Extra-cellular vesicles of the male genital tract: new actors in male fertility?

AbstractExtracellular Vesicles (EVs) are membrane-limited particles containing proteins, lipids, metabolites and nucleic acids that are secreted by healthy and cancerous cells. These vesicles are very heterogeneous in size and content and mediate a variety of biological functions. Three subtypes of EV have been described in the male genital tract: microvesicles, myelinosomes and exosomes. Each type of EVs depends on the location of secretion such as the testis, prostate or epididymis. It has been shown that EVs can fuse together and deliver information to recipient cells, for example spermatozoa in the male genital tract. Cryo-electron microscopy remains the reference technique for determining EV morphology, but quantifying the absolute concentration of these EVs in biological fluids remains a challenge from a clinical point of view. The field of bio detection has considerably increased with the introduction of nanomaterials in biosensors and will provide a better understanding of the impact of these EVs. However, functional modifications of male gametes result from interactions with the components of the intraluminal fluid all along the genital tract and depend on the secretion and absorption of proteins and lipids from the local microenvironment. We cannot therefore exclude the possibility of epigenetic modulation of the information that will be transmitted to the embryo and therefore to the next generation via EVs.

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From Ancient to Emerging Infections: The Odyssey of Viruses in the Male Genital Tract

Physiological Reviews ◽

10.1152/physrev.00021.2019 ◽

2020 ◽

Vol 100 (3) ◽

pp. 1349-1414 ◽

Cited By ~ 8

Author(s):

Anna Le Tortorec ◽

Giulia Matusali ◽

Dominique Mahé ◽

Florence Aubry ◽

Séverine Mazaud-Guittot ◽

...

Keyword(s):

Genital Tract ◽

Viral Infections ◽

Sexual Transmission ◽

Peripheral Circulation ◽

Future Research ◽

Emerging Infections ◽

Male Genital Tract ◽

Emerging Viruses ◽

The Impact ◽

Male Genital

The male genital tract (MGT) is the target of a number of viral infections that can have deleterious consequences at the individual, offspring, and population levels. These consequences include infertility, cancers of male organs, transmission to the embryo/fetal development abnormalities, and sexual dissemination of major viral pathogens such as human immunodeficiency virus (HIV) and hepatitis B virus. Lately, two emerging viruses, Zika and Ebola, have additionally revealed that the human MGT can constitute a reservoir for viruses cleared from peripheral circulation by the immune system, leading to their sexual transmission by cured men. This represents a concern for future epidemics and further underlines the need for a better understanding of the interplay between viruses and the MGT. We review here how viruses, from ancient viruses that integrated the germline during evolution through old viruses (e.g., papillomaviruses originating from Neanderthals) and more modern sexually transmitted infections (e.g., simian zoonotic HIV) to emerging viruses (e.g., Ebola and Zika) take advantage of genital tract colonization for horizontal dissemination, viral persistence, vertical transmission, and endogenization. The MGT immune responses to viruses and the impact of these infections are discussed. We summarize the latest data regarding the sources of viruses in semen and the complex role of this body fluid in sexual transmission. Finally, we introduce key animal findings that are relevant for our understanding of viral infection and persistence in the human MGT and suggest future research directions.

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Emtricitabine Seminal Plasma and Blood Plasma Population Pharmacokinetics in HIV-Infected Men in the EVARIST ANRS-EP 49 Study

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01517-15 ◽

2015 ◽

Vol 59 (11) ◽

pp. 6800-6806 ◽

Cited By ~ 7

Author(s):

Elodie Valade ◽

Jean-Marc Tréluyer ◽

Silvia M. Illamola ◽

Naïm Bouazza ◽

Frantz Foissac ◽

...

