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The lysogenic and lytic cycle of bacteriophages. The lysogenic and lytic cycle can pass into one another (https://kullabs.com/classes/subjects/units/lessons/notes/note-detail/8287).
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The increase in bacterial drug resistance causes major difficulties in the clinical treatment of a growing number of bacterial infections worldwide. Consequently, there is an urgent need to develop novel anti-bacterial agents to control these resistant pathogens and to complement the currently used antibiotics. Mastitis is the most prevalent diseas...
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... or shortly phages, are viruses that infect bacteria. Each phage can infect only one bacte- rial species (or even strain) because it recognizes an adhesion molecule on the cell wall of the bacterium. When the phage is attached, it infects its host by in- jecting its genetic material through the production of endolysins. These endolysins are enzymes, which are capable of digesting the bacterial cell wall. Subse- quently, there are two possibilities: 1. the phage ge- nome can pass a lysogenic cycle, in which the genome is incorporated into the bacterial DNA (prophage) and will replicate together with the bacterium, 2. the phage genome can start a lytic cycle, in which it uses the bacterial replication mechanisms to multiply its DNA ( Figure 1). The genome then assembles with the viral proteins to create a new virion. Due to the massive production of virus particles, the bacterium eventually undergoes lysis. It is this feature which gives phages their ability to kill bacteria and there- fore, they are proposed as an alternative to antibiotics. Phage-derived endolysins have also been suggested as a novel antimicrobial agent, because of their ability to lyse bacterial cell walls (Weber-D?browska, ...
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... a cocktail consisting of four different bacteriophages has been proposed against E. coli through several in vitro tests (Porter et al., 2016). A 3.3 to 5.6 log reduction of growth in raw milk was ob- served when E. coli was co-incubated with this phage cocktail for twelve hours. Moreover, bacterial growth decreased with 1.6 ? 10? CFU/mL (colony forming units/mL) when tested against a mastitis-derived E. coli ...
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... several researchers have claimed that promising candidate bacteriophages and endolysins should now be tested in vivo to evaluate the effects of this novel treatment strategy in mammary gland of ro- dents, but preferably in the target species i.e. the cow (Schmelcher et al., 2015; Porter et al., 2016). How-ever, even if the envisaged phage therapy confirms to be promising in these follow-up studies, several prac- tical hurdles will raise during its development. It is known that raw milk inhibits staphylococcal phage K proliferation due to the formation of bacterial clusters associated with fat globules and/or the presence of IgG (O' Flaherty et al., 2005;Tanji et al., 2015). In ad- dition, Phage K has been reported to cause an increase in the SCC of healthy quarters ( Gill et al., 2006). Most strains belonging to the group of Gram-positive mas- titis pathogens are also known to cause biofilms, a property associated with their difficult eradication by traditional antimicrobial drugs. It should be remarked that biofilm-formation also occurs in some Gram-nega- tive mastitis-causing bacteria such as Klebsiella. As mentioned above, phages and endolysins have been described to have the unique characteristic to digest these protective structures and are expected to be able to infect and lyse these problematic biofilm-forming, mastitis-causing bacteria ( Latka et al., 2017;Zhou et al. 2017;Gerstmans et al. 2016;Guti?rrez et al., ...
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... endolysins are enzymes, which are capable of digesting the bacterial cell wall. Subse- quently, there are two possibilities: 1. the phage ge- nome can pass a lysogenic cycle, in which the genome is incorporated into the bacterial DNA (prophage) and will replicate together with the bacterium, 2. the phage genome can start a lytic cycle, in which it uses the bacterial replication mechanisms to multiply its DNA ( Figure 1). The genome then assembles with the viral proteins to create a new virion. ...
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... a cocktail consisting of four different bacteriophages has been proposed against E. coli through several in vitro tests (Porter et al., 2016). A 3.3 to 5.6 log reduction of growth in raw milk was ob- served when E. coli was co-incubated with this phage cocktail for twelve hours. ...
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... several researchers have claimed that promising candidate bacteriophages and endolysins should now be tested in vivo to evaluate the effects of this novel treatment strategy in mammary gland of ro- dents, but preferably in the target species i.e. the cow (Schmelcher et al., 2015; Porter et al., 2016). How-ever, even if the envisaged phage therapy confirms to be promising in these follow-up studies, several prac- tical hurdles will raise during its development. ...
