What is the link between HIV / AIDS / COVID-19 and the microbiome?


Men who contracted HIV in the early days of the HIV/AIDS pandemic harbored a greater relative abundance of pro-inflammatory vs. anti-inflammatory gut microbes before they became HIV-positive compared to their counterparts who remained HIV-negative, according to new research published today in the journal Microbiome.

In addition, the men who progressed to AIDS the quickest had the least favorable gut microbiome composition.

The study, which was conducted at the University of Pittsburgh and used patient samples preserved from the beginning of the HIV/AIDS pandemic in the early 1980s, is the first to link the composition of the gut microbiome before infection to HIV susceptibility and progression.

“There was something going on in the intestinal tract of these men before they acquired HIV that was different than the men who did not contract the virus,” said co-senior author Charles Rinaldo, Ph.D., professor of infectious diseases at Pitt. “Not only were they at greater risk of acquiring HIV, but once HIV-positive, they also were at greater risk of developing AIDS compared to people with a more normal microbiome.

This discovery helps us understand what was underlying the susceptibility of men to HIV well before we had antiviral drugs to control the virus. It could also have implications for disease cure or even prevention.”

The scientists analyzed stool and blood samples donated starting in the spring of 1984 – months before HIV was found to be responsible for AIDS – by gay men enrolled in the National Institutes of Health (NIH)-funded Multicenter AIDS Cohort Study (MACS), which had four sites nationwide, including in Pittsburgh.

At the time, AIDS was killing the participants’ friends, but scientists didn’t know why, so MACS collected stool samples from volunteers every six months to try to find a cause. Once HIV was discovered, they stopped collecting such samples, but instead of throwing away the ones they already had, the MACS team cryogenically froze and stored them in a biorepository.

In 2017, Rinaldo—then chair of the Pitt Graduate School of Public Health’s Department of Infectious Diseases and Microbiology – was discussing the biorepository with Shyamal Peddada, Ph.D., who was then chair of the Department of Biostatistics at the school and has expertise in the microbiome.

“At that time, a new and growing body of research tied the microbiome to our immune response,” said Peddada, co-senior author and now chief of the Biostatistics and Bioinformatics Branch at the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

“It became apparent to both of us that MACS had, thankfully, preserved a treasure trove of specimens. Science had advanced to the point that we could now revisit this biorepository to find out what was happening in the microbiome and immune system of men before and after they got HIV.”

The researchers obtained preserved samples of blood and stool from 265 participants who did not have HIV when they enrolled in MACS. Of the participants, 109 contracted the virus in that first year; the rest did not.

Yue Chen, Ph.D., associate professor at Pitt Public Health and co-lead author, processed the 35-year-old stool samples with the help of Alison Morris, M.D., M.S., chair of pulmonary, allergy and critical care medicine at Pitt.

The data were then analyzed by co-lead author Huang Lin, Ph.D., a fellow at the NICHD, who determined which families and species of microbes were inhabiting the participants’ intestines and how the abundances of these microbes differed among samples using novel statistical methods he developed as part of his Ph.D. dissertation work under Peddada’s supervision in Pitt Public Health’s Department of Biostatistics.

Participants who went on to contract HIV had a greater relative abundance of Prevotella stercorea, a bacterium that promotes inflammation, and lower levels of four Bacteroides species that are known to be involved in immune response.

At the same time, Chen was also investigating markers of inflammation in the blood of participants. She found that the participants who eventually contracted HIV had higher levels of inflammation before infection than their counterparts who did not go on to get HIV.

The scientists believe that the gut microbiome was aggravating the immune response and promoting inflammation, making the men with unfavorable microbiome profiles more susceptible to contracting HIV and less able to prevent the disease from progressing to full-blown AIDS in a time before antiretroviral therapy existed.

“This kind of study hasn’t been done before with HIV – as far as our team is aware,” Rinaldo said. “If the gut microbiome influences a person’s susceptibility to HIV in this way, it could be doing the same for other pathogens, such as COVID-19.”