Keyword(s):

Blood Plasma ◽

Seminal Plasma ◽

Genital Tract ◽

Compartment Model ◽

Effect Compartment ◽

Population Pharmacokinetic ◽

Male Genital Tract ◽

Time Curve ◽

The Impact ◽

Male Genital

ABSTRACTWe aimed to describe blood plasma (BP) and seminal plasma (SP) pharmacokinetics of emtricitabine (FTC) in HIV-1-infected men, assess its penetration in the male genital tract, and evaluate its impact on seminal plasma HIV load (spVL) detection. Men from the EVARIST ANRS EP49 study receiving combined antiretroviral therapy with FTC and with suppressed BP viral load were included in the study. A total of 236 and 209 FTC BP and SP concentrations, respectively, were available. A population pharmacokinetic model was developed with Monolix 4.1.4. The impact of FTC seminal exposure on spVL detection was explored by receiver operating characteristic (ROC) curves and mixed-effects logistic regressions. FTC BP pharmacokinetics was described by a two-compartment model. The addition of an effect compartment with different input and output constants best described FTC SP pharmacokinetics. No covariates were found to explain the variability in SP. FTC exposures (area under the concentration-time curve from 0 to 24 h [AUC0–24]) were higher in SP than in BP (median AUC0–24, 38.04 and 12.95 mg · liter−1· h, respectively). The median (range) SP-to-BP AUC0–24ratio was 2.91 (0.84 to 10.08). Less than 1% of FTC AUC0–24ratios were lower than 1. The impact of FTC SP AUC0–24or FTC SP-to-BP AUC0–24ratio on spVL detection was not significant (P= 0.943 or 0.893, respectively). This is the first population model describing FTC pharmacokinetics simultaneously in both BP and SP. FTC distributes well in the male genital tract with higher FTC concentrations in SP than in BP. FTC seminal plasma exposures were considered efficient in the majority of men.

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Deep Sequencing Reveals Compartmentalized HIV-1 in the Semen of Men with and without Sexually Transmitted Infection-Associated Urethritis

Journal of Virology ◽

10.1128/jvi.00151-20 ◽

2020 ◽

Vol 94 (12) ◽

Author(s):

Olivia D. Council ◽

Shuntai Zhou ◽

Chase D. McCann ◽

Irving Hoffman ◽

Gerald Tegha ◽

...

Keyword(s):

Viral Replication ◽

Deep Sequencing ◽

Sexually Transmitted Infection ◽

Genital Tract ◽

Male Genital Tract ◽

Transmitted Infection ◽

Sexually Transmitted ◽

The Impact ◽

Hiv 1 ◽

Male Genital

ABSTRACT Concurrent sexually transmitted infections (STI) can increase the probability of HIV-1 transmission primarily by increasing the viral load present in semen. In this study, we explored the relationship of HIV-1 in blood and seminal plasma in the presence and absence of urethritis and after treatment of the concurrent STI. Primer ID deep sequencing of the V1/V3 region of the HIV-1 env gene was done for paired blood and semen samples from antiretroviral therapy (ART)-naive men living in Malawi with (n = 19) and without (n = 5) STI-associated urethritis; for a subset of samples, full-length env genes were generated for sequence analysis and to test entry phenotype. Cytokine concentrations in the blood and semen were also measured, and a reduction in the levels of proinflammatory cytokines was observed following STI treatment. We observed no difference in the prevalence of diverse compartmentalized semen-derived lineages in men with or without STI-associated urethritis, and these viral populations were largely stable during STI treatment. Clonal amplification of one or a few viral sequences accounted for nearly 50% of the viral population, indicating a recent bottleneck followed by limited viral replication. We conclude that the male genital tract is a site where virus can be brought in from the blood, where localized sustained replication can occur, and where specific genotypes can be amplified, perhaps initially by cellular proliferation but further by limited viral replication. IMPORTANCE HIV-1 infection is a sexually transmitted infection that coexists with other STI. Here, we examined the impact of a concurrent STI resulting in urethritis on the HIV-1 population within the male genital tract. We found that viral populations remain largely stable even with treatment of the STI. These results show that viral populations within the male genital tract are defined by factors beyond transient inflammation associated with a concurrent STI.

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Population Pharmacokinetic Modeling of Tenofovir in the Genital Tract of Male HIV-Infected Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02062-16 ◽

2016 ◽

Vol 61 (3) ◽

Cited By ~ 2

Author(s):

Elodie Valade ◽

Naïm Bouazza ◽

Gabrielle Lui ◽

Silvia M. Illamola ◽

Sihem Benaboud ◽

...