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... endolysins are enzymes, which are capable of digesting the bacterial cell wall. Subse- quently, there are two possibilities: 1. the phage ge- nome can pass a lysogenic cycle, in which the genome is incorporated into the bacterial DNA (prophage) and will replicate together with the bacterium, 2. the phage genome can start a lytic cycle, in which it uses the bacterial replication mechanisms to multiply its DNA ( Figure 1). The genome then assembles with the viral proteins to create a new virion. ...
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... a cocktail consisting of four different bacteriophages has been proposed against E. coli through several in vitro tests (Porter et al., 2016). A 3.3 to 5.6 log reduction of growth in raw milk was ob- served when E. coli was co-incubated with this phage cocktail for twelve hours. ...
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... several researchers have claimed that promising candidate bacteriophages and endolysins should now be tested in vivo to evaluate the effects of this novel treatment strategy in mammary gland of ro- dents, but preferably in the target species i.e. the cow (Schmelcher et al., 2015; Porter et al., 2016). How-ever, even if the envisaged phage therapy confirms to be promising in these follow-up studies, several prac- tical hurdles will raise during its development. ...
Citations
... Endolysins offer several advantages over antibiotics in the treatment of bovine mastitis. They are effective against biofilms, a common cause of persistent infections, do not remain in milk, and contribute to safeguarding the well-being of both humans and animals by reducing the development of antibiotic resistance [163,164]. Moreover, replacing antibiotics with endolysins may offer cost savings due to their lower production costs, shorter treatment periods, and faster recovery [165]. ...
Antimicrobial resistance is a significant global public health issue, and the dissemination of antibiotic resistance in Gram-positive bacterial pathogens has significantly increased morbidity, mortality rates, and healthcare costs. Among them, Staphylococcus, especially methicillin-resistant Staphylococcus aureus (MRSA), causes a wide range of diseases due to its diverse pathogenic factors and infection strategies. These bacteria also present significant issues in veterinary medicine and food safety. Effectively managing staphylococci-related problems necessitates a concerted effort to implement preventive measures, rapidly detect the pathogen, and develop new and safe antimicrobial therapies. In recent years, there has been growing interest in using endolysins to combat bacterial infections. These enzymes, which are also referred to as lysins, are a unique class of hydrolytic enzymes synthesized by double-stranded DNA bacteriophages. They possess glycosidase, lytic transglycosylase, amidase, and endopeptidase activities, effectively destroying the peptidoglycan layer and resulting in bacterial lysis. This unique property makes endolysins powerful antimicrobial agents, particularly against Gram-positive organisms with more accessible peptidoglycan layers. Therefore, considering the potential benefits of endolysins compared to conventional antibiotics, we have endeavored to gather and review the characteristics and uses of endolysins derived from staphylococcal bacteriophages, as well as their antibacterial effectiveness against Staphylococcus spp. based on conducted experiments and trials.
... genome is inserted into the bacterial genome and replicates together with the bacterium (i.e., prophage), or (ii) the phage passes a lytic cycle in which it reprograms the bacterial host cell to synthesize and assemble new viral particles [2,3]. These lysogenic and lytic cycles can transfer into one another, but strictly virulent phages exist and replicate by a lytic infection cycle only. ...
... Indeed, when endolysins hydrolyse the bacterial cell wall of Gram-positive bacteria, the high internal osmotic pressure inside the bacterial cell causes the bacterium to 'burst' or 'lyse' . From that perspective, endolysins have been proposed and investigated as promising, novel antimicrobials [3,4,7,8]. ...
... Antibiotics currently provide therapeutic relief, but their use is increasingly questioned, particularly antibiotics that are regarded critical for human health care [103,104]. In this context, bacteriophage-derived endolysins have emerged as promising antimicrobials to either replace or complement existing treatments against Gram-positive bovine mastitis pathogens [3]. ...
