Biology subjects

Haase, A. T.

Publications and source records attributed to Haase, A. T..

5 recordsLinked to original sources

bioRxiv2026

HIV-producing resting T cells monopolize virus production, associated PANoptosis, and persistence in lymphoid tissue

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/703840v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@167c265org.highwire.dtl.DTLVardef@10ba2beorg.highwire.dtl.DTLVardef@e97e06org.highwire.dtl.DTLVardef@150c07c_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphic:C_FLOATNO In chronic HIV infection, HIV is produced before antiretroviral therapy (ART) by resting CD4+ T cells in lymphoid tissue germinal centers. Virus production is associated with destruction of T cells, follicular dendritic cells (FDCs), and B cells required for humoral immune responses by PANoptosis (apotosis, pyroptosis and necroptosis) mediated by the PANoptosome, a cellular structure that incorporates cell contents and programmed cell death pathways in a nodal latticework that mediates cell emptying and disruption in progressive stages indicated by the numbers. During ART, persistent HIV-producing resting T cells represent an immediate source of virus for infection rebound on treatment interruption. C_FIG Activated CD4+ T cells have long been considered the principal source of HIV production before treatment and reactivated latently infected cells the source of virus rebound on treatment interruption, based largely on studies of peripheral blood T cells. Here we show before ART in the lymphoid tissue reservoir that HIV-producing resting CD4+ T cells are essentially the sole source of virus production in germinal centers. Virus is produced in infection complexes of virus bearing follicular dendritic cells (FDCs) that induce high multiplicity multi-HIV-DNA copy infections in overlying resting T cells. HIV production is associated with destruction by PANoptosis (pyroptosis, necroptosis and apoptosis) of interacting antibody-producing populations of FDCs, T cells and B cells. PANoptosis is mediated by the PANoptosome, visualized and defined here as a cellular structure incorporating cytoplasmic and nuclear contents and programmed cell death pathway components in a nodal latticework that executes cell emptying and disruption. During ART, HIV-producing resting T cells persist in lymphoid tissues when virus is undetectable in peripheral blood. These HIV-producing resting T cells that persist during ART represent an immediate source of virus to reignite infection on treatment interruption and are thus identified as an important new target for functional cure strategies.

microbiology↗

bioRxiv2026

Ongoing lymphoid HIV production drives pyroptosis and GLP-1 counter-regulation in ART-suppressed infection

Despite effective antiretroviral therapy (ART), many people with HIV (PWH) exhibit persistent immune activation (IA) and suffer metabolic comorbidities. We investigated whether residual HIV production in lymphoid tissues drives IA. Among 20 ART-suppressed PWH, HIV RNA+ cells were detected in lymph nodes and correlated directly with markers of pyroptosis, assessed via cleaved gasdermin D positivity, but not with most plasma cytokines or IA markers. Notably, glucagon-like peptide 1 (GLP-1), an enteroendocrine hormone with anti-inflammatory roles, was upregulated in the ileum of PWH and correlated directly with systemic cytokines but inversely with lymph node pyroptosis. These findings suggest that chronic occult inflammation in people with successfully suppressed HIV infection is mediated by persistent virus production in lymph nodes leading to pyroptosis, which may trigger compensatory anti-inflammatory enteroendocrine activation that may dampen pyroptosis. Targeting pyroptosis or enhancing GLP-1 signaling represent potential therapeutic strategies for modulating IA and managing metabolic comorbidities in PWH. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/698696v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@af8909org.highwire.dtl.DTLVardef@4dbc95org.highwire.dtl.DTLVardef@197ff48org.highwire.dtl.DTLVardef@1f9051a_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2022

Productive and latent HIV infections originate in resting CD4+ T cells

Productively and latently HIV-infected cells are the source of virus that respectively establishes and sustains systemic infections and the reservoir in which HIV persists and rebounds when anti-retroviral therapy (ART) is interrupted. While infected activated CD4+ T cells are thought to be the principal source of HIV production, and reversion of activated infected cells to a resting state as the major pathway to establishment of the latently infected cell reservoir, we now show that in the earliest stages of detectable HIV infection in the lymphoid tissue reservoir, infection of resting CD4+ T cells establishes the first populations of both productively and latently infected cells. We further show that the early infection of resting T cells reflects their predominance in lymphoid tissues and the expression of pTEFb in vivo in resting T cells to support their infection. The immediate establishment of productively and latently infected cell populations enable HIV to propagate and persist, and generates reservoirs from which infection can rebound despite instituting ART at the earliest stage of detectable infection.

