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    • br Acknowledgments This publication was supported by

    2022-07-15


    Acknowledgments This publication was supported by NORAD (Norwegian Agency for Development Cooperation) under the NORHED-Program, agreement no. ETH-13/0024. MCM works at the MRC Integrative Epidemiology Unit which receives infrastructure funding from the UK Medical Research Council (MRC) (MC_UU_12013/5). MCM was funded by a UK MRC fellowship (MR/M009351/1). This work was also partly supported by the Research Council of Norway through the Centers of Excellence funding scheme (project number 262700).
    Introduction HIV-1 spreads by both cell-free virions and by cell-contact-dependent transmission between CD4+ T cells (Jolly et al., 2004, Sattentau, 2008). The latter form of viral transmission is several orders of magnitude more efficient than the spread of cell-free particles (Chen et al., 2007, Zhong et al., 2013b). Two important features may account for the high efficiency of cell-to-cell viral transmission. First, cell contacts promote the formation of virally induced junctions, or virological synapses, between CD4+ T cells, which concentrate large numbers of particles at the site of cell-cell contact (Johnson and Huber, 2002, Jolly et al., 2004, Phillips, 1994). This process delivers a high MOI to the target cell (Del Portillo et al., 2011, Duncan et al., 2014, Zhong et al., 2013a). Second, cell contact helps to overcome cellular and environmental barriers that normally prevent infection by cell-free HIV, such as antiviral factors, neutralizing antibodies, some anti-retroviral therapies, and poor viral fitness (Agosto et al., 2015b, Brandenberg et al., 2014, Gupta et al., 1989, Jolly et al., 2010, Mathez et al., 1993, Sigal et al., 2011, Zhong et al., 2013a). However, despite the efficiency of cell-to-cell HIV-1 transmission, it remains unclear whether this process contributes to the pathogenesis of HIV. The most significant barrier for the eradication of HIV-1 infection is the existence of a small pool of latently infected ataluren that survive despite long-term suppression of viral replication by highly active anti-retroviral therapy (HAART) (Finzi et al., 1997, Ruelas and Greene, 2013, Strain et al., 2003). Following treatment interruption, this pool of cells contributes to the re-emergence of viremia (Chun et al., 1997b, Davey et al., 1999, Wong et al., 1997). The reservoir of latently infected T cells is established within 3–10 days after exposure to virus and prior to the detection of viremia (Chun et al., 1998, Whitney et al., 2014). The vast majority of these latently infected cells are composed of resting memory CD4+ T cells that have a long half-life and are maintained by homeostatic proliferation without the induction of viral replication (Brenchley et al., 2004, Chomont et al., 2009, Chun et al., 1997a, Douek et al., 2002, Maldarelli et al., 2014, Ostrowski et al., 1999, Wagner et al., 2014). Significant progress has been made toward understanding the molecular mechanisms that regulate proviral transcription and latency in T cells. Latently infected T cells are characterized by inefficient proviral transcription due to insufficient expression and binding of cellular transcription factors to the proviral promoter, the inefficient elongation of transcription, and a closed chromatin environment (Agosto et al., 2015a, Mbonye and Karn, 2017, Ruelas and Greene, 2013). Despite the knowledge of these molecular mechanisms that regulate latent infection, it remains unclear how the pool of latently infected resting CD4+ T cells is initially generated. Early studies suggested that cell activation, as defined by cell cycle progression beyond G1b, is not only required for proviral production but also for efficient reverse transcription and proviral integration (Bukrinsky et al., 1991, Korin and Zack, 1998, Stevenson et al., 1990, Sun and Clark, 1999, Unutmaz et al., 1999, Zack et al., 1992). This led to the hypothesis that latently infected cells are generated as activated HIV-infected CD4+ T cells return to a resting state (Ruelas and Greene, 2013). An alternative mechanism for the formation of latently infected CD4+ T cells is that resting cells are directly infected. Although direct infection of resting CD4+ T cells has been estimated to be 10-fold less efficient compared to activated cells, the process can be successfully completed but with slower kinetics than in activated cells (Agosto et al., 2007, Lassen et al., 2012, Plesa et al., 2007, Swiggard et al., 2005, Vatakis et al., 2007). Resting CD4+ T cells represent a large proportion of the total population of CD4+ T cells, and because these cells are already at a cellular state that would favor latent infection, it is possible that directly infected resting cells may represent a significant proportion of the latent reservoir. Understanding the requirements for infection of these cells is therefore important for better understanding HIV-1 pathogenesis (Zack et al., 2013). Several factors could influence the susceptibility of resting CD4+ T cells to HIV-1 infection without resulting in full activation of the cell and progression through the cell cycle. These factors may include the cytokine environment in tissues and cell-cell interactions (Eckstein et al., 2001, Kinter et al., 2003, Nishimura et al., 2005, Saleh et al., 2007, Shen et al., 2013, Zhang et al., 1999). Indeed, as previously shown by Evans et al. (2013) and Kumar et al. (2015), cell-cell interactions, such as those between antigen-presenting cells and CD4+ T cells, can mediate latent infection in CD4+ T cells. Thus, it is likely that cell-to-cell transmission between CD4+ T cells may facilitate the establishment of latency by increasing the likelihood of direct infection of resting CD4+ T cells.