Bacteriophage-encoded endolysins, peptidoglycan hydrolases breaking down the Gram-positive bacterial cell wall, represent a groundbreaking class of novel antimicrobials to revolutionize the veterinary medicine field. Wild-type endolysins exhibit a modular structure, consisting of enzymatically active and cell wall-binding domains, that enable genetic engineering strategies for the creation of chimeric fusion proteins or so-called 'engineered endolysins'. This biotechnological approach has yielded variants with modified lytic spectrums, introducing new possibilities in antimicrobial development. However, the discovery of highly similar endolysins by different groups has occasionally resulted in the assignment of different names that complicate a straightforward comparison. The aim of this review was to perform a homology-based comparison of the wild-type and engineered endolysins that have been characterized in the context of bovine mastitis-causing streptococci and staphylococci, grouping homologous endolysins with ≥ 95.0% protein sequence similarity. Literature is explored by homologous groups for the wild-type endolysins, followed by a chronological examination of engineered endolysins according to their year of publication. This review concludes that the wild-type endolysins encountered persistent challenges in raw milk and in vivo settings, causing a notable shift in the field towards the engineering of endolysins. Lead candidates that display robust lytic activity are nowadays selected from screening assays that are performed under these challenging conditions, often utilizing advanced high-throughput protein engineering methods. Overall, these recent advancements suggest that endolysins will integrate into the antibiotic arsenal over the next decade, thereby innovating antimicrobial treatment against bovine mastitis-causing streptococci and staphylococci.
... Endolysins, unlike antibiotics, have remarkable specificity, being a promising alternative to combat antibiotic-resistant bacterial strains. Furthermore, they minimize adverse effects to bovine hosts when used to treat conditions such as bovine mastitis [94,95]. Tables 6 and 7 provide a comprehensive summary of the findings from in vitro and in vivo tests evaluating the activity of bacteriophages and endolysins against bovine mastitis causing bacteria. ...
... PlySs2), P128 and Staphefekt being staphylococcal endolysins currently being evaluated in diverse human clinical trials (World Health Organization, 2021a). Also within the field of Gram-positive bovine mastitis, a few promising studies about the application of endolysins exist (Scholte et al., 2018;Vander Elst et al., 2020;Vander Elst & Meyer, 2018). We previously evaluated the wild-type endolysins PlySs2 and PlySs9 against S. uberis, and other endolysins have been reported with in vitro and in vivo activity against bovine mastitis streptococci (PlyC, Ply700, λSA2 and B30) (Celia et al., 2008;Schmelcher et al., 2015;Scholte et al., 2018), staphylococci (trx-SA1, phi11, phiH5, Lys109 and LysRODI) (Donovan et al., 2006;Fan et al., 2016;Gutiérrez et al., 2020;Obeso et al., 2008;Son et al., 2021) or both (PlySs2, ClyR) (Huang et al., 2015;Vander Elst et al., 2020;Yang et al., 2015). ...
... European Green Deal, WHO and a new EU Regulation on Veterinary Medicines 2019/06), indicating the need to develop alternatives that can phase out especially the critical antibiotics from animal production. Our group proposed bacteriophage-derived endolysins as replacement or add-on strategies and also previously characterized the S. suis wild-type endolysins PlySs2 and PlySs9 with potent lytic activity against S. uberis (Vander Elst et al., 2020;Vander Elst & Meyer, 2018). In addition, we reported that improved engineered endolysins can be conveniently engineered through domain swapping by the VersaTile DNA assembly technique (Duyvejonck et al., 2021;Gerstmans et al., 2020). ...
Bacteriophage‐derived endolysins are a novel class of antimicrobials known to rapidly kill bacteria, including antibiotic‐resistant strains. We here engineered endolysins against the bovine mastitis pathogens Streptococcus uberis, Streptococcus agalactiae and Streptococcus dysgalactiae, also targeting intracellular survival and biofilm formation. For this purpose, high‐throughput DNA assembly was used to create a library with >80,000 theoretical endolysin variants for screening of their bacteriolytic activity against Gram‐positive isolates from (sub)clinically affected cows. This lytic activity was evaluated by turbidity reduction and time‐kill assays in phosphate‐buffered saline and pasteurized whole cow's milk to allow a rank up of the most potent leading candidates. A top candidate was selected with a 4.0 log killing efficacy against S. uberis, also showing similar activity against S. agalactiae and S. dysgalactiae. This top candidate eradicated S. uberis biofilm and showed intracellular activity in two bovine mammary epithelial cell lines as was confirmed by confocal microscopy. A potentiating effect on cloxacillin, a beta‐lactam penicillin used to intramammarily treat bovine Gram‐positive mastitis, was observed for this top candidate endolysin in raw cow's milk from (sub)clinically infected udders. Our in vitro results indicate that engineered endolysins may have a future role as add‐on in the treatment of bovine streptococcal mastitis.
