Can gut microbiota and systemic inflammation limit HIV vaccine effectiveness? PDF Print E-mail
Written by Jean Pierre ROUTY   
Tuesday, 20 June 2017 14:24

Can gut microbiota and systemic inflammation limit HIV vaccine effectiveness?


In this elegant article, Professor Jean-Pierre Routy, asks the question of the gut microbia and systemic inflammation that could limit HIV vaccine effectiveness, and its implication for the succèes of preventive and therapeutic vaccine development.

Dr Routy is Professor of Medicine in Montreal, Canada.

The development of an HIV vaccine is difficult considering the unparalleled capacity of HIV to mutate its genome, 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.

Vaccine efficacy can be predicted using a correlate of protection (CoP), which is a measurable immune biomarker that identifies immunity in the host, such as the antibody titre. Establishing immune determinants responsible for the protection remain difficult as several type of immune responses are intertwined. In the case of an HIV vaccine such CoP are defined as vaccine-induced immune responses associated with the rate of HIV-1 infection among vaccine recipients. Importantly, immune responses may depend on type of vaccine, level of immune activation prior to vaccination, micro-environment and host genetic factors. Host and environmental factors that may influence CoP are also intertwined with immune activation. Host factors include immune exhaustion, senescence, metabolic reprogramming and tissue inflammation, contributing to T-cell dysfunction and modulation of B cell response to neo-antigens or vaccines. Among the environmental factors, gut microbial composition, gut mucosal barrier damage and cytomegalovirus (CMV) co-infection are the most studied and differ in Northern and Southern hemispheres.

The RV144 vaccine trial investigated the efficacy of a combined HIV vaccine regimen in young adults in Thailand. Its encouraging results 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 neutralisation may contribute to protection, as Fc characteristics and ADCC have been identified as CoP against HIV acquisition conversely to the induction of neutralising 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.

Observations of inter-individual variation highlight a knowledge gap in the role of human pre-immune repertoires in driving vaccine response. One such repertoire is the gut microbiota, as it can elicit influences that are indirect and can act at a distance. These mechanisms may involve cross-reactivity between microbial and vaccine antigens shaping T cell repertoires, and/or microbial products stimulating pattern recognition receptors that influence the type and intensity of vaccine responses. Preliminary data show that T helper cells cross react with HIV antigens which are identified in uninfected healthy individuals and are usually missed by standard intracellular assay for the measurement of Th1 cytokines. Such cross reactive responses may shape subsequent responses to HIV vaccine candidates in both magnitude and function. This is further illustrated by the HVTN 055 trial which showed a lack of protection against HIV, owing to the unexpected induction of non-neutralizing gp41-reactive anti-HIV antibodies. The antibodies elicited by the vaccine were related to a polyreactive antibody repertoire response from pre-existing B-cells that were cross-reactive with Escherichia coli likely originating from the gut. Understanding the contribution of the microbiome and/or microbial translocation to both vaccine-induced immunity and non-specific immune activation represents a new and unforeseen challenge for the development of an optimal vaccine response.

Gut microbiota, metabolites and vaccine response. Gut-associated lymphoid tissue (GALT) represents a major site of immune response. This is due to the fact that GALT harbours a large fraction of activated CD4 T-cell populations, which are preferential targets for HIV replication. The interaction of GALT CD4-T cells with commensal/pathogenic microflora promotes cellular activation that favours general immune activation. In the context of treated HIV-infection, the predictors of commercialised vaccine response are linked with the levels of T cell activation and translocation of bacterial products such as LPS into the systemic circulation. Secretary IgA (sIgA) which represent an important barrier from gut infection is dependent on the presence of microbiota in the colon, which may also influence the HIV vaccine specific IgA response.

Manipulation of microbiota composition and their metabolites via diet alteration or microbiota engraftment is under intense evaluation in cancer, autoimmune disorders and vaccinology. Learning from our gut endogenous original adjuvants and tolerogenic microbes or their metabolites will be critical in overcoming the HIV vaccine challenge. We recently showed that 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 and cancer. 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 immunisation. Certain microbes like Taenia crassiceps, a parasite that causes a gut helminthic infection, have been shown to impair antibody response to pneumococcal vaccine in mice. Similarly, another group showed that immunisation against Hepatitis B and Tetanus Toxoid in Kenyan adults having schistosomiasis caused by members of the Schistosoma genus, resulted in a more rapid decline in antibody titres that can be prevented by a prior anti-helminthic treatment. All these observations highlight the importance of gut microbial dysbiosis on distal immune response in physiology and disease.

CMV infection, ageing, tobacco and vaccine response. Human cytomegalovirus (CMV) establishes a latent infection that remains generally asymptomatic but can lead to serious illness in immune-suppressed individuals. The long-term control of CMV shapes the immune system contributing to a chronic inflammation induced by CD8 specific response. Such CMV-associated low-grade inflammation also contributes to human ageing and has been termed as "inflammaging”. 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. Life style including tobacco usage also influence systemic level of inflammation and influence vaccine response.

In addition to established factors of inflammation like age, CMV, tobacco usage, we now have identified the importance of pre-existing inflammation linked to gut microbial composition in vaccine response, even that of healthy individuals. Such determinants of inflammation should guide HIV vaccine development. Modulation of chronic immune activation prior to vaccine administration or immunotherapy for HIV-infected persons may elicit persistent memory antibody response combined with CD8 T-cell cytotoxic function.



Key words: HIV inflammation, HIV persistence, HIV reservoirs, HIV;, Jean-Pierre Routy, Microbiote
Last Updated on Tuesday, 20 June 2017 14:53


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