Reduced Immune Activation During Tenofovir–Emtricitabine Therapy in HIV-Negative Individuals

Castillo‐Mancilla, José; Meditz, Amie L.; Wilson, Cara C.; Zheng, Jia‐Hua; Palmer, Brent E.; Lee, Eric J.; Gardner, Edward M.; Seifert, Sharon M; Kerr, Becky Jo; Bushman, Lane R.; MaWhinney, Samantha; Anderson, Peter L.

doi:10.1097/qai.0000000000000529

Cited by 20 publications

(11 citation statements)

References 44 publications

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“…We did find interesting trends of decreased expression of genes involved in monocyte responses to pathogens ( MARCO , GLRX , PTFAR , and CERK ) and cytoskeletal reorganization and cell movement ( MSN and CEP350 ). These findings suggest that ART may impact monocyte functions by dysregulating gene transcripts, sometimes decreasing their levels to below those seen with uninfected cells rather than restoring them to the uninfected levels, as had been suggested previously ( 94 – 97 ). Thus, ART might contribute to the monocyte dysfunction that persists in PLWH in the ART era, and ART-specific changes should be examined in future studies.…”

Section: Discussionsupporting

confidence: 78%

Interactions of Monocytes, HIV, and ART Identified by an Innovative scRNAseq Pipeline: Pathways to Reservoirs and HIV-Associated Comorbidities

León-Rivera

Morsey

Niu

et al. 2020

mBio

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HIV reservoirs persist despite successful antiretroviral therapy (ART) and are a major obstacle to the eradication and cure of HIV. The mature monocyte subset, CD14+CD16+, contributes to viral reservoirs and HIV-associated comorbidities. Only a subset of monocytes harbors HIV (HIV+), while the rest remain uninfected, exposed cells (HIVexp). We developed an innovative single cell RNA sequencing (scRNAseq) pipeline that detects HIV and host transcripts simultaneously, enabling us to examine differences between HIV+ and HIVexp mature monocytes. Using this, we characterized uninfected, HIV+, and HIVexp primary human mature monocytes with and without ART. We showed that HIV+ mature monocytes do not form their own cluster separately from HIVexp but can be distinguished by significant differential gene expression. We found that ART decreased levels of unspliced HIV transcripts potentially by modulating host transcriptional regulators shown to decrease viral infection and replication. We also identified and characterized mature monocyte subpopulations differentially impacted by HIV and ART. We identified genes dysregulated by ART in HIVexp monocytes compared to their uninfected counterpart and, of interest, the junctional protein ALCAM, suggesting that ART impacts monocyte functions. Our data provide a novel method for simultaneous detection of HIV and host transcripts. We identify potential targets, such as those genes whose expression is increased in HIV+ mature monocytes compared to HIVexp, to block their entry into tissues, preventing establishment/replenishment of HIV reservoirs even with ART, thereby reducing and/or eliminating viral burden and HIV-associated comorbidities. Our data also highlight the heterogeneity of mature monocyte subsets and their potential contributions to HIV pathogenesis in the ART era. IMPORTANCE HIV enters tissues early after infection, leading to establishment and persistence of HIV reservoirs despite antiretroviral therapy (ART). Viral reservoirs are a major obstacle to the eradication and cure of HIV. CD14+CD16+ (mature) monocytes may contribute to establishment and reseeding of reservoirs. A subset of monocytes, consisting mainly of CD14+CD16+ cells, harbors HIV (HIV+), while the rest remain uninfected, exposed cells (HIVexp). It is important to identify cells harboring virus to eliminate reservoirs. Using an innovative single-cell RNA sequencing (scRNAseq) pipeline to detect HIV and host transcripts simultaneously, we characterized HIV+ and HIVexp primary human mature monocytes with and without ART. HIV+ mature monocytes are not a unique subpopulation but rather can be distinguished from HIVexp by differential gene expression. We characterized mature monocyte subpopulations differently impacted by HIV and ART, highlighting their potential contributions to HIV-associated comorbidities. Our data propose therapeutic targets to block HIV+ monocyte entry into tissues, preventing establishment and replenishment of reservoirs even with ART.

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Section: Discussionsupporting

confidence: 78%

Interactions of Monocytes, HIV, and ART Identified by an Innovative scRNAseq Pipeline: Pathways to Reservoirs and HIV-Associated Comorbidities

León-Rivera

Morsey

Niu

et al. 2020

mBio

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“…No significant differences were found with regard to risk of hospitalization or death among HIV-infected patients on several ARVs (risk of hospitalization was 10.5% for TDF/FTC, 20.3% for TAF/FTC, 23.4% for ABC/3TC, and 20.0% for others) [ 95 , 96 ]. It is not easy to find the explanation for these results, but we must take into account several considerations: first, TAF is prescribed for patients who are less healthy that those prescribed with TDF; second, TDF reaches higher extracellular concentration with higher mucosal penetration; and third, possibly, it has a more potent immunomodulatory effect [ 97 , 98 ].…”

