Biology subjects

Matschke, L. M.

Publications and source records attributed to Matschke, L. M..

5 recordsLinked to original sources

bioRxiv2025

Modeling simian immunodeficiency virus (SIV) latency in primary rhesus macaque CD4+ T cells

Simian immunodeficiency virus (SIV)-infected rhesus macaques are valuable models for HIV cure research, offering insights into tissue reservoirs and testing reservoir-reduction strategies. Despite this utility, low frequencies of latently infected cells in vivo limit mechanistic studies of viral latency ex vivo. In vitro latency models have addressed this limitation for HIV, advancing our understanding of viral persistence. However, no comparable models exist for SIV. To address this gap, we developed an in vitro model of SIV latency in primary rhesus macaque CD4+ T cells, optimizing conditions to promote viral entry while maintaining cells in a minimally activated, non-proliferating state. After 12 days in culture, [~]1-3.3% of cells harbored SIV DNA, primarily as intact proviruses within central and transitional memory CD4+ T cell subsets. These cells remained quiescent, exhibiting minimal spontaneous viral protein production, but could be reactivated by potent T-cell stimulation and benchmark latency-reversing agents. Collectively, this model generates SIV-latently infected cells that resemble predominant cellular reservoirs in vivo--quiescent memory CD4+ T cells carrying inducible proviruses. This system provides a platform for investigating mechanisms of SIV latency, identifying shared and virus-specific features of HIV and SIV persistence, and evaluating strategies to reactivate or silence viral reservoirs. ImportanceViral latency-HIVs ability to persist in a dormant state within CD4+ T cells-remains a critical barrier to developing a cure. Rhesus macaques infected with simian immunodeficiency virus (SIV) are valuable models for studying HIV, but mechanistic studies of viral persistence are limited by the low frequency of latently infected cells in vivo. While in vitro models have advanced our understanding of HIV latency, comparable tools for studying SIV were lacking. To address this gap, we established a novel model of SIV latency using rhesus macaque CD4+ T cells, mirroring key features of natural reservoirs. This model provides a platform for studying how viral latency is established and maintained, conducting direct comparisons between HIV and SIV infections, and evaluating potential cure strategies.

immunology↗

bioRxiv2023

CD8+ cells and small viral reservoirs facilitate post-ART control of SIV in Mauritian cynomolgus macaques

Sustainable HIV remission after antiretroviral therapy (ART) withdrawal, or post-treatment control (PTC), remains a top priority for HIV treatment. We observed surprising PTC in an MHC-haplomatched cohort of MHC-M3+ SIVmac239+ Mauritian cynomolgus macaques (MCMs) initiated on ART at two weeks post-infection (wpi). For six months after ART withdrawal, we observed undetectable or transient viremia in seven of eight MCMs. In vivo depletion of CD8+ cells induced rebound in all animals, indicating the PTC was mediated, at least in part, by CD8+ cells. We found that MCMs had smaller acute viral reservoirs than a cohort of identically infected rhesus macaques, a population that rarely develops PTC. The mechanisms by which unusually small viral reservoirs and CD8+ cell-mediated virus suppression enable PTC can be investigated using this MHC-haplomatched MCM model. Further, defining the immunologic mechanisms that engender PTC in this model may identify therapeutic targets for inducing durable HIV remission in humans.

immunology↗

bioRxiv2022

Transient T cell expansion, activation, and proliferation in therapeutically vaccinated SIV+ macaques treated with N-803

Vaccine strategies aimed at eliciting HIV-specific CD8+ T cells are one major target of interest in HIV functional cure strategies. We hypothesized that CD8+ T cells elicited by therapeutic vaccination during antiretroviral therapy (ART) would be recalled and boosted by treatment with the IL-15 superagonist N-803 after ART discontinuation. We intravenously immunized four SIV+ Mauritian cynomolgus macaques (MCM) receiving ART with vesicular stomatitis virus (VSV), modified vaccinia virus Ankara strain (MVA), and recombinant adenovirus serotype 5 (rAd-5) vectors all expressing SIVmac239 Gag. Immediately after ART cessation, these animals received three doses of N-803. Four control animals received no vaccines or N-803. The vaccine regimen generated a high magnitude of Gag-specific CD8+ T cells that were proliferative and biased toward an effector memory phenotype. We then compared cells elicited by vaccination (Gag-specific) to cells elicited by SIV infection and unaffected by vaccination (Nef-specific). We found that N-803 treatment enhanced both the frequencies of bulk and proliferating antigen-specific CD8+ T cells elicited by vaccination and the antigen-specific CD8+ T cells elicited by SIV infection. In sum, we demonstrate that a therapeutic heterologous prime-boost-boost (HPBB) vaccine can elicit antigen-specific effector memory CD8+ T cells that are boosted by N-803.

