Temporal Response of the Human Virome to Immunosuppression and Antiviral Therapy

Abstract

Summary There are few substantive methods to measure the health of the immune system, and the connection between immune strength and the viral component of the microbiome is poorly understood. Organ transplant recipients are treated with a post-transplant therapy that combines immunosuppressive and antiviral drugs, offering a window into the effects of immune modulation on the virome. We used sequencing of cell-free DNA in plasma to investigate drug-virome interactions in a cohort of organ transplant recipients (656 samples, 96 patients), and find that antivirals and immunosuppressants strongly affect the structure of the virome in plasma. We observe marked virome compositional dynamics at the onset of the therapy and find that the total viral load increases with immunosuppression, whereas the bacterial component of the microbiome remains largely unaffected. The data provide insight into the relationship between the human virome, the state of the immune system, and the effects of pharmacological treatment, and offer a potential application of the virome state to predict immunocompetence.

Numerous uncharacterized and highly divergent microbes which colonize humans are revealed by circulating cell-free DNA

“…S19) on the basis of immune system status. TTVs encompass anellovirus families and are known to be enriched in immunocompromised patients (17). Their detection here represents another validation of the taxonomic assignment based on gene homology.…”

“…It is not only human cells that shed their nucleic acids into the blood: DNA from plant-based foods has been detected (15), and other life forms such as viruses, bacteria, and fungi release their DNA and RNA into the blood, a phenomenon which has been exploited to determine the presence of infectious disease (12,16) and to measure alterations of the virome due to pharmacological immunosuppression (17). There are roughly an order of magnitude more nonhuman cells than nucleated human cells in the body (18,19); combining this observation with the average genome sizes of a human, bacterium, and virus (Gb, Mb, and kb, respectively) suggests that approximately 1% of DNA by mass in a human is derived from nonhost origins.…”

Torque teno virus in patients undergoing allogeneic hematopoietic stem cell transplantation for hematological malignancies

“…6 It is currently believed that 490% of the population is infected but that the viral load in blood may remain undetectable because genome replication is efficiently controlled by the immune system. The latter is clearly illustrated by the fact that the viral load increases greatly after immune suppression given to prevent rejection of transplanted organs 7,8 and that high copy numbers are present in the blood during secondary immune deficiencies in patients with AIDS 9 or after HSCT. 10,11 As TTV is not sensitive to current antiviral prophylaxis/therapy, 8 the number of viral copies in the patient's blood may be an appropriate parameter to measure immunocompetence.…”

“…This lag time of 41 month is very similar to the one observed after the beginning of immunosuppression in organ transplantation. 7,8 Hence, at transplant, the majority of patients still disposes of sufficient residual immunity to keep TTV in check while others already have lost this capacity. Interestingly, supranormal TTV-titers at transplant were strongly associated with the type of disease (right panel of the Figure 1).…”

Impact of environmental factors on alloimmunity and transplant fate

“…Long-term immunosuppression in transplant patients was associated with changes in the salivary bacteriome, increased bacterial richness, and outgrowth of potentially opportunistic pathogens (132). Systemic immunosuppression also increased the total load of the virome, the analysis of which might be useful to monitor immunocompetence (133). Conversely, the microbiota may affect immunosuppression dose requirements.…”