Torquetenovirus (TTV) load in people infected by SARS-CoV-2 can be used as a marker of COVID-19 severity and recovery


Torquetenovirus (TTV) is one of the viruses most frequently found in the human organism. It is also common in monkeys and domestic animals.

Its presence has not been associated with any known disease, but its excessive replication is a sign that something is wrong with the immune system.

The correlation between high TTV load and immunosuppression has been used in medicine in certain contexts, such as monitoring transplant patients who take medication to prevent rejection of the transplanted organ.

A study by researchers at the University of São Paulo (USP) in Brazil suggests that TTV load in people infected by SARS-CoV-2 can be used as a marker of COVID-19 severity and recovery. The findings are reported in an article in PLOS ONE.

“We used analyzed samples from 91 patients diagnosed with SARS-CoV-2 by RT-PCR, and from 126 people with flu symptoms who tested negative. We found TTV titer to be higher in subjects infected by the novel coronavirus. The higher the titer, the longer they remained sick. Symptoms disappeared as viral load decreased.

In uninfected subjects, TTV titer remained stable throughout the symptomatic period,” said Maria Cássia Mendes-Correa, a professor at the Medical School (FM-USP) and first author of the article.

Mendes-Correa heads the Virology Laboratory (LIM52) at the Institute of Tropical Medicine (IMT-USP), where TTV has been analyzed for several years in a variety of contexts. The research line is led by Tania Regina Tozetto-Mendoza, a biologist and second author of the study just published.

“We’re studying TTV as a potential biomarker for certain clinical outcomes measured in different biological fluids,” Tozetto-Mendoza said.

The study was conducted under the aegis of the São Caetano Corona Program, an online platform established to organize remote monitoring of inhabitants of São Caetano do Sul (a city in metropolitan São Paulo) with symptoms of COVID-19 by healthcare workers, and home collection of samples for diagnosis.

The program is an initiative of the Municipal University of São Caetano do Sul (USCS) in partnership with IMT-USP, the city government, and a startup called Modular Research System (MRS).

Analyzing samples from patients treated via this program, the IMT-USP researchers have investigated how elimination of SARS-CoV-2 varies over time in different body fluids, such as blood, urine and saliva. The research is supported by FAPESP.

“We then had the idea of analyzing TTV load in these samples in order to find out whether it correlated with COVID-19 severity. The results showed that TTV can indeed serve as a marker of the progression and outcome of this disease. The more symptomatic the patient, the higher the TTV load in the sample,” Mendes-Correa said.

All patients included in the study had mild or moderate COVID-19, she explained. TTV and SARS-CoV-2 viral loads were measured in saliva samples. According to the answers to a questionnaire, none of the participants had diseases that cause immunosuppression, such as cancer or HIV/AIDS.

“COVID-19 appears to lead to a degree of immunodepression by causing an immune system imbalance, and this favors replication of TTV,” Mendes-Correa said.

Support for diagnosis

The discovery has no direct clinical applications, but may in future contribute to improved COVID-19 diagnosis and prognosis. “We’re all looking for ways to obtain rapid and accurate diagnosis,” Mendes-Correa said.

“One of the possibilities is to develop a kit that doses several biomarkers of the disease at the same time and then assess the results with the aid of algorithms. Measuring TTV titer is one of several tests that could be included in these algorithms to support diagnosis. This is the direction medicine is going in.”

Torque Tenuis Virus (TTV), formerly called Transfusion Transmitted Virus was first described in 1997 [1]. It belongs to the Anelloviridae family that includes Alphatorquevirus genus and represents about 70% of the human virome [2]. It is a small, non-enveloped, single-stranded and circular DNA virus that infects human very early in life [3].

Probably more than 65% of the population worldwide is chronically infected by this virus [4], even if the immune system can control virus replication, which results in low or undetectable viral load.

Although no clinical diseases have been related to TTV infection [3], increased levels of plasma TTV viral load have been observed in various situations of immune deficiency or dysregulation (sepsis, HIV infection, cancer, and autologous or allogeneic hematopoietic stem cell transplantation) [5–8]. Several studies have suggested that TTV levels may be inversely correlated with immune competence [9], as TTV replication is under the control of T lymphocytes [10].

Based on this observation, the measurement of TTV viremia by qPCR has been proposed as a biomarker for the follow-up of functional immune competence in immunosuppressed individuals, particularly hematopoietic stem cell transplant recipients [11–16].

TTV levels were described as relevant biomarker to predict the risk of microbial infections or graft versus host disease, and guide the administration of immunosuppressive therapy or antimicrobial prophylaxis after hematopoietic stem cell transplantation.

T lymphocytes are essential players of cancer immunosurveillance. However, they may present an exhausted phenotype characterized by poor functionality and high expression of “immune checkpoint” receptors such as PD-1 and CTLA-4 when infiltrating tumors. PD-1 and CTLA-4 binding to their ligands, respectively PD-L1 and CD80/CD86, expressed by tumor and other cells, leads to functional exhaustion [17] and impairs anti-tumor immunity.

Immune checkpoint inhibitors [ICI] are monoclonal antibodies that were developed to block these ligand/receptor interactions and thus restore T lymphocyte-based immunity and improve clinical outcomes. They were first approved for melanoma, non-small-cell lung cancer and kidney cancer and they have now been shown to provide a survival advantage in many other types of cancer. However, despite promising results in different studies [18–21], only a fraction of patients treated by ICI have clinical benefit whereas many patients experience adverse events or become resistant [22, 23].

In recent years, significant efforts have been undertaken to identify predictive markers of response/toxicity, exploring many immunological and genetic markers. The most widely studied is the expression of PD-L1 on tumor cells or in tumor infiltrating lymphocytes in patients with lung cancer [24–26], and it appears that patients with high PD-L1 expression have a better response rate to PD-1/PD-L1 therapy [27, 28].

Genomic biomarkers, such as tumor mutation burden, could also be good predictive biomarkers of efficacy [29–31]; patients with high burden of tumor mutations deriving greater benefits of the treatment. Similarly, transcriptomic analysis has found a tumor transcriptional signature of poor prognosis [32] or good prognosis; the latter includes high expression of TH1 genes including those coding for IFNγ and PD-L1 [33].

Furthermore, an evaluation of the tumor micro-environment particularly a description of the major phenotype of tumor infiltrating lymphocytes, seems to be very useful to guide ICI treatment [34]. However, almost all biomarkers that have been used to assess ICI biotherapy response suffer from a lack of sensitivity or specificity. There is therefore still a great need for new sensitive and specific predictive biomarkers of ICI efficacy.

In the present study, we hypothesized that TTV viral load could be used as a prognostic marker of ICI efficacy. We investigated this biomarker in a population of melanoma patients, which was described as a condition of immunosuppression [35, 36]: TTV viral load was measured in patients with treatment-sensitive tumor and patients with treatment-resistant tumor before and after 6 months of treatment with anti-PD-1 monoclonal antibodies [nivolumab or pembrolizumab.

It was found that TTV viral load was not different in melanoma patients compared to healthy volunteers (HV) before anti-PD-1 introduction. In addition, TTV viral load was neither modified by ICI treatment or allowed to distinguish patients with treatment-sensitive tumor from patients with treatment-resistant tumor.

reference link :

More information: Maria C. Mendes-Correa et al, Torquetenovirus in saliva: A potential biomarker for SARS-CoV-2 infection?, PLOS ONE (2021). DOI: 10.1371/journal.pone.0256357


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