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  • Furthermore the immunoassays described in our study showed e

    2021-09-11

    Furthermore, the immunoassays described in our study showed excellent concordance of more than 93.33% with the LAg-Avidity EIA (Table 2). Using a panel of samples obtained from HIV-1 seroconverters over the course of up to 602 days post-infection, the gp41 peptide-based MP3 or MP4 assay identified seroconversion within the previous 130 and 166 days, respectively. The MDRI of our study were comparable to that of the LAg-Avidity EIA (Duong et al., 2012). These results indicated that our assays are similar to the single-well LAg-Avidity EIA, which relies on the avidity of HIV-1-specific IgG to discriminate recent and long-term HIV-1 infections (Duong et al., 2012). However, our assays use the 57-mer gp41 peptides derived from the predominant HIV-1 genotypes in China without the need to limit the concentration of coating antigens.
    Conflict of interests
    Acknowledgements
    Introduction Despite the ability of combination antiretroviral therapy (cART) to reduce plasma viremia to undetectable levels, treatment does not lead to viral eradication in HIV-infected persons, committing them to lifelong therapy. The inability to eradicate HIV is predominantly due to a reservoir of resting CD4+ T cells non-productively infected by HIV (Bukrinsky et al., 1991, Chun et al., 1997, Finzi et al., 1997, Massanella and Richman, 2016, Siliciano et al., 2003, Soriano-Sarabia et al., 2014). Resting CD4+ T cells are permissive for HIV entry (Tilton et al., 2014), but once inside, cytoplasmic host restriction factors such as SAMHD1 can impede the reverse transcription of viral RNA into cDNA (Baldauf et al., 2012, Descours et al., 2012), leading to abortive infection. The resulting cDNA fragments are sensed by interferon-γ (IFN-γ)-inducible protein (IFI-16) and induce pyroptosis, leading to the production of pro-inflammatory cytokines and subsequent CD4+ T cell depletion (Doitsh et al., 2010, Doitsh et al., 2014, Monroe et al., 2014). Although HIV infection of resting CD4+ T cells is mostly abortive (Doitsh et al., 2010, Tilton et al., 2014), reverse transcription can occasionally be completed and the viral cDNA imported into the nucleus, resulting in either pre- or post-integration latency (Chavez et al., 2015, Pan et al., 2013, Zhou et al., 2005) without an intermediate phase of productive infection (Chavez et al., 2015, Vatakis et al., 2009). Pre-integration latency occurs when viral cDNA is blocked in the nucleus of a resting cell without being able to integrate into the host chromosome (Petitjean et al., 2007, Pierson et al., 2002, Sloan and Wainberg, 2011); subsequent Risperidone can occur after cellular activation, leading to productive infection (Thierry et al., 2015). Post-integration latency is the most stable form of latency in which viral cDNA is efficiently integrated but leads to no or few viral transcripts (Dahabieh et al., 2015, Hakre et al., 2012, Stevenson, 1997). These cells contain a viral genome that can be reactivated by different factors, leading to the production of new infectious particles (Bruner et al., 2015, Chun et al., 1997, Chun et al., 1998, Davey et al., 1999, Ho et al., 2013, Laird et al., 2015, Wong et al., 1997). Both forms of latency contribute to a reservoir of resting infected cells that are presumed to be invisible to HIV-specific CD8+ T cell responses. The persistence of this HIV reservoir is a major obstacle to current cure efforts (Archin and Margolis, 2014, Katlama et al., 2013, Massanella et al., 2013, Pitman et al., 2018, Siliciano and Siliciano, 2013). Killing HIV-infected resting CD4+ T cells early after viral entry before the reverse transcription step would abrogate both abortive and latent infection and would thus help to decrease CD4+ T cell depletion and inflammation, and could affect the size of the latent viral reservoir. It has been shown that HIV Gag and Pol-specific CD8+ T cell lines recognize peptides from incoming particles after HIV entry into activated CD4+ T cells (Payne et al., 2010, Kløverpris et al., 2013), and at least one study indicates that resting cells may also be targeted (Buckheit et al., 2013), although the role of antigen processing, restricting human leukocyte antigen (HLA) alleles, and synapse formation in the observed elimination of infected cells was not evaluated. We tested the hypothesis that HIV-specific CD8+ T cells from HIV controllers, a very small proportion of the HIV-infected population who manage to spontaneously control viral replication and maintain stable CD4+ T cell counts without the need for antiretroviral therapy (Carrington and Walker, 2012, Deeks and Walker, 2007, Walker and Yu, 2013), could recognize and kill non-activated, infected CD4+ T cells due to the recognition of processed viral proteins following viral entry, without requiring productive infection. We used a combination reporter virus system that allowed us to sensitively and specifically track the kinetics of infection of resting CD4+ T cells after viral entry and before any de novo viral protein production. We show that CD8+ T cells from HIV controllers readily establish functional synapses with non-activated infected CD4+ T cells, leading to HLA class I-restricted degranulation, cytokine production, and target cell death, and does not require reverse transcription, indicating that de novo viral protein production is not needed. Moreover, we show that cell-cell transmission also sensitized cells to HIV-specific CD8+ T cell recognition, before viral reverse transcription occurs. This response is significantly more potent in HIV controllers than in progressors, suggesting a mechanism whereby the immune response may influence the size of the HIV reservoir.