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Potential for Virus Endogenization in Humans Through Testicular Germ Cell Infection: the 2 Case of HIV

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Potential for Virus Endogenization in Humans Through Testicular Germ Cell Infection: the 2 Case of HIV bioRxiv preprint doi: https://doi.org/10.1101/2020.06.04.135657; this version posted June 7, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Potential for virus endogenization in humans through testicular germ cell infection: the 2 case of HIV 3 Dominique Mahé1, Giulia Matusali1, Claire Deleage 1,2, Raquel L. L. S. Alvarenga3, Anne- 4 Pascale Satie1, Amélie Pagliuzza4 , Romain Mathieu5, Sylvain Lavoué6, Bernard Jégou1, Luiz 5 R. de França3, Nicolas Chomont4, Laurent Houzet1, Antoine D. Rolland1, Nathalie Dejucq- 6 Rainsford1 7 1 Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S1085, F- 8 35000 Rennes, France ;2 AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc. Frederick National 9 Laboratory for Cancer Research, Frederick, Maryland, USA (current affiliation) ; 3 Laboratory of Cellular 10 Biology, Department of Morphology, Federal University of Minas Gerais, Belo Horizonte, Brazil ; 4 Department 11 of Microbiology, Infectiology and Immunology, Faculty of Medecine, Université de Montréal, and Centre de 12 recherche du CHUM, Montréal, Quebec, Canada ; 5 Centre Hospitalier Universitaire de Pontchaillou, Service 13 Urologie, Rennes, France ; 6 Centre Hospitalier Universitaire de Pontchaillou, Centre de Coordination des 14 prélèvements, Rennes, France. 15 16 * Corresponding author: 17 Nathalie DEJUCQ-RAINSFORD 18 IRSET-Inserm U1085 19 9 avenue du Pr Léon Bernard 20 F-35000 Rennes, France 21 E-mail : [email protected] 22 Phone : +33 2 2323 5069 23 24 25 Short title: HIV infection of the germ line 26 Key words: virus-HIV- SIV- testis- germ line-spermatogenesis-gametes-entry- integration- 27 replication-endogenization 28 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.06.04.135657; this version posted June 7, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 29 Abstract 30 31 Viruses have colonized the germ line of our ancestors at several occasions during evolution, 32 leading to the integration in the human genome of viral sequences from over 30 retroviral 33 groups and a few non-retroviruses. Among the recently emerged viruses infecting humans, 34 several target the testis (eg HIV, Zika and Ebola viruses). Here we aimed to investigate whether 35 human testicular germ cells (TGCs) can support integration by HIV, a contemporary retrovirus 36 that started to spread in the human population during the last century. We report that albeit 37 alternative receptors enabled HIV-1 binding to TGCs, HIV virions failed to infect TGCs in 38 vitro. Nevertheless, exposure of TGCs to infected lymphocytes, naturally present in the testis 39 from HIV+ men, led to HIV-1 entry, integration and early protein expression. Similarly, cell- 40 associated infection or bypassing viral entry led to HIV-1 integration in a spermatogonial cell 41 line. Using DNAscope, HIV-1 and SIV DNA were detected within a few TGCs in the testis 42 from one infected patient, one rhesus macaque and one African Green monkey in vivo. 43 Molecular landscape analysis revealed that early TGCs were enriched in HIV early co-factors 44 up to integration and had overall low antiviral defenses when compared with testicular 45 macrophages and Sertoli cells. In conclusion, our study reveals that TGCs can support the entry 46 and integration of HIV upon cell-associated infection. This could represent a way for this 47 contemporary virus to integrate our germline and become endogenous in the future, as happened 48 during human evolution for a number of viruses. 49 50 51 52 Importance 53 Viruses have colonized the host germ line at many occasions during evolution to eventually 54 become endogenous. Here we aimed at investigating whether human testicular germ cells 55 (TGCs) can support such viral invasion by studying HIV interactions with TGCs in vitro. Our 56 results indicate that isolated primary TGCs express alternative HIV-1 receptors allowing virions 57 binding but not entry. However, HIV-1 entered and integrated in TGCs upon cell-associated 58 infection, and produced low level of viral proteins. In vivo, HIV-1 and SIV DNA was detected 59 in a few TGCs. Molecular landscape analysis showed that TGCs have overall weak antiviral 60 defenses. Altogether, our results indicate that human TGCs can support HIV-1 early replication 61 including integration, suggesting potential for endogenization in the future generations. 