Deleage, C. | Search bioRxiv

bioRxiv2021

IL-10 driven memory T cell survival and Tfh differentiation promote HIV persistence

Mechanisms regulating HIV persistence are complex and not well understood. Increased IL-10 levels were positively associated with HIV reservoir in blood and lymph nodes (LN) of treated HIV aviremic individuals. In LNs, B cells, regulatory T cells, follicular T helper cells (Tfh), monocytes and macrophages contributed to the frequencies of IL10+ cells. Cells with HIV DNA in LNs were in close proximity to IL-10+ cells and/or had the active form of STAT3, the transcription downstream of IL-10. Gene signatures and proteins associated to cell survival, Co-inhibitory receptors expression, maintenance of memory T cells, immune metabolism and Tfh frequencies were all modulated by IL-10 and associated with HIV reservoir persistence. In vitro, STAT3 knockout or neutralization of IL-10, reverted all the aforementioned pathways and resulted in 10-fold decay in HIV reservoir. Collectively, these results provide strong evidence for a pivotal role of IL-10 in HIV persistence, and a potential therapeutic strategy for HIV cure.

immunology↗

bioRxiv2020

Potential for virus endogenization in humans through testicular germ cell infection: the case of HIV

Viruses have colonized the germ line of our ancestors at several occasions during evolution, leading to the integration in the human genome of viral sequences from over 30 retroviral groups and a few non-retroviruses. Among the recently emerged viruses infecting humans, several target the testis (eg HIV, Zika and Ebola viruses). Here we aimed to investigate whether human testicular germ cells (TGCs) can support integration by HIV, a contemporary retrovirus that started to spread in the human population during the last century. We report that albeit alternative receptors enabled HIV-1 binding to TGCs, HIV virions failed to infect TGCs in vitro. Nevertheless, exposure of TGCs to infected lymphocytes, naturally present in the testis from HIV+ men, led to HIV-1 entry, integration and early protein expression. Similarly, cell-associated infection or bypassing viral entry led to HIV-1 integration in a spermatogonial cell line. Using DNAscope, HIV-1 and SIV DNA were detected within a few TGCs in the testis from one infected patient, one rhesus macaque and one African Green monkey in vivo. Molecular landscape analysis revealed that early TGCs were enriched in HIV early co-factors up to integration and had overall low antiviral defenses when compared with testicular macrophages and Sertoli cells. In conclusion, our study reveals that TGCs can support the entry and integration of HIV upon cell-associated infection. This could represent a way for this contemporary virus to integrate our germline and become endogenous in the future, as happened during human evolution for a number of viruses. ImportanceViruses have colonized the host germ line at many occasions during evolution to eventually become endogenous. Here we aimed at investigating whether human testicular germ cells (TGCs) can support such viral invasion by studying HIV interactions with TGCs in vitro. Our results indicate that isolated primary TGCs express alternative HIV-1 receptors allowing virions binding but not entry. However, HIV-1 entered and integrated in TGCs upon cell-associated infection, and produced low level of viral proteins. In vivo, HIV-1 and SIV DNA was detected in a few TGCs. Molecular landscape analysis showed that TGCs have overall weak antiviral defenses. Altogether, our results indicate that human TGCs can support HIV-1 early replication including integration, suggesting potential for endogenization in the future generations.

microbiology↗