Biology subjects

Immonen, T. T.

Publications and source records attributed to Immonen, T. T..

3 recordsLinked to original sources

bioRxiv2025

CD8α+ cells suppress SIV replication without evidence of viral immune escape during post treatment control

Post-treatment control (PTC) is a rare phenomenon in which people living with HIV (PLWH) maintain viral control following ART interruption. Characterizing virus populations present in PTCs may help elucidate mechanisms of immunologic control, but this is challenging without detectable plasma viremia. To model PTC, eight Mauritian cynomolgus macaques (MCM) were infected with barcoded SIVmac239M and began an 8-month ART regimen two weeks post-infection (wpi). Six months following ART interruption, all MCM were rechallenged with non-barcoded SIVmac239 followed by CD8[a]+ cell depletion two months later. Animals were grouped as viremic (n=5) or aviremic (n=3) based on the detection of plasma viremia between ART interruption and CD8[a]+ cell depletion; all animals became viremic post-depletion. Barcode sequencing of plasma virus revealed that lineages with high pre-ART viral loads dominated the rebounding populations post-depletion and detectable rechallenge virus in two animals post-depletion. Additional sequencing of three CD8+ T cell epitopes within plasma viruses identified point mutations only in viruses isolated from the viremic group post-depletion. A second cohort of 5 MCM who initiated ART 8 wpi was examined to identify the impact of the timing of ART initiation on viral epitope diversity and showed increased diversity prior to ART initiation and following ART interruption. These results suggest that early ART initiation is associated with reduced diversity within cytotoxic T lymphocyte (CTL) epitopes and a longer time to rebound, as well as highlight an important role of restricting the emergence of CTL immune escape variants in increasing the likelihood of PTC. ImportanceWhile rare, a subset of PLWH, termed post-treatment controllers (PTCs), can maintain viral control following ART interruption. However, little is known about whether this control reflects a complete absence of viral replication or continual, subclinical replication. Here we address a key knowledge gap regarding how viral populations change during CD8[a]+ cell-mediated PTC of SIV. We utilized our Mauritian cynomolgus macaque model of HIV infection, in combination with the barcoded SIVmac239M and deep sequencing, to characterize viral lineages and MHC-I-restricted CD8+ T cell epitopes throughout the study. Our findings demonstrate that early ART initiation limits viral diversity, that pre-ART replication predicts post-ART reactivation, and that CD8[a]+ cells can suppress viral replication without evidence of immune escape. These insights establish MCMs as a valuable model for dissecting mechanisms of durable ART-free viral control and highlight the potential of CD8-mediated immune control as a therapeutic target for HIV cure strategies.

microbiology↗

bioRxiv2025

Dissecting the steps in early Simian Immunodeficiency Virus dissemination following mucosal and intravenous infection of rhesus macaques

In cases of HIV transmission, the typical delay from exposure to detectable viremia is approximately one week. This delay from exposure to viremia suggests that during initial expansion of virus from a limited number of founder lineages, there exists a period of low infected cell population. It is during this period of low infected cell population that the virus may be more vulnerable to clearance via primed immune responses targeting infected cells (e.g., antibody-dependent cellular cytotoxicity (ADCC) or CD8+ T cell killing/suppression). Potential future prophylactic harnessing of these immune mechanisms for early virally infected cell clearance will rely on an understanding of the earliest stages of viral replication and dissemination. The factors that dictate the rate of early viral spread, termed the dissemination bottleneck could include target-cell-mediated effects, the anatomical microenvironment, or the organ of the first infected cells. In this study, we use the barcoded Simian Immunodeficiency Virus (SIV) infection model to assess the contribution of various anatomical and cellular mechanisms to the SIV dissemination bottleneck. Viral, cellular, and anatomically-mediated heterogeneity in viral replication each introduce a degree of variability into the early phases of viral spread, and when multiple founder lineages are present, this variability in early growth results in a large distribution in lineage sizes. Therefore, we use a comparison of viral lineage size variability across multiple experimental SIV infection models to examine the relative contribution to the overall dissemination bottleneck of viral-mediated stochasticity of cellular infection (e.g., integration site), infected cell phenotype (e.g., activation state), anatomical variability, and initial viral spread within the genital tract. We estimate that inherent heterogeneity in viral production by infected cells corresponds to 23 to 44% of the dissemination bottleneck, but the majority (56 to 77%) arises from anatomical heterogeneity (presumably heterogeneity in how conducive local microenvironments are to viral replication). Author SummaryA brief window exists immediately following HIV transmission where low initial levels of virus and infected cells may be susceptible to immune clearance. A better understanding of the bottlenecks encountered by the virus during this window is necessary when designing therapies to clear HIV during this early period. We used a barcoded Simian Immunodeficiency Virus (SIV) infection model to track the early dissemination of multiple viral lineages after mucosal and intravenous inoculation. We observed up to 105-fold differences in lineage size between transmitted barcodes within a single animal two weeks after infection, suggesting very different trajectories of virial growth. By comparing lineage size diversity after mucosal and intravenous transmission and in vitro replication, we determined the contribution of anatomical and cellular mechanisms to the relative growth of different clonotypes. Although we expected that the processes of local dissemination may lead to greater lineage size diversity after mucosal transmission, this was not the case, and we saw no difference compared to intravenous transmission. We found that around a quarter of the diversity in clonotype size could be attributed to early cellular infection events, with the remainder likely attributable to differences in clonotype specific establishment and dissemination in vivo.

bioinformatics↗

bioRxiv2024

Adeno-associated viral delivery of Env-specific antibodies prevents SIV rebound after discontinuing antiretroviral therapy

An alternative to lifelong antiretroviral therapy (ART) is needed to achieve durable control of HIV-1. Here we show that adeno-associated virus (AAV)-delivery of two rhesus macaque antibodies to the SIV envelope glycoprotein (Env) with potent neutralization and antibody-dependent cellular cytotoxicity can prevent viral rebound in macaques infected with barcoded SIVmac239M after discontinuing suppressive ART. Following AAV administration, sustained antibody expression with minimal anti-drug antibody responses was achieved in all but one animal. After ART withdrawal, SIV replication rebounded within two weeks in all of the control animals but remained below the threshold of detection in plasma (<15 copies/mL) for more than a year in four of the eight animals that received AAV vectors encoding Env-specific antibodies. Viral sequences from animals with delayed rebound exhibited restricted barcode diversity and antibody escape. Thus, sustained expression of antibodies with potent antiviral activity can afford durable, ART-free containment of pathogenic SIV infection.

immunology↗