62 2 bioRxiv preprint doi: https://doi.org/10.1101/2020.06.04.135657; this version posted June 7, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 63 Introduction 64 Retroviruses have repeatedly infected the germline during our evolution and integrated their 65 DNA into the host genome , which has been passed on to the next generations by Mendelian 66 inheritance [1,2]. When not detrimental, the integration of viral sequences has led to their 67 fixation and endogenization in the population [3]. Thus, about 8% of the human genome is now 68 composed of endogenous retroviruses (ERVs), representing 31 distinct viral groups [2]. Such 69 integration, still ongoing in mammals [4], has driven the acquisition of new functions in the 70 host, including a protective role against exogenous infections [5,6]. Within the retrovirus 71 family, several lentiviruses have been endogenized in mammals, including SIV in pro- 72 lemurians [7–12]. A few non-retroviruses have also colonized the germline of their host but the 73 mechanisms for their integration are unclear [1]. 74 HIV-1 is an emerging zoonotic lentivirus that has infected over 70 million people since its 75 worldwide spreading in the human population from the beginning of the 1980s. Current 76 antiretroviral treatments effectively control but do not eradicate the virus, which still represents 77 a major threat for the human population, with an average of nearly 2 million new infections 78 each year. Horizontal transmission through semen plays a key role for HIV-1 dissemination, 79 and is most likely mediated by the free viral particles and infected leukocytes present in this 80 fluid [13]. We and others found that HIV/SIV strains in semen are locally produced in a subset 81 of individuals (reviewed in [13]) and arise from several organs within the male genital tract 82 [14]. Interestingly, HIV-1 can associate with spermatozoa in vitro [15] and was detected by 83 some authors in a small proportion of patients’ sperm [16–25]. Since spermatozoa have a highly 84 compact nucleus and are transcriptionally silent, this detection may suggest infection of their 85 germ cell progenitors in the testis. 86 The testis is an immune-privilege organ with restricted drugs penetration, considered to 87 constitute a tissue reservoir for HIV and other emerging viruses such as Zika and Ebola 88 [1,26,27]. HIV-1 productively infects testicular T lymphocytes and resident macrophages, 89 which are naturally localized in close proximity to the early germ cells present in the basal 90 compartment of the seminiferous epithelium and therefore outside the blood testis/Sertoli cell 91 barrier [27–31]. A couple of early studies reported HIV nucleic acids in isolated cells 92 resembling germ cells within the seminiferous tubules of deceased patients using in situ PCR, 93 a controverted technique suspected of generating false positives [30,32,33]. These findings 94 have therefore been largely dismissed [34,35]. Furthermore, the detection of viral RNA in TGCs 95 could reflect an accumulation of virions bound to the cell surface rather than a true infection. 96 Unfortunately, the scarce access to testicles of HIV-1+ men has hindered further investigations 97 on this debated issue [35]. SIV RNA and proteins were later described in TGCs from non- 98 human primates, using in situ hybridization and immunohistochemistry [36,37]. Whether 99 human TGCs are infected by HIV and to which extent remains an open question. 100 In this study, we aimed to investigate whether human TGCs support HIV entry and integration 101 as a proxy to evaluate potential for viral colonization in the next generations’ human genome. 102 We found that HIV-1 binds to primary TGCs, but that viral entry was inefficient. However, 103 virus integration and early viral protein expression were observed following cell-associated 104 infection. In vivo, testicular germ cells harboring viral DNA were detected in the testis from an 105 HIV-infected individual using next generation in situ hybridization DNAscope. SIV-infected 106 TGCs were also detected in one experimentally-infected rhesus macaque and one African Green 107 monkey, a natural host for SIV. To determine whether human TGC had evolved elevated 108 defense mechanisms to prevent vertical transmission of viral sequences to the offspring and 109 thus potential endogenization, we analyzed the molecular landscape of TGCs and compared it 110 with that of HIV-permissive and non-permissive testicular somatic cells using single-cell RNA- 3 bioRxiv preprint doi: https://doi.org/10.1101/2020.06.04.135657; this version posted June 7, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license.
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