HSV-2 Cellular Programming Enables Productive HIV Infection in Dendritic Cells.

Elisa Crisci,Rada Ellegård,Cecilia Svanberg,Pradyot Bhattacharya,Esaki M Shankar,Kristina Eriksson,Julia Hellblom,Kazuki Okuyama,Mohammad Khalid,Marie Larsson,Sofia Nyström

doi:10.3389/fimmu.2019.02889

Abstract

Genital herpes is a common sexually transmitted infection caused by herpes simplex virus type 2 (HSV-2). Genital herpes significantly enhances the acquisition and transmission of HIV-1 by creating a microenvironment that supports HIV infection in the host. Dendritic cells (DCs) represent one of the first innate cell types that encounter HIV-1 and HSV-2 in the genital mucosa. HSV-2 infection has been shown to modulate DCs, rendering them more receptive to HIV infection. Here, we investigated the potential mechanisms underlying HSV-2-mediated augmentation of HIV-1 infection. We demonstrated that the presence of HSV-2 enhanced productive HIV-1 infection of DCs and boosted inflammatory and antiviral responses. The HSV-2 augmented HIV-1 infection required intact HSV-2 DNA, but not active HSV-2 DNA replication. Furthermore, the augmented HIV infection of DCs involved the cGAS-STING pathway. Interestingly, we could not see any involvement of TLR2 or TLR3 nor suppression of infection by IFN-β production. The conditioning by HSV-2 in dual exposed DCs decreased protein expression of IFI16, cGAS, STING, and TBK1, which is associated with signaling through the STING pathway. Dual exposure to HSV-2 and HIV-1 gave decreased levels of several HIV-1 restriction factors, especially SAMHD1, TREX1, and APOBEC3G. Activation of the STING pathway in DCs by exposure to both HSV-2 and HIV-1 most likely led to the proteolytic degradation of the HIV-1 restriction factors SAMHD1, TREX1, and APOBEC3G, which should release their normal restriction of HIV infection in DCs. This released their normal restriction of HIV infection in DCs. We showed that HSV-2 reprogramming of cellular signaling pathways and protein expression levels in the DCs provided a setting where HIV-1 can establish a higher productive infection in the DCs. In conclusion, HSV-2 reprogramming opens up DCs for HIV-1 infection and creates a microenvironment favoring HIV-1 transmission.

Highlights

Human immunodeficiency virus (HIV) infection is a sexually transmitted disease that reportedly afflicts almost 37 million people globally [1]
We evaluated the role of Dendritic cells (DCs) in the enhanced infection by assessing the effects pre-exposure to herpes simplex virus type 2 (HSV-2) exerted on HIV infection of human monocyte-derived DCs, and the role of opsonization of the viruses with complement
The DCs exposed to complement opsonized HSV-2 gave a higher tyrosine kinese (TK) in both dual and single exposed DCs compared to free virus as shown previously, but there was no alteration in the HSV2 infection when measured by TK expression in the HIV/HSV

Summary

Introduction

Human immunodeficiency virus (HIV) infection is a sexually transmitted disease that reportedly afflicts almost 37 million people globally [1]. The risk of contracting HIV-1 infection during a sexual encounter is three-fold higher for individuals infected with genital herpes simplex virus type-2 (HSV-2) [2, 3], and the greatest risk is seen in individuals that have encountered HSV-2 recently [4]. Evidences point to that antiviral treatment is unable to suppress HSV2 infection completely [5,6,7]. The presence of both HIV-1 and HSV-2 creates an environment where immune cells such as dendritic cells (DCs) and Langerhans cells (LCs) can be exposed to and conditioned by either viruses or virus-derived factors. The presence of both HSV-2 and HIV-1 appears to enhance HIV DNA levels several fold in DCs [8], LCs [9], and macrophages [10]

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