to mutate its genome, allowing it to evade antibody recognition of its viral envelope , in addition to its ability to suppress the major conductor of the immune response, the helper CD4 T-cells . The ideal HIV vaccine should provide protection against the broad genetic diversity of HIV, control CD4 T-cell activation and likely elicit long-term cytotoxic CD8 T-cell response to block both mucosal and parenteral transmission routes.
Recent information generated from yellow fever and hepatitis B on CoP will be useful to further guide HIV vaccine development and implementation.
As noted, the encouraging results of the Thai RV144 vaccine trial provided insight into future HIV vaccine development . The investigators identified that IgG for the V1V2 region of Env gp120 was associated with protection from infection. However, the protection did not persist and was temporally linked with antibodies mediating antibody-dependent-cellular cytotoxicity (ADCC). Importantly, mounting evidence indicates that antibody mechanisms beyond neutralization may contribute to protection, as Fc characteristics and ADCC have been identified as CoP against HIV acquisition conversely to the induction of neutralizing antibodies and/or cytotoxic T-cells . Such findings suggest that combinations of broad antibodies targeting different binding sites on the Env protein could block immune escape. More recent findings from this trial support correlation between T follicular help (Tfh) function relevant for B-cell help and envelope-specific antibody development. Tfh responses generated by RV144 show a marked inter-individual variation indicating the presence of determinants that remain largely unknown .
Manipulation of microbiota composition and their metabolites via diet alteration or microbiota engraftment is under intense evaluation in cancer and autoimmune disorders and vaccinology. Learning from our gut endogenous original adjuvants and/or tolerogenic microbes and their metabolites will be critical in overcoming the HIV vaccine challenge . We recently showed the contribution of dietary tryptophan (Trp), one of the essential amino acids mainly obtained from protein-rich foods, contributed to immune suppression by the production of an immunosuppressive catabolite in the context of HIV/HCV infections [25–27]. Other groups have identified a similar change in cancer, autism, and multiple sclerosis indicating the influence of kynurenine, a metabolite of Trp used in the production of niacin, as an immunosuppressor present in several chronic conditions [28, 29]. Of note, several Trp metabolites produced by bacteria in the gut are endogenous ligands for the transcription factor aryl hydrocarbon receptor (AhR) which has been recently shown to control B-cell fate decisions including suppression of class switching in vivo after influenza immunization . AhR activation is linked to both diet and gut microbiota composition and leads to the local production of IL-22, a cytokine that plays an important role in maintaining mucosal immunity and integrity, mainly by innate lymphoid cells group 3 (ILC3) [31, 32]. Only specific subsets of bacteria, particularly Lactobacilli, an important member of Firmicutes, can metabolize dietary Trp into idole-3-aldehyde to modulate AhR/IL-22 axis, thus contributing to gut mucosal homeostasis [32, 33]. In addition, AhR activation occurring in macrophages and DCs further contributes to the local anti-inflammatory response.
Human cytomegalovirus (CMV) establishes a latent infection that remains generally asymptomatic but can lead to serious illness in immune-suppressed individuals [37, 38]. The long-term control of CMV shapes the immune system contributing to a memory inflammation induced by CD8 T-cell specific response. Such CMV-associated low-grade inflammation also contributes to human aging and has been termed as “inflammaging” [39, 40]. CMV seropositivity has been shown to have a negative effect on influenza vaccine-specific antibody responses in the elderly as well as in the young . CMV infection is prevalent in Africa and may contribute to a lower vaccine response observed in this population. Furthermore, CMV co-infection has been associated with faster disease progression and elevated CMV-specific IgG antibody levels in untreated HIV-infected individuals, further contributing to disease progression and immune activation . For patients receiving long-term antiretroviral therapy (ART), CMV-co-infection remains an independent contributor to persistent CD8 T-Cell expansion and inflammation .
We are starting to appreciate the importance of pre-existing inflammation linked to gut microbial composition in vaccine response that should influence HIV vaccine development where the bulk of epidemic prevails in developing countries. The complex interplay between microbial composition and the gut epithelial barrier contributes to the state of systemic immune activation representing an emerging area to be considered to optimize HIV vaccine response. Modulation of chronic immune activation prior to vaccine administration may elicit persistent memory antibody response with CD8 T-cell cytotoxic function. Collaborative effort between microbiologists, immunologists epidemiologists and clinicians will be needed to foster HIV vaccine research.