... Nevertheless, due to their proteinaceous nature, they may induce allergic reactions. PGHs can be applied not only in medicine [273] but also in the food industry [172,174,202,213,242,[274][275][276][277][278][279][280], during biofuel production [210,281], in agriculture [282][283][284], and in veterinary medicine [258,[285][286][287][288][289][290][291][292][293]. As with PSDs, they are suitable for a range of formulations and can be delivered via different routes, such as topical (creams, ointments, and gels), injections (intravenous or intraperitoneal), orally, transnasally, or vaginally [55,157,158]. ...
Over the past few decades, we have witnessed a surge around the world in the emergence of antibiotic-resistant bacteria. This global health threat arose mainly due to the overuse and misuse of antibiotics as well as a relative lack of new drug classes in development pipelines. Innovative antibacterial therapeutics and strategies are, therefore, in grave need. For the last twenty years, antimicrobial enzymes encoded by bacteriophages, viruses that can lyse and kill bacteria, have gained tremendous interest. There are two classes of these phage-derived enzymes, referred to also as enzybiotics: peptidoglycan hydrolases (lysins), which degrade the bacterial peptidoglycan layer, and polysaccharide depolymerases, which target extracellular or surface polysaccharides, i.e., bacterial capsules, slime layers, biofilm matrix, or lipopolysaccharides. Their features include distinctive modes of action, high efficiency, pathogen specificity, diversity in structure and activity, low possibility of bacterial resistance development, and no observed cross-resistance with currently used antibiotics. Additionally, and unlike antibiotics, enzybiotics can target metabolically inactive persister cells. These phage-derived enzymes have been tested in various animal models to combat both Gram-positive and Gram-negative bacteria, and in recent years peptidoglycan hydrolases have entered clinical trials. Here, we review the testing and clinical use of these enzymes.
... Viruses recruit host ribosomes to produce viral proteins and eventually kill the cell in a lytic cycle ( Fig. 10.7A). However, many viruses do not kill their host organism, but instead become integrated into its genome and then reproduce together with the host in a lysogenic cycle (Vander Elst and Meyer 2018). In this case, a parasite and its host become integrated into a system with mixed identity, where subagents do not attempt to get full control over each other. ...
In this chapter we argue that the multiplicity of subagents is a typical feature of agency which is necessary for a higher-level agent’s reliable self-construction, robustness, and adaptability. The composite organization allows for a dialectic balance between interests and functions of the whole and its parts. We argue that subagents are semi-autonomous and coexist in a partially cooperative, partially antagonistic unity that evolves over time. They generate adaptive variations of structures and functions that help organisms to improve performance and/or survive severe environmental changes. Subagents interact at both physiological and evolutionary time scales. One interaction strategy is guiding semiogenesis, which happens when one subagent
provides scaffolding that facilitates, represses, or re-directs the evolution or learning of another subagent
. Composite agents emerge either via integration of homogenous components, i.e. reproduction of identical low-level agents without separation followed by specialization, or symbiogenesis, i.e. integration of diverse low-level agents into a symbiotic community followed by co-adaptation. The long-term future fate of specific composite agents is fundamentally uncertain, and this gives rise to a “mixed identity”. In some cases, agents can acquire subagents (e.g., genes or symbionts) from other organisms. Some subagents may break free, infect other agents, or kill their host organism
.
... Viruses recruit host ribosomes to produce viral proteins and eventually kill the cell in a lytic cycle (Fig. 10.7a). However, many viruses do not kill their host organism, but instead become integrated into its genome and then reproduce together with the host in a lysogenic cycle (Vander Elst & Meyer, 2018). In this case, a parasite and its host become integrated into a system with mixed identity, where subagents do not attempt to get full control over each other. ...
