Dynamics of HIV-Containing Compartments in Macrophages Reveal Sequestration of Virions and Transient Surface Connections

101

113

Section: Discussionmentioning

confidence: 80%

High-Multiplicity HIV-1 Infection and Neutralizing Antibody Evasion Mediated by the Macrophage-T Cell Virological Synapse

Duncan

Williams

Schiffner

et al. 2014

101

113

“…Infected macrophages are considered to play an important role from the onset of infection to the development of the pathogenesis (3). The HIV-1 cycle in macrophages possesses specific features compared to T cells: macrophages are resistant to HIV-1 cytopathic effects (4), and virus assembly and budding take place in an apparently intracellular compartment in which HIV-1 accumulates and remains infectious (5,6). Moreover, in patients exposed to antiretroviral therapies, HIV-1-infected macrophages may maintain a constant viral production due in part to the low doses of antiviral drugs that reach the tissues (7).…”

mentioning

confidence: 99%

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

Decalf

Desdouits

Rodrigues

et al. 2017

Self Cite

Along with CD4 ϩ 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. KEYWORDS human immunodeficiency virus, innate immunity, interferons, macrophages, virus entry M acrophages are present in most tissues and endowed with many functions, including sensing and clearing of pathogens. However, pathogens frequently exploit macrophages as a privileged niche for their replication (1). This is the case for HIV-1, which mainly targets two cell types for replication: macrophages and CD4 ϩ T cells (2). Infected macrophages are considered to play an important role from the onset of infection to the development of the pathogenesis (3). The HIV-1 cycle in macrophages possesses specific features compared to T cells: macrophages are resistant to

“…Electron microscopy and tomography revealed that HIV-1 buds at the limiting membrane of the VCCs (87,88,106). VCCs are distinct from endosomes since they lack classical markers such as EE1A and are inaccessible to bovine serum albumin (BSA)-gold beads (103) and show unique vesicular structures (104)(105)(106). VCCs also contain tetraspanin proteins such as CD81, CD82, CD63, and CD36 (110,111), a hallmark of the MVB, that were also shown to be critical for viral release in T cells.…”

Section: Viral Transfer To T Cells After DC Cis-infectionmentioning

confidence: 99%

“…Whether transfer occurs via formation of a VS, involving MTOC relocalization in infected DCs and polarized budding, or via an infectious synapse, i.e., independently of Env protein recognition, is unclear (102) (Fig. 3).In infected macrophages, HIV-1 is found in large intracytoplasmic vacuoles that are often referred to as virus-containing compartments (VCCs) (87,88,(103)(104)(105)(106)(107)(108)(109). Interestingly, these membrane structures also exist in DCs (106).…”

mentioning

confidence: 99%

Cell-Free versus Cell-to-Cell Infection by Human Immunodeficiency Virus Type 1 and Human T-Lymphotropic Virus Type 1: Exploring the Link among Viral Source, Viral Trafficking, and Viral Replication

Dutartre

Claviere

Journo

et al. 2016

Human immunodeficiency virus type 1 (HIV-1) and human T-lymphotropic virus type 1 (HTLV-1) are complex retroviruses mainly infecting CD4؉ T lymphocytes. In addition, antigen-presenting cells such as dendritic cells (DCs) are targeted in vivo by both viruses, although to a lesser extent. Interaction of HIV-1 with DCs plays a key role in viral dissemination from the mucosa to CD4؉ T lymphocytes present in lymphoid organs. While similar mechanisms may occur for HTLV-1 as well, most HTLV-1 data were obtained from T-cell studies, and little is known regarding the trafficking of this virus in DCs. We first compared the efficiency of cell-free versus cell-associated viral sources of both retroviruses at infecting DCs. We showed that both HIV-1 and HTLV-1 cell-free particles are poorly efficient at productively infecting DCs, except when DC-SIGN has been engaged. Furthermore, while SAMHD-1 accounts for restriction of cell-free HIV-1 infection, it is not involved in HTLV-1 restriction. In addition, cell-free viruses lead mainly to a nonproductive DC infection, leading to trans-infection of T-cells, a process important for HIV-1 spread but not for that of HTLV-1. Finally, we show that T-DC cell-to-cell transfer implies viral trafficking in vesicles that may both increase productive infection of DCs ("cis-infection") and allow viral escape from immune surveillance. Altogether, these observations allowed us to draw a model of HTLV-1 and HIV-1 trafficking in DCs. Human T-lymphotropic virus type 1 (HTLV-1) and human immunodeficiency virus type 1 (HIV-1) infect 5 to 10 million (1) and 30 million (2) individuals worldwide, respectively. HTLV-1 is present in clusters of high endemicity such as in Japan, intertropical Africa, the Caribbean, and South America (3), whereas HIV-1 is pandemic. Interestingly, while both viruses infect CD4 ϩ T cells in vivo, the consequences of infection are opposite. After a long period of clinical latency, HTLV-1 infection leads either to adult T-cell leukemia (ATL) (4), an uncontrolled CD4 ϩ T lymphocyte proliferation with a very poor prognosis, or to an inflammatory disorder named HTLV-1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP) in a fraction of infected individuals (5). On the other hand, HIV-1 is associated with CD4 ϩ T-lymphocyte death and causes AIDS (for a review, see reference 6).Interestingly, both viruses also infect antigen-presenting cells (APCs) to a lesser extent, among which are different subtypes of dendritic cells (DCs), such as myeloid DCs, monocyte-derived DCs (MDDCs), and plasmacytoid DCs (pDCs) (7-10). After viral entry in mucosal tissues during sexual intercourse or breastfeeding (11,12), DCs can be used as viral carriers, thus allowing the virus to reach lymphoid organs, where it infects CD4 ϩ T lymphocytes (13). Thus, both retroviruses may hijack (i) the ability of DCs to capture pathogens and (ii) their vesicular traffic pathways in order to be transmitted to target cells without requiring a productive viral cycle (i.e., by trans-infection of T cells). tra...