immunology↗

bioRxiv2022

The Defenders of the Alveolus Succumb in COVID-19 Pneumonia to SARS-CoV-2, Necroptosis, Pyroptosis and Panoptosis

The alveolar type II (ATII) pneumocyte has been called the defender of the alveolus because, amongst the cells many important roles, repair of lung injury is particularly critical. We investigated the extent to which SARS-CoV-2 infection incapacitates the ATII reparative response in fatal COVID-19 pneumonia, and describe massive infection and destruction of ATI and ATII cells. We show that both type I interferon-negative infected ATII and type I-interferon-positive uninfected ATII cells succumb to TNF-induced necroptosis, BTK-induced pyroptosis and a new PANoptotic hybrid form of inflammatory cell death that combines apoptosis, necroptosis and pyroptosis in the same cell. We locate pathway components of these cell death pathways in a PANoptosomal latticework that mediates emptying and disruption of ATII cells and destruction of cells in blood vessels associated with microthrombi. Early antiviral treatment combined with inhibitors of TNF and BTK could preserve ATII cell populations to restore lung function and reduce hyperinflammation from necroptosis, pyroptosis and panoptosis. Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC="FIGDIR/small/503050v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@8bf28dorg.highwire.dtl.DTLVardef@1e1335eorg.highwire.dtl.DTLVardef@1f3a0e2org.highwire.dtl.DTLVardef@1c77c62_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIIn fatal COVID-19 pneumonia, the initial destruction of Type II alveolar cells by SARS-CoV-2 infection is amplified by infection of the large numbers of spatially contiguous Type II cells supplied by the proliferative reparative response. C_LIO_LIInterferon-negative infected cells and interferon-positive uninfected cells succumb to inflammatory forms of cell death, TNF-induced necroptosis, BTK-induced pyroptosis, and PANoptosis. C_LIO_LIAll of the cell death pathway components, including a recently identified NINJ1 component, are localized in a PANoptosome latticework that empties in distinctive patterns to generate morphologically distinguishable cell remnants. C_LIO_LIEarly combination treatment with inhibitors of SARS-CoV-2 replication, TNF and BTK could reduce the losses of Type II cells and preserve a reparative response to regenerate functional alveoli. C_LI

immunology↗

bioRxiv2022

Detecting sources of immune activation and viral rebound in HIV infection

Antiretroviral therapy (ART) generally suppresses HIV replication to undetectable levels in peripheral blood, but immune activation associated with increased morbidity and mortality is sustained during ART, and infection rebounds when treatment is interrupted. To identify drivers of immune activation and potential sources of viral rebound, we modified RNAscope in situ hybridization to visualize HIV-virus producing cells as a standard to compare the following assays of potential sources of immune activation and virus rebound following treatment interruption: 1) EDITS (envelope detection by induced transcription-based sequencing) assay; 2) HIV-Flow; and 3) Flow-FISH assays that can scan tissues and cell suspensions to detect rare cells expressing env mRNA, gag mRNA/Gag protein and p24 respectively; and 4) an ultrasensitive immunoassay that detects p24 in cell/tissue lysates at subfemtomolar levels. We show that the sensitivity of these assays is sufficient to detect a rare HIV-producing/env mRNA+/p24+ cell in a million uninfected cells. These high-throughput technologies thus provide contemporary tools to detect and characterize rare cells producing virus and viral antigens as potential sources of immune activation and viral rebound. ImportanceAnti-retroviral therapy (ART) has greatly improved the quality and length of life for people living with HIV, but immune activation does not normalize during ART, and persistent immune activation has been linked to increased morbidity and mortality. We report a comparison of assays of two potential sources of immune activation during ART: rare cells producing HIV virus or the virus major viral protein, p24, benchmarked on a cell model of active and latent infections and a method to visualize HIV-producing cells. We show that assays of HIV Envelope mRNA (EDITS assay) and gag mRNA and p24 (Flow-FISH, HIV-Flow and ultrasensitive p24 immunoassay) detect HIV-producing cells and p24 at sensitivities of one infected cell in a million uninfected cells, thus providing validated tools to explore sources of immune activation during ART in the lymphoid and other tissue reservoirs.

immunology↗