This book invites readers to embark on a journey into the world of agency encompassing humans, other organisms, cells, intracellular molecular agents, colonies, populations, ecological systems, and artificial autonomous systems. We combine mechanistic and non-mechanistic approaches in the analysis of the function and evolution of organisms, their subagents, and multi-organism systems, and in this way offer a theoretical platform for integrating biosemiotics with both natural science and the humanities/social sciences. Agents are autonomous systems that incorporate knowledge on how to make sense of their environment and use it to achieve their goals. The functions of all agents are supported by mechanisms at the lowest level; however, the explanatory power of mechanistic analysis is not sufficient for complex agents. Non-mechanistic methods rely on the goal-directedness of agents whose dynamics follow self-stabilized dynamic attractors. The properties of attractors depend on stable or slowly changing factors, and such dependencies can be interpreted as sign relations if they are adaptive in nature. Agents can replace or redirect mechanisms on demand in order to preserve their functions; for performing higher-level semiotic functions, mechanisms are thus only means. We assume that mechanism and semiosis are not mutually exclusive, and that simple agents can interpret signs mechanistically. This assumption allows us to extend semiotic analysis to all agents, including ribosomes in cells, computers, and robots. This book challenges established traditions in natural science and the humanities/social sciences: semiotics no longer appears as restricted to humans and rational thinking, and biology is no longer limited to rely exclusively on mechanistic reasoning.
... The use of bacteriophages (phages) and their lytic enzymes have been proposed as strategies that may supplement the current antibiotic arsenal [14][15][16][17][18]. Although phage therapy was initially considered promising, more recent insights revealed several remaining hurdles i.e., unpredictable pharmacokinetics and -dynamics, large molecular size compared to antibiotics, low tissue penetration, narrow bacterial specificity, the necessity to replicate in vivo, elevation of the somatic cell count in the cow's milk and inactivation of bacteriophage by whey proteins [19][20][21]. ...
... Local, topical therapy as well as single intravenous injections are either recently available on the pharmaceutical market or in full development, albeit only for human applications [25,26]. Hence, endolysins offer an interesting potential within the context of veterinary medicine [14,[16][17][18]. More specifically, several endolysins have already been proposed to target Gram-positive pathogens associated with bovine mastitis [27][28][29][30][31]. ...
... Several preventive, prophylactic and therapeutic measures have been proposed to combat this infectious disease, but antibiotics currently remain the standard antimicrobial preventive and therapeutic treatment [6,9]. This systematic (over)use of antibiotics in the dairy sector is being questioned and as such, endolysins have been proposed as either replacement or add-on strategy [14,16,18]. We here characterized two endolysins, i.e., PlySs2 and PlySs9, with muralytic activity against bovine mastitis-causing S. uberis. ...
Bovine mastitis, an infection of the cow's mammary gland, is frequently caused by Streptococcus uberis and causes major economic losses in the dairy industry. The intramammary administration of antibiotics currently remains the predominant preventive and therapeutic measure. These antimicrobial compounds, of which some are considered critical in human health care, are frequently applied as dry therapy resulting in their consistent overuse. Therefore, the use of antibiotics in the dairy sector is being questioned. We here identified two endolysins, i.e., PlySs2 and PlySs9, respectively derived from Streptococcus suis serotype-2 and-9 prophages, with lytic activity against S. uberis in an in vitro setting. Both endolysins gave clear lysis zones in spot-on-plate assays and caused a reduction of the optical density in a turbidity reduction assay. In depth characterization identified PlySs9 as the more potent endolysin over PlySs2 with a lower MIC value and about one additional log of killing. PlySs2 and PlySs9 were challenged to a panel of subclinical and clinical S. uberis milk isolates and were both able to lyse all strains tested. Molecular dissection of these endolysins in catalytic and cell wall binding subdomains resulted in major loss of killing and binding activity, respectively. Taken together, we here propose PlySs2 and PlySs9 as candidate compounds to the current antimicrobial arsenal known against bovine mastitis-causing S. uberis as future add-on or replacement strategy to the currently used intramammary antibiotics.
... The use of bacteriophages and phage-derived endolysins represent a potential alternative for the treatment of bacterial infection of the mammary gland and uterus in cows Basdew and Laing, 2011;Vander Elst and Meyer, 2018;Gutiérrez et al., 2014). Bacteriophages (phages) are viruses that specifically infect bacteria. ...
Bacteriophages and the associated endolysins have been proposed as an alternative to antibiotic treatment of mastitis and metritis in cows. Many bacteriophages have been isolated and characterized with a large amount of lytic potential against the bacteria causing mastitis and metritis in cows. Several endolysins with marked lytic activity against mastitis pathogens in vitro were also produced from staphylococcal and streptococcal bacteriophages. In the few clinical studies, however, there has been marginal efficacy of bacteriophages in the therapy of mastitis caused by Staphylococcus aureus. Similarly, lytic bacteriophages have marked antimicrobial activity in vitro against E. coli strains from the uteri of postpartum dairy cows. In clinical studies, however, neither administration of bacteriophages early postpartum nor prepartum was effective in the prevention of metritis in cows. More clinical studies on the effectiveness of bacteriophages and the associated endolysins in the prevention and therapy of mastitis and metritis in cows, therefore, are needed.
