Virus-stimulated Dendritic Cells Elicit a T Antiviral Transcriptional Signature in Human CD4+ Lymphocytes.

Dendritic cells (DCs) play a pivotal role in the functional differentiation of CD4+ T cells in response to pathogens. In CD4+ T cells, HIV-1 replicates efficiently, while HIV-2, a related virus of reduced pathogenicity, is better controlled. How the DC response to HIV-1 vs HIV-2 contributes to programming an antiviral state in CD4+ T cells is not known. Here, we identify a transcriptional signature associated with progressive resistance to HIV infection in CD4+ T cells. We developed a model of naïve CD4+ T cell priming by DCs stimulated with a panel of seven viruses or synthetic ligands for the viral nucleic acid sensors cGAS and TLRs. DCs produced a cytokine response to HIV-2 infection more similar to the response to cGAS ligands than TLR ligands. In response to these signals, naive CD4+ T cells acquired a gradual antiviral resistance to subsequent HIV infection. The antiviral state was concomitant with the induction of the TH1 cytokine IFNγ and the type I interferon-stimulated gene (ISG) MX1, while the TFH cytokine IL-21 was not increased. By performing a transcriptional network analysis in T cells, we identified five distinct gene modules with characteristic ISG, TH1, TFH, IFN-I and proliferative signatures. Finally, we leverage this module to assemble a T antiviral signature of 404 genes that correlate with the antiviral state in T cells. Altogether, the study illuminates the programming of the antiviral state in T cells. The T antiviral gene signature in human CD4+ lymphocytes constitutes a resource for genetic screens and genomics analysis.

Constitutive resistance to viral infection in human CD141+ dendritic cells.

Dendritic cells (DCs) are critical for the launching of protective T cell immunity in response to viral infection. Viruses can directly infect DCs, thereby compromising their viability and suppressing their ability to activate immune responses. How DC function is maintained in light of this paradox is not understood. By analyzing the susceptibility of primary human DC subsets to viral infections, we report that CD141+ DCs have an innate resistance to infection by a broad range of enveloped viruses, including HIV and influenza virus. In contrast, CD1c+ DCs are susceptible to infection, which enables viral antigen production but impairs their immune functions and survival. The ability of CD141+ DCs to resist infection is conferred by RAB15, a vesicle-trafficking protein constitutively expressed in this DC subset. We show that CD141+ DCs rely on viral antigens produced in bystander cells to launch cross-presentation-driven T cell responses. By dissociating viral infection from antigen presentation, this mechanism protects the functional capacity of DCs to launch adaptive immunity against viral infection.

Sensing of HIV-1 Entry Triggers a Type I Interferon Response in Human Primary Macrophages.

Along with CD4+ T lymphocytes, macrophages are a major cellular source of HIV-1 replication and a potential viral reservoir. Following entry and reverse transcription in macrophages, cloaking of the viral cDNA by the HIV-1 capsid limits its cytosolic detection, enabling efficient replication. However, whether incoming HIV-1 particles are sensed by macrophages prior to reverse transcription remains unclear. Here, we show that HIV-1 triggers a broad expression of interferon (IFN)-stimulated genes (ISG) in monocyte-derived macrophages within a few hours after infection. This response does not require viral reverse transcription or the presence of HIV-1 RNA within particles, but viral fusion is essential. This response is elicited by viruses carrying different envelope proteins and thus different receptors to proceed for viral entry. Expression of ISG in response to viral entry requires TBK1 activity and type I IFNs signaling. Remarkably, the ISG response is transient but affects subsequent viral spread. Together, our results shed light on an early step of HIV-1 sensing by macrophages at the level of entry, which confers an early protection through type I IFN signaling and has potential implications in controlling the infection.IMPORTANCE HIV infection is restricted to T lymphocytes and macrophages. HIV-1-infected macrophages are found in many tissues of infected patients, even under antiretroviral therapy, and are considered a viral reservoir. How HIV-1 is detected and what type of responses are elicited upon sensing remain in great part elusive. The kinetics and localization of the production of cytokines such as interferons in response to HIV is of critical importance to understanding how the infection and the immune response are established. Our study provides evidence that macrophages can detect HIV-1 as soon as it enters the cell. Interestingly, this sensing is independent of the presence of viral nucleic acids within the particles but requires their fusion with the macrophages. This triggers a low interferon response, which activates an antiviral program protecting cells against further viral challenge and thus potentially limiting the spread of the infection.