Section: Clinical Datamentioning

confidence: 99%

Tenofovir, Another Inexpensive, Well-Known and Widely Available Old Drug Repurposed for SARS-COV-2 Infection

et al. 2021

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is spreading worldwide with different clinical manifestations. Age and comorbidities may explain severity in critical cases and people living with human immunodeficiency virus (HIV) might be at particularly high risk for severe progression. Nonetheless, current data, although sometimes contradictory, do not confirm higher morbidity, risk of more severe COVID-19 or higher mortality in HIV-infected people with complete access to antiretroviral therapy (ART). A possible protective role of ART has been hypothesized to explain these observations. Anti-viral drugs used to treat HIV infection have been repurposed for COVID-19 treatment; this is also based on previous studies on severe acute respiratory syndrome virus (SARS-CoV) and Middle East respiratory syndrome virus (MERS-CoV). Among them, lopinavir/ritonavir, an inhibitor of viral protease, was extensively used early in the pandemic but it was soon abandoned due to lack of effectiveness in clinical trials. However, remdesivir, a nucleotide analog that acts as reverse-transcriptase inhibitor, which was tested early during the pandemic because of its wide range of antiviral activity against several RNA viruses and its safety profile, is currently the only antiviral medication approved for COVID-19. Tenofovir, another nucleotide analog used extensively for HIV treatment and pre-exposure prophylaxis (PrEP), has also been hypothesized as effective in COVID-19. No data on tenofovir’s efficacy in coronavirus infections other than COVID-19 are currently available, although information relating to SARS-CoV-2 infection is starting to come out. Here, we review the currently available evidence on tenofovir’s efficacy against SARS-CoV-2.

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“…Finally, tenofovir disoproxil fumarate has immunomodulatory effects [ 37,38], which could be of importance in limiting the cytokine storm during the second week of COVID-19, known as the "inflammatory" phase of the disease. For example, the administration of tenofovir disoproxil fumarate plus emtricitabine for 30 days was associated with a significant decrease of HLA-DR+ CD38+ co-expression on CD8+ T-cells, a marker of immune activation amongst 19 healthy volunteers [39]. Of note, HLA-DR+ CD38+ co-expression on CD8+ T-cells was significantly associated with COVID-19 severity in a cohort of 125 COVID-19 patients [40].…”

Section: Discussionmentioning

confidence: 99%

Effect of Tenofovir Disoproxil Fumarate and Emtricitabine on nasopharyngeal SARS-CoV-2 viral load burden amongst outpatients with COVID-19: A pilot, randomized, open-label phase 2 trial

et al. 2021

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Background Tenofovir and emtricitabine interfere with the SARS CoV-2 ribonucleic acid (RNA)-dependent RNA polymerase (RdRp). Several cohorts reported that people treated by tenofovir disoproxil fumarate and emtricitabine are less likely to develop SARS CoV-2 infection and related severe COVID-19. Methods We conducted a pilot randomized, open-label, controlled, phase 2 trial at two hospitals in France. Eligible patients were consecutive outpatients (aged ≥18 years) with RT-PCR-confirmed SARS-CoV-2 infection and an interval from symptom onset to enrolment of 7 days or less. Patients were randomly assigned in a 1:1 ratio to receive oral tenofovir disoproxil fumarate and emtricitabine (2 pills on day 1 followed by 1 pill per day on days 2–7) or the standard of care. The primary and secondary endpoints were SARS-CoV-2 viral clearance from baseline assessed by cycle threshold (Ct) RT-PCR on nasopharyngeal swab collected at day 4 and day 7, respectively. A higher Ct corresponds to a lower SARS CoV-2 viral burden. Other endpoints were the time to recovery and the number of adverse events. This trial is registered with ClinicalTrials.gov, NCT04685512. Findings From November, 20 th 2020 to March, 19 th 2021, 60 patients were enrolled and randomly assigned to a treatment group (30 to tenofovir disoproxil fumarate and emtricitabine and 30 to standard of care). The median number of days from symptom onset to inclusion was 4 days (IQR 3–5) in both groups. Amongst patients who received tenofovir disoproxil fumarate, the difference from standard of care in the increase in Ct RT-PCR from baseline was 2.3 (95% confidence interval [-0.6 to 5.2], p = 0.13) at day 4 and 2.9 (95% CI [0.1 to 5.2], p = 0.044) at day 7. At day 7, 6/30 in the tenofovir disoproxil fumarate and emtricitabine group and 3/30 in the standard of care group reported no COVID-related symptoms. Adverse events included 11 cases of gastrointestinal side effects (grade ≤ 2), three of which leaded to drug discontinuation. Three patients had COVID-19 related hospitalisation, no participant died. Interpretation In this pilot study of outpatients adult with recent non-severe COVID-19, tenofovir disoproxil fumarate plus emtricitabine appeared to accelerate the natural clearance of nasopharyngeal SARS-CoV-2 viral burden. These findings support the conduct of larger trials of tenofovir-based therapies for the prevention and early treatment of COVID-19. Funding No external funding.

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Reduced Immune Activation During Tenofovir–Emtricitabine Therapy in HIV-Negative Individuals

Cited by 20 publications

References 44 publications

Interactions of Monocytes, HIV, and ART Identified by an Innovative scRNAseq Pipeline: Pathways to Reservoirs and HIV-Associated Comorbidities

Interactions of Monocytes, HIV, and ART Identified by an Innovative scRNAseq Pipeline: Pathways to Reservoirs and HIV-Associated Comorbidities

Tenofovir, Another Inexpensive, Well-Known and Widely Available Old Drug Repurposed for SARS-COV-2 Infection

Effect of Tenofovir Disoproxil Fumarate and Emtricitabine on nasopharyngeal SARS-CoV-2 viral load burden amongst outpatients with COVID-19: A pilot, randomized, open-label phase 2 trial

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