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Biomedical subjects

Jonathan Z Li

Publications and source records attributed to Jonathan Z Li.

4 recordsLinked to original sources
PubMed2026

Effect of inhaled interferon-β1a on SARS-CoV-2 diversity and evolution.

Interferon resistance has been implicated in SARS-CoV-2 escape from innate immunity, but exogenous interferon's impact on viral evolution and diversity is unknown. SNG001, an inhaled interferon-β1a treatment, was evaluated in the ACTIV-2/A5401 randomized controlled trial of therapeutics for COVID-19. We measured viral kinetics and performed whole-genome sequencing on longitudinal nasal swabs collected from ACTIV-2 participants who received either SNG001 or placebo to assess viral sequence diversity. No difference in nasal viral load decay was detected between study arms when stratifying by SARS-CoV-2 variant or by viral culture conversion. Compared to placebo participants, the SNG001-treated participants displayed significantly lower nonsynonymous amino acid average pairwise distance, indicating lower sequence diversity. Similarly, SNG001-treated individuals also developed numerically fewer nonsynonymous mutations during their infection in ORF1a, ORF1b, Spike, and Nucleocapsid. No specific emerging SARS-CoV-2 nonsynonymous amino acid changes indicating signatures of viral escape were enriched in those receiving SNG001. These in vivo data provide an intriguing signal that exogenous interferon-β1a may restrict SARS-CoV-2 viral diversity and add to growing evidence that interferon levels play a critical role in antiviral responses during COVID-19.IMPORTANCESARS-CoV-2 encodes several genes which can antagonize the interferon signaling cascade, preventing it from activating antiviral responses and thereby facilitating viral establishment and dissemination. It is unknown how the administration of exogenous interferon might affect viral evolution and immune escape. ACTIV-2/A5401 represents a unique opportunity to study the virologic effects of interferon treatment in a rigorous randomized, placebo-controlled clinical trial setting. Our characterization of longitudinal nasal samples shows that interferon-treated individuals had lower viral diversity and no evidence of viral escape mutations.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04518410.

Humans↗
PubMed2025

A New Type of Nonsuppressible Viremia Produced by HIV-Infected Macrophage.

BACKGROUND: HIV-1 RNA typically declines rapidly after initiation of antiretroviral therapy (ART); often reaching undetectable levels within a few weeks and remaining undetectable by standard assays. However, some patients on ART have persistent nonsuppressible viremia (NSV) that does not respond to treatment optimization or intensification. NSV can emerge at the time of ART initiation (primary NSV) or after being ART-suppressed (secondary NSV). Here, we examine mechanisms producing primary NSV in four people on ART. METHODS: Blood samples were collected from four participants who, despite being adherent to ART, required approximately a year or more to become virologically suppressed. Viral RNA and proviral DNA genomes were sequenced to examine HIV-1 drug resistance, genome intactness and genetic diversity. The ability of HIV-1 Envs to facilitate efficient entry into cells expressing low levels of CD4 (a proxy for macrophage tropism) was assessed. RESULTS: Before ART, the blood contained HIV-1 RNA genomes that were adapted to replication in CD4+ T cells and rapidly decayed after ART initiation. During ART, the blood contained HIV-1 genomes that were drug sensitive, genetically diverse, macrophage-tropic, not evolving and often had defects in vpr. CONCLUSIONS: Our results suggest that in individuals with primary NSV, ART stopped virus replication, but large pools of long-lived, HIV-infected macrophage continued to produce virus. This is mechanistically distinct from secondary NSV produced by CD4+ T cell clones. In addition, defects in vpr independently accumulation in macrophage-tropic lineages found in three participants, suggesting that vpr may impact survival of, or virus production from, HIV-infected macrophage.

Journal Article↗
PubMed2023

Autologous neutralizing antibodies increase with early antiretroviral therapy and shape HIV rebound after treatment interruption.

Early initiation of antiretroviral therapy (ART) alters viral rebound kinetics after analytic treatment interruption (ATI) and may play a role in promoting HIV-1 remission. Autologous neutralizing antibodies (aNAbs) represent a key adaptive immune response in people living with HIV-1. We aimed to investigate the role of aNAbs in shaping post-ATI HIV-1 rebound variants. We performed single-genome amplification of HIV-1 env from pre-ART and post-ATI plasma samples of 12 individuals who initiated ART early after infection. aNAb activity was quantified using pseudoviruses derived from the most common plasma variant, and the serum dilution that inhibited 50% of viral infections was determined. aNAb responses matured while participants were on suppressive ART, because on-ART plasma and purified immunoglobulin G (IgG) demonstrated improved neutralizing activity against pre-ART HIV-1 strains when compared with pre-ART plasma or purified IgG. Post-ATI aNAb responses exerted selective pressure on the rebounding viruses, because the post-ATI HIV-1 strains were more resistant to post-ATI plasma neutralization compared with the pre-ART virus. Several pre-ATI features distinguished post-treatment controllers from noncontrollers, including an infecting HIV-1 sequence that was more similar to consensus HIV-1 subtype B, more restricted proviral diversity, and a stronger aNAb response. Post-treatment control was also associated with the evolution of distinct N-glycosylation profiles in the HIV-1 envelope. In summary, aNAb responses appeared to mature after early initiation of ART and applied selective pressure on rebounding viruses. The combination of aNAb activity with select HIV-1 sequence and reservoir features identified individuals with a greater chance of post-treatment control.

Humans↗
PubMed2021

Drug resistance mutations in HIV provirus are associated with defective proviral genomes with hypermutation.

BACKGROUND: HIV proviral sequencing overcomes the limit of plasma viral load requirement by detecting all the 'archived mutations', but the clinical relevance remains to be evaluated. METHODS: We included 25 participants with available proviral sequences (both intact and defective sequences available) and utilized the genotypic sensitivity score (GSS) to evaluate the level of resistance in their provirus and plasma virus. Defective sequences were further categorized as sequences with and without hypermutations. Personalized GSS score and total GSS score were calculated to evaluate the level of resistance to a whole panel of antiretroviral therapies and to certain antiretroviral therapy that a participant was using. The rate of sequences with drug resistance mutations (DRMs) within each sequence compartment (intact, defective and plasma viral sequences) was calculated for each participant. RESULTS: Defective proviral sequences harbored more DRMs than other sequence compartments, with a median DRM rate of 0.25 compared with intact sequences (0.0, P&#x200a;=&#x200a;0.014) and plasma sequences (0.095, P&#x200a;=&#x200a;0.30). Defective sequences with hypermutations were the major source of DRMs, with a median DRM rate of 1.0 compared with defective sequences without hypermutations (0.042, P&#x200a;<&#x200a;0.001). Certain Apolipoprotein B Editing Complex 3-related DRMs including reverse transcriptase gene mutations M184I, E138K, M230I, G190E and protease gene mutations M46I, D30N were enriched in hypermutated sequences but not in intact sequences or plasma sequences. All the hypermutated sequences had premature stop codons due to Apolipoprotein B Editing Complex 3. CONCLUSION: Proviral sequencing may overestimate DRMs as a result of hypermutations. Removing hypermutated sequences is essential in the interpretation of proviral drug resistance testing.

Anti-HIV Agents↗