Abstract
Semen is important in determining HIV-1 susceptibility but it is unclear how it affects virus transmission during sexual contact. Mucosal Langerhans cells (LCs) are the first immune cells to encounter HIV-1 during sexual contact and have a barrier function as LCs are restrictive to HIV-1. As semen from people living with HIV-1 contains complement-opsonized HIV-1, we investigated the effect of complement on HIV-1 dissemination by human LCs in vitro and ex vivo. Notably, pre-treatment of HIV-1 with semen enhanced LC infection compared to untreated HIV-1 in the ex vivo explant model. Infection of LCs and transmission to target cells by opsonized HIV-1 was efficiently inhibited by blocking complement receptors CR3 and CR4. Complement opsonization of HIV-1 enhanced uptake, fusion, and integration by LCs leading to an increased transmission of HIV-1 to target cells. However, in the absence of both CR3 and CR4, C-type lectin receptor langerin was able to restrict infection of complement-opsonized HIV-1. These data suggest that complement enhances HIV-1 infection of LCs by binding CR3 and CR4, thereby bypassing langerin and changing the restrictive nature of LCs into virus-disseminating cells. Targeting complement factors might be effective in preventing HIV-1 transmission.
Highlights
Even though the number of new HIV-1 infections globally continues to decline, with 1.7 million new infection in 20181, the pandemic is still a major health burden
Human semen enhances HIV-1 transmission by Langerhans cells ex vivo As semen has been shown to affect infection by HIV-110,12, we investigated the role of semen in HIV-1 transmission by LCs using the ex vivo tissue model
We have shown that HIV-1 subverts the complement system to infect the host and we identified complement as an important component in semen to enhance HIV-1 susceptibility
Summary
Even though the number of new HIV-1 infections globally continues to decline, with 1.7 million new infection in 20181, the pandemic is still a major health burden. Sexual transmission of HIV-1 is the most common route of infection[2,3]. HIV-1 susceptibility is affected by different host factors[4] such as the physical barrier of the mucosa[5,6], or immune activation by genital inflammation established by other sexual transmitted infections[7,8,9]. HIV-1 prevents complement dependent lysis by acquiring host cell-derived proteins during the budding process[16]. Several studies suggest that complement-opsonized HIV-1 differently interacts with immune cells, modulating immunity, and enhancing infection[10,12]. Little is known about the role of complement in semen in HIV-1 transmission across mucosal tissues.
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