Biology subjects

Schacker, T.

Publications and source records attributed to Schacker, T..

6 recordsLinked to original sources

bioRxiv2026

HIV lymphoid tissue fibrosis occurs in the earliest stages of acute HIV infection and is associated with macrophage-derived TGF-β

HIV infection is associated with lymphatic tissue damage caused by collagen deposition in the fibroblastic reticular cell network (FRCn) of the parafollicular T cell zone (TZ), which leads to impaired antigen presentation, T cell depletion, and reduced antibody formation. In treated chronic HIV infection, damage persists despite antiretroviral therapy (ART), but it is not known if very early initiation of ART could limit damage and preserve immune function. We studied participants in the Thai RV254 acute infection cohort and found significant collagen deposition in the FRCn even in the earliest Fiebig stage 1 acute infection. The amount of TZ collagen correlates with the frequency of TGF-{beta}+ macrophages which, in turn, correlates with the frequency of HIV RNA-producing cells. We conclude that immediate initiation of ART may have limited impact in preventing or reversing collagen accumulation in LNs.

microbiology↗

bioRxiv2025

Pre-treatment Microbiome Diversity and Function is associated with Expansion of Cytotoxic and Regulatory Immune Populations after N-803 treatment in People with HIV

BackgroundN-803, an IL-15 superagonist, is currently being studied in clinical trials as a treatment to reverse HIV latency. However, its effects on the gut microbiome are not well understood. MethodsIn this longitudinal metagenomic study, we analyzed fecal microbiomes from ART-suppressed people with HIV at four different timepoints before, during, and after N-803 treatment. ResultsOverall taxonomic and functional diversity did not change significantly, yet beneficial microbial taxa and pathways were enriched after N-803. Specifically, the relative abundance of Faecalibacterium prausnitzii increased significantly after N-803, whereas histidine degradation pathways, often associated with pro-inflammatory mucosal state, decreased. A higher baseline microbial diversity correlated with stronger CD8+ and natural killer (NK) cells activation and reduced frequency of rectal HIV RNA+ cells. MaAsLin2 analyses further associated short-chain fatty acid (SCFA)-producing taxa and pathways with increased immune activation markers. ConclusionsThese results indicate that gut microbiome diversity prior to immunotherapy influences host response and suggest that microbiome-based strategies could improve efforts to cure HIV.

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↗

bioRxiv2020

Biophysical modeling of the SARS-CoV-2 viral cycle reveals ideal antiviral targets

Effective therapies for COVID-19 are urgently needed. Presently there are more than 800 COVID-19 clinical trials globally, many with drug combinations, resulting in an empirical process with an enormous number of possible combinations. To identify the most promising potential therapies, we developed a biophysical model for the SARS-CoV-2 viral cycle and performed a sensitivity analysis for individual model parameters and all possible pairwise parameter changes (162 = 256 possibilities). We found that model-predicted virion production is fairly insensitive to changes in most viral entry, assembly, and release parameters, but highly sensitive to some viral transcription and translation parameters. Furthermore, we found a cooperative benefit to pairwise targeting of transcription and translation, predicting that combined targeting of these processes will be especially effective in inhibiting viral production.Competing Interest StatementThe authors have declared no competing interest.View Full Text

systems biology↗