Human immunodeficiency virus (HIV) infection is now considered a chronic disease thanks to the extended use of antiretroviral treatment (ART). However, chronic immune activation, inflammation, and increased bacterial translocation (BT) could persist in these patients despite ART. These facts have been described as predictors for clinical events and mortality in these patients. Gut microbiota (GM) changes induced by HIV infection and ART seem to be related to such inflammatory state. The role of integrase strand transfer inhibitors (INSTIs), the preferred choice for the treatment of naive patients, on GM (bacteriome) has not been deeply investigated. There are also no studies focused on the effects of HIV infection and/or ART on gut virome, despite the fact that viruses are the most abundant components of human GM. The main objective of this Doctoral Thesis was to deeply characterize GM composition (both bacteriome and virome) and oral bacteriome of HIV-infected patients in comparison with non-HIV-infected subjects, and to analyse the impact of INSTIs-based treatments. To accomplish this objective, 26 non-HIV-infected volunteers and 30 HIV-infected patients (15 naive and 15 under INSTI-regimen) were recruited. Blood samples were extracted to analyse biochemical parameters and markers of BT, inflammation, cardiovascular risk, gut permeability, and bacterial metabolism. Gut bacteriome composition and oral bacteriome composition was analysed using 16S rRNA gene sequencing and gut virome composition was studied using shotgun sequencing.
Our results showed that HIV-infection increased BT, inflammation, cardiovascular risk, and gut permeability, whereas INSTIs counteracted these effects. Regarding gut bacteriome, the reduction in bacterial richness induced by HIV infection was restored by INSTIs (p<0.05 naive vs. control Observed features and Chao1 estimator indexes). β-diversity revealed that HIV-infected people were separated from the control group independently of treatment (p<0.05 naive vs. control and p<0,05 INSTIs vs. control). Considering gut virome, the results showed that bacteriophages are the most abundant and diverse viruses in the gut independent from the HIV status and the use of treatment. Neither HIV infection nor INSTIs-based treatment had an effect on eukaryotic viruses composition. On the other hand, HIV infection was accompanied by a decrease in phage richness which was reverted after INSTIs-based treatment (p<0.01 naive vs. control Observed features index and p<0.05 naive vs. control Fisher’s alpha index). β-diversity of phages revealed that samples from HIV-infected patients clustered separately from those belonging to the control group (padj<0.01 naive vs. control and padj<0.05 INSTIs vs. control). However, it is worth mentioning that samples coming from INSTIs-treated patients grouped more closely together compared to naive patients. Differential abundant analysis showed an increase in phages belonging to the Caudoviricetes class in the naive group compared to the control group (padj<0.05) and a decrease of Malgrandaviricetes class phages in the INSTIs-treated group compared to the control group (padj<0.001). Besides, it was observed that INSTIs-based treatment was not able to reverse the increase of lysogenic phages associated with HIV infection (p<0.05 vs. control) or to modify the decrease observed on the relative abundance of Proteobacteria-infecting phages (p<0.05 vs. control). Finally, with respect to oral bacteriome, our study was unable to detect differences neither in α-diversity nor in β-diversity between the three groups analysed, although some taxa were revealed to be increased in the naive group and in the INSTIs-treated group compared to controls.
In conclusion, this Doctoral Thesis shows that current antiretroviral regimens based on INSTIs are able to reverse the impact of HIV infection on BT, systemic inflammation, gut permeability, and gut bacterial diversity/richness reaching similar levels than those observed in an uninfected/control population. Besides, our study describes for the first time the impact of HIV and INSTIs on the gut virome and demonstrates that INSTIs-based treatments are able to partially restore gut dysbiosis, not only at the bacterial, but also at the viral level. These results suggest a protective role of INSTIs in disease progression, in subsequent immune activation, and in the development of future age-related complications such as cardiovascular events and opens several opportunities for new studies focused on microbiota-based therapies.