More research is needed before the findings can be used to craft specific guidance for people looking to improve their microbiome to prevent HIV acquisition, the scientists noted.

“But we know that, in general, a diet rich in fruits, vegetables and fiber typically results in a healthier gut microbiome,” Pedadda said. “I would tell anyone looking to improve their health to consider improving their diet.”

Additional authors are Mariah Cole, M.S., Jeremy Martinson, D.Phil., Adam Fitch, M.S., Barbara Methé, Ph.D., and Vatsala Rangachar Srinivasa, M.P.H., all of Pitt at the time of the research; Heather McKay, Ph.D., and Joseph Margolick, M.D., Ph.D., both of Johns Hopkins University; and Matthew Mimiaga, Ph.D., of the University of California at Los Angeles.

Early studies have shown that the intestinal mucosa is the primary site of early HIV-1 reproduction, irrespective of the way in which HIV-1 invades the body, whether by sexual contact or blood transfusion (Mehandru et al., 2004). HIV-1, which enters the intestinal mucosa at the very early stages of infection, can cause the Th17 CD4+T cells of the intestine to be destroyed and depleted and the integrity of the intestinal mucosa to be impaired (Epple et al., 2010; Hirao et al., 2014).

In addition, gut microbiome translocation can occur, and the gut microbiome and its products can enter the systemic blood circulation (Balagopal et al., 2008), eventually leading to activation of the immune system and spread of the HIV-1 infection (Brenchley et al., 2006).

In recent years, exploration of the role and mechanism of the gut microbiome in the development of HIV infection has gradually become a popular topic of academic research. However, there is still inconsistent evidence about the alpha diversity and composition of the gut microbiome after HIV infection.

Most current studies suggest that HIV+ status is related to the downregulation of alpha diversity in the gut microbiome (Mutlu et al., 2014; Yu et al., 2014; Nowak et al., 2015; Dubourg et al., 2016; Noguera-Julian et al., 2016; Pinto-Cardoso et al., 2017; Vesterbacka et al., 2017; Villanueva-Millan et al., 2017). Some researchers (McHardy et al., 2013; Dinh et al., 2015; Nowak et al., 2017) also compared the alpha diversity of the gut microbiome in HIV+ and HIV– individuals, but no significant difference was found.

The study by Lozupone et al. (2013) showed that the alpha diversity of the gut microbiome in HIV+ individuals who did not receive antiretroviral therapy (ART) was significantly higher than that of HIV– individuals. Moreover, in many studies, there are inconsistent results regarding the change in the composition of the gut microbiome after HIV infection.

Some studies have shown that the abundance of Prevotella increases significantly and the abundance of Bacteroides decreases significantly in HIV+ individuals compared to HIV– individuals (Vujkovic-Cvijin et al., 2013; Dillon et al., 2014; Mutlu et al., 2014; Vázquez-Castellanos et al., 2015; Sun et al., 2016; Yang et al., 2016; Armstrong et al., 2018; Neff et al., 2018).

However, a study by Noguera-Julian et al. (2016) showed that the increase in the Prevotella/Bacteroides ratio is associated with MSM status rather than HIV status, which has since been corroborated by several other studies (Armstrong et al., 2018; Neff et al., 2018; Li et al., 2019).

Although many studies have explored the changes in the gut microbiome associated with HIV infection, the pattern of these changes has not been elucidated. MSM status is very likely an independent influencing factor of the gut microbiome, but there is still a lack of relevant research to explore it.

In addition, HIV infection can cause dysregulation of multiple functional pathways in the human body (Vázquez-Castellanos et al., 2015, 2018). On the one hand, HIV-related gut microbiomes are well-adapted to inflammatory environments, such as the high expression of the anti-oxidative stress response pathway and the low expression of the anti-inflammatory response process.