immunology↗

bioRxiv2021

MHC-matched allogeneic bone marrow transplant fails to eliminate SHIV-infected cells from ART-suppressed Mauritian cynomolgus macaques

BackgroundAllogeneic hematopoietic stem cell transplants (allo-HSCTs) dramatically reduce HIV reservoirs in antiretroviral therapy (ART) suppressed individuals. However, the mechanism(s) responsible for these post-transplant viral reservoir declines are not fully understood but may include pre-transplant conditioning regimens, ART-mediated protection of donor cells, and graft-versus-host (GvH) responses. Therefore, we modeled allo-HSCT in ART-suppressed simian-human immunodeficiency virus (SHIV)-infected Mauritian cynomolgus macaques (MCMs) to illuminate factors contributing to transplant-induced viral reservoir decay. ResultsWe infected four MCMs with CCR5-tropic SHIV162P3 and started ART 6-16 weeks post-infection (p.i.) to establish robust viral reservoirs. We maintained the MCMs on continuous ART during myeloablative conditioning with total body irradiation (TBI) and while transplanting allogeneic MHC-matched /{beta} T cell-depleted bone marrow cells. Post-transplant, we prophylactically treated the MCMs with cyclophosphamide and tacrolimus to prevent GvH disease (GvHD). The transplants produced ~85% whole blood donor chimerism without causing high-grade GvHD. Consequently, three MCMs had undetectable SHIV DNA in their peripheral blood mononuclear cells post-transplant. However, SHIV-harboring cells persisted in various tissues. We detected viral DNA in lymph node biopsies and terminal analyses of tissues between 38 and 62 days post-transplant. Further, we removed ART from one MCM at 63 days post-transplant, resulting in viral rebound within seven days and viral loads nearing 1x108 SHIV RNA copies/ml of plasma after treatment interruption. ConclusionsOur results indicate that myeloablative conditioning and maintaining ART through the peri-transplant period alone are insufficient for eradicating latent viral reservoirs early after allo-HSCTs. Furthermore, our findings suggest that extended ART and GvH responses may be necessary to substantially deplete viral reservoirs after allo-HSCTs.

immunology↗

bioRxiv2020

Identification of a lymphocyte minor histocompatibility antigen in Mauritian cynomolgus macaques

Allogeneic hematopoietic stem cell transplantation can lead to dramatic reductions in human immunodeficiency virus (HIV) reservoirs. This effect is mediated in part by donor T cells that recognize lymphocyte-expressed minor histocompatibility antigens (mHAgs). The potential to mark malignant and latently infected cells for destruction makes mHAgs attractive targets for cellular immunotherapies. However, testing such HIV reservoir reduction strategies will likely require preclinical studies in nonhuman primates (NHPs). In this study, we used a combination of alloimmunization, whole exome sequencing, and bioinformatics to identify a mHAg in Mauritian cynomolgus macaques (MCMs). We mapped the minimal optimal epitope to a 10-mer peptide (SW10) in apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3C (APOBEC3) and determined the major histocompatibility complex class I restriction element as Mafa-A1*063, which is expressed in almost 90% of MCMs. APOBEC3C SW10-specific CD8+ T cells recognized immortalized B cells but not fibroblasts from a mHAg positive MCM. These results collectively provide a framework for identifying mHAgs in a nontransplant setting and suggest that APOBEC3C SW10 could be used as a lymphocyte-restricted model antigen in NHPs to test various mHAg-targeted immunotherapies. ImportanceCellular immunotherapies developed to treat blood cancers may also be effective against latent HIV. Preclinical studies of such immunotherapies are hindered by a lack of known target antigens. We used a combination of alloimmunization, basic immune assays, whole exome sequencing, and bioinformatics to identify a lymphocyte-restricted minor histocompatibility antigen in a genetically related population of nonhuman primates. This minor histocompatibility antigen provides an actionable target for piloting cellular immunotherapies designed to reduce or eliminate latent reservoirs of HIV.

immunology↗