Abstract
BackgroundSexual transmission is the main route of HIV-1 infection and the CCR5-using (R5) HIV-1 is predominantly transmitted, even though CXCR4-using (X4) HIV-1 is often abundant in chronic HIV-1 patients. The mechanisms underlying this tropism selection are unclear. Mucosal Langerhans cells (LCs) are the first immune cells to encounter HIV-1 and here we investigated the role of LCs in selection of R5 HIV-1 using an ex vivo epidermal and vaginal transmission models.ResultsImmature LCs were productively infected by X4 as well as R5 HIV-1. However, only R5 but not X4 viruses were selectively transmitted by immature LCs to T cells. Transmission of HIV-1 was depended on de novo production of HIV-1 in LCs, since it could be inhibited by CCR5 fusion inhibitors as well as reverse transcription inhibitors. Notably, the activation state of LCs affected the restriction in X4 HIV-1 transmission; immune activation by TNF facilitated transmission of X4 as well as R5 HIV-1.ConclusionsThese data suggest that LCs play a crucial role in R5 selection and that immature LCs effectively restrict X4 at the level of transmission.
Highlights
Sexual transmission is the main route of Human immunodeficiency virus-1 (HIV-1) infection and the Chemokine receptor type 5 (CCR5)-using (R5) HIV-1 is predominantly transmitted, even though CXCR4-using (X4) HIV-1 is often abundant in chronic HIV-1 patients
These data suggest that Langerhans cells (LCs) play a crucial role in CCR5-using HIV-1 (R5) selection and that immature LCs effectively restrict CXCR4using HIV-1 (X4) at the level of transmission
Migrated LCs were harvested and cocultured with CCR5 vector-transduced Jurkat T cells (CCR5 Jurkat T cells) that are permissive for both R5 and X4 HIV-1
Summary
Sexual transmission is the main route of HIV-1 infection and the CCR5-using (R5) HIV-1 is predominantly transmitted, even though CXCR4-using (X4) HIV-1 is often abundant in chronic HIV-1 patients. The mechanisms underlying this tropism selection are unclear. With an estimated 34 million people infected worldwide, HIV-1 is a major health burden [1]. HIV-1 is a lentivirus that infects a variety of immune cells such as CD4+ T cells, macrophages and dendritic cells (DCs). Chemokine receptor type 5 (CCR5) and C-X-C chemokine receptor type 4 (CXCR4) are the most important co-receptors for the two main HIV-1 variants, R5 and X4 viruses, respectively. HIV-1 infection predominantly occurs with the R5 HIV-1 strains.
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