On the other hand, the gut microbiome can promote the occurrence and development of intestinal inflammation. Therefore, exploration of the functional changes related to HIV infection based on the gene expression profile of the gut microbiome can increase our understanding of the interaction between the gut microbiome and the human body.

To clarify the diversity of the gut microbiome related to HIV infection, to determine whether MSM status is an independent factor influencing the gut microbiome, and to explore the consistent change in the gut microbiome and functional pathways in HIV+ individuals and MSM, we screened 12 published studies of 16S rRNA gene amplicon sequencing of the gut microbiome related to HIV/AIDS (six of these studies contain data that is relevant and available to MSM) from NCBI and EBI databases.

The alpha diversity indexes, beta diversity indexes, genera, species, and KEGG functional pathways related to the gut microbiome were calculated. Finally, the overall trend in the above indicators was evaluated.

. . . .

We identified the genus and species that cause changes in the composition of the gut microbiome of HIV+ individuals and MSM. In at least three studies, the genus of Bacteroides, Coprococcus, Faecalibacterium, and SMB53 and the species of Bifidobacterium adolescentis, Bacteroides caccae, Coprococcus catus, Parabacteroides distasonis, Akkermansia muciniphila, Blautia obeum, Bacteroides ovatus, Faecalibacterium prausnitzii, and Bacteroides uniformis were significantly reduced in HIV+ individuals.

The species of Prevotella stercorea was significantly increased in HIV+ individuals (Figure 8). In MSM, the genus of Catenibacterium, Eubacterium, Mitsuokella, Phascolarctobacterium, Prevotella, and Slackia and the species of Eubacterium biforme, Prevotella copri, and Prevotella stercorea were significantly increased, and the genus of Adlercreutzia, Bacteroides, Bifidobacterium, Bilophila, Holdemania, Odoribacter, Parabacteroides and the species of Bacteroides caccae, Parabacteroides distasonis, Bacteroides ovatus, Ruminococcus torques, and Bacteroides uniformis were significantly reduced (Figure 9).

reference link :https://www.frontiersin.org/articles/10.3389/fcimb.2020.00434/full

The gut as reservoir for HIV and SARS-CoV-2

The mucosal surface of the gut plays a key role during infection with HIV.32 33 In fact, the gut contains a large number of infected cells, even in individuals receiving antiretroviral therapy (ART). This process is facilitated by the increased susceptibility of mucosal CD4+ T cells for HIV infection due to greater C-C chemokine receptor (CCR)-5 expression and local T cell activation.34 35 On infection, there is a rapid loss of mucosal barrier function with translocation of microbial products36 and loss of mucosal CD4+ T cells.37

These changes favour local and systemic inflammation in HIV-infected individuals. Probiotic treatment of HIV-infected patients has been shown to suppress microbial translocation and serum inflammatory markers in ART-naive patients,38 39 highlighting a leaky barrier as key component of HIV-induced gut inflammation. Moreover, it has been shown that the mucosa, as the largest lymphoid organ of the body, is an important reservoir for HIV-infected cells.

Consistently, studies reported that HIV-DNA levels in CD4+ T cells were on average 5–6 times higher in the ileum compared with blood in patients on ART,40 and 2-fold to 12-fold higher in the duodenum, ileum, right colon and rectum as compared with peripheral blood.41 Based on these findings it was estimated that the gut harbours 83%–95% of all HIV-infected cells in the body and thus provides a key reservoir for disease persistence.