Keyword(s):

Seminal Plasma ◽

Genital Tract ◽

Effect Compartment ◽

Population Pharmacokinetic ◽

Nucleotide Polymorphisms ◽

Male Genital Tract ◽

Time Curve ◽

Population Pharmacokinetic Modeling ◽

The Impact ◽

Male Genital

ABSTRACT The aims of this study were to describe the blood plasma (BP) and seminal plasma (SP) pharmacokinetics of tenofovir (TFV) in HIV-1-infected men, to assess the role of genetic polymorphism in the variability of TFV transfer into the male genital tract, and to evaluate the impact of TFV SP exposure on seminal plasma HIV load (spVL). Men from the Evarist-ANRS EP 49 study treated with TFV as part of their antiretroviral therapy were included in the study. A total of 248 and 217 TFV BP and SP concentrations from 129 men were available for the analysis. For pharmacogenetic assessment, a total of 121 single nucleotide polymorphisms (SNP) were genotyped. Data were analyzed using a nonlinear mixed-effects modeling approach. TFV pharmacokinetics were best described by a two-compartment model for BP and by an effect compartment with different input and output constants for SP. TFV exposures (area under the concentration-time curve from 0 to 24 h [AUC0–24]) were higher in SP than in BP (median AUC0–24, 7.01 versus 2.97 mg · liter−1 · h, respectively). The median (range) SP-to-BP AUC0–24 ratio was 2.24 (0.53 to 34.13). After correction for multiple testing, none of the SNPs were significantly associated with the TFV transfer rate constant. The impact of the TFV SP AUC0–24 or TFV SP-to-BP AUC0–24 ratio on spVL was not significant (P = 0.808 and 0.768, respectively). This is the first population model describing TFV pharmacokinetics in the male genital tract. TFV SP concentrations were higher than BP concentrations. Despite TFV SP exposures being higher than BP exposures, an spVL was detectable for 12.2% of the men.

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Deep Sequencing Reveals Compartmentalized HIV-1 in the Semen of Men with and without STI-associated Urethritis

10.1101/2020.01.28.924225 ◽

2020 ◽

Author(s):

Olivia D. Council ◽

Shuntai Zhou ◽

Chase D. McCann ◽

Irving Hoffman ◽

Gerald Tegha ◽

...

Keyword(s):

Viral Replication ◽

Deep Sequencing ◽

Genital Tract ◽

Cellular Proliferation ◽

Viral Population ◽

Male Genital Tract ◽

Sexually Transmitted ◽

The Impact ◽

Hiv 1 ◽

Male Genital

AbstractConcurrent sexually transmitted infections (STI) can increase the probability of HIV-1 transmission primarily by increasing the viral load present in semen. In this study, we explored the relationship of HIV-1 in blood and seminal plasma in the presence and absence of urethritis and after treatment of the concurrent STI. Primer ID deep sequencing of the V1/V3 region of the HIV-1 env gene was done for paired blood and semen samples from ART-naïve men living in Malawi with (n = 19) and without (n = 5) STI-associated urethritis; for a subset of samples full length env genes were generated for sequence analysis and to test entry phenotype. Cytokine concentrations in the blood and semen were also measured, and a reduction in the levels of pro-inflammatory cytokines was observed following STI treatment. We observed no difference in the prevalence of diverse compartmentalized semen-derived lineages in men with or without STI-associated urethritis, and these viral populations were largely stable during STI treatment. Clonal amplification of one or a few viral sequences accounted for nearly 50% of the viral population indicating a recent bottleneck followed by limited viral replication. We documented a case of superinfection where the new strain was restricted to the genital tract. We conclude that the male genital tract is a site where virus can be brought in from the blood, where localized sustained replication can occur, where a superinfecting strain can persist, and where specific genotypes can be amplified perhaps initially by cellular proliferation but further by limited viral replication.ImportanceHIV-1 is a sexually transmitted infection that co-exists with other STIs. Here we examine the impact of a concurrent STI resulting in urethritis on the HIV-1 population within the male genital tract. We found that viral populations remain largely stable even with treatment of the STI. These results show that viral populations within the male genital tract are defined by factors beyond transient inflammation associated with a concurrent STI.

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