Local, infected CD13+ myeloid cells and CD4+ T cells may reach regional lymph nodes and the bloodstream via immune cell trafficking, thereby favouring viral dissemination throughout the body.35 42 43 This concept has important implications for clinical therapy. In fact, ART does not cure HIV infection due to the persistence of HIV reservoirs in long-lived memory CD4 T cells present in the blood, lymph nodes and intestinal tract.44

The COVID-19 pandemic is caused by SARS-CoV-2. Infection of more than 144 million cases has been reported and has led to 3 million confirmed deaths.45 As intestinal epithelial cells express high amounts of the SARS-CoV-2 receptor ACE2 and transmembrane protease serine subtype 2 (TMPRSS2), a cellular protease important for viral entry, GI infection is frequently seen in COVID-19 and GI symptoms have been reported in 30%–70% of patients.46–48

Remarkably, GI infection results in limited or absent signs of local inflammation as well as low mortality in COVID-19, suggesting a potential role of the GI tract in attenuating SARS-CoV-2 infection.49 Stool analyses confirmed the presence of SARS-CoV-2 genomic and subgenomic RNA in affected patients,50 but isolation of the virus from stool samples has rarely been successful,51 indicating that GI infection may be self-limiting.

However, local infection of intestinal epithelial cells in COVID-19 may affect the gut virome. In patients with COVID-19, a significantly reduced viral Shannon diversity was noted as compared with the gut viromes of healthy controls.52 Specifically, viromes were composed of DNA/RNA viruses (mainly Herelleviridae and Virgaviridae families) as well as bacteriophages (Caudovirales, crAss-like phage, Inoviridae, Microviridae, Myoviridae, Podoviridae and Siphoviridae families).52

A recent metagenomic study profiled the faecal RNA and DNA viromes of patients with COVID-19 and found that the faecal virome in SARS-CoV-2 infection harboured more stress-associated, inflammation-associated and virulence-associated gene-encoding capacities, including those pertaining to bacteriophage integration, DNA repair, and metabolism and virulence associated with their bacterial host. Several gut viruses also correlated with COVID-19 disease severity, suggesting that the gut virome may calibrate host immunity and regulate severity to SARS-CoV-2 infection.53

Cellular and humoral immunity mediated by T and B cells plays a key role in COVID-19.54–57 In particular, B cell-derived antibodies against the spike protein and its receptor-binding domain are relevant in this context, as they prevent virus binding to epithelial cells.54 55 Moreover, an expansion of T follicular helper cells is indicative of a matured humoral immune response allowing memory B cells to prevent possible reinfection.54

However, the reasons for persistent antigen-specific memory responses in COVID-19 remained mysterious, despite the above findings, suggesting the presence of reservoirs for viral proteins that might trigger prolonged immune responses. Interestingly, there is a high rate of positive PCR findings in stool even weeks or months after respiratory samples became negative, indicating persistence of mucosal SARS-CoV-2 mRNA in patients with COVID-19.58

This could be due to infection of intestinal epithelial cells, as SARS-CoV-2 could infect and productively replicate in human intestinal tissues ex vivo with subsequent release of infectious virus particles, suggesting that the GI tract serves as a potential route of virus dissemination within an infected host.59

Consistently, a recent study showed that SARS-CoV-2 nucleoprotein (N) is present in intestinal epithelial cells of approximately 35% of patients with COVID-19 even several weeks or months after initial diagnosis, indicating antigen persistence in the intestine after resolution of clinical illness.60 Given the high turnover of intestinal epithelial cells persistence of the viral antigen is also suggestive of continuous virus replication.

As even small amounts of persistent viral antigen have been suggested to fuel antibody evolution, the observation on persistent N protein expression over prolonged periods of time is consistent with the relative persistence of SARS-CoV-2 IgA antibodies and continued antibody evolution, as well as persistent polyfunctional SARS-CoV-2 antigen-specific B and T cell memory responses.61

These immune responses in turn are likely to support a rapid and effective adaptive immune response to the virus on re-exposure and thus provide a critical cornerstone in immune protection against COVID-19. However, one cannot exclude the possibility that long-term shedding of viruses might contribute to long-term COVID-19 and we feel that this point requires further investigation.

REFERENCE LINK : https://gut.bmj.com/content/70/9/1605

More information: Signature changes in gut microbiome are associated with increased susceptibility to HIV-1 infection in MSM, Microbiome, 2021.



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