Biology subjects

Boritz, E.

Publications and source records attributed to Boritz, E..

5 recordsLinked to original sources

bioRxiv2026

Transmission of mutated SARS-CoV-2 variants is favored by relatively prolonged infections due to delayed immunity

SARS-CoV-2 evolution enhanced viral fitness and immune evasion, extending the COVID-19 pandemic and resulting in millions of excess deaths. Viral diversity is generated within infected individuals, yet the timing and interplay of viral and immunological forces that drive transmissible evolution are incompletely understood. We developed a multi-scale within host phylodynamic (WiPhy) model of SARS-CoV-2 infection which couples viral replication, innate and acquired immune responses, and viral mutation. We then validated the model against quantitative viral and phylodynamic metrics. Model output predicts that typical acute infections rapidly generate genetic diversity due to accumulation of minor variants which in most cases do not achieve sufficient concentrations for transmission. Delayed innate immune responses correlate with higher peak viral load and diversification, allowing higher transmission risk of the founder virus or with a novel variant that is equally or less fit. In contrast, the risk of transmitting a fitter variant is highest during the ~10% of infections in which viral loads remain sufficiently high for transmission after 10-14 days. In these cases, non-sustained innate and/or weak acquired immune responses allow sufficient time for selection of a variant with one or more fitness enhancing non-synonymous mutations. Across a simulated cohort of ~1500 individuals, 5% of transmission risk came from variants with enhanced fitness from nonsynonymous mutations, and 13% of simulated infections accounted for 90% of fitter variant transmission risk. Our results highlight how the timing and interplay of viral and immunological forces within a host create bottlenecks that severely limit between host evolution.

evolutionary biology↗

bioRxiv2024

Neutralization activity in chronic HIV infection is characterized by a distinct programming of follicular helper CD4 T cells

A subset of people living with HIV (PLWH) can produce broadly neutralizing antibodies (bNAbs) against HIV, but the lymph node (LN) dynamics that promote the generation of these antibodies are poorly understood. Here, we explored LN-associated histological, immunological, and virological mechanisms of bNAb generation in a cohort of anti-retroviral therapy (ART)-naive PLWH. We found that participants who produce bNAbs, termed neutralizers, have a superior LN-associated B cell follicle architecture compared with PLWH who do not. The latter was associated with a significantly higher in situ prevalence of Bcl-6hi follicular helper CD4 T cells (TFH), expressing a molecular program that favors their differentiation and stemness, and significantly reduced IL-10 follicular suppressor CD4 T cells. Furthermore, our data reveal possible molecular targets mediating TFH-B cell interactions in neutralizers. Together, we identify cellular and molecular mechanisms that contribute to the development of bNAbs in PLWH.

immunology↗

bioRxiv2021

Durability of immune responses to the BNT162b2 mRNA vaccine

The development of the highly efficacious mRNA vaccines in less than a year since the emergence of SARS-CoV-2 represents a landmark in vaccinology. However, reports of waning vaccine efficacy, coupled with the emergence of variants of concern that are resistant to antibody neutralization, have raised concerns about the potential lack of durability of immunity to vaccination. We recently reported findings from a comprehensive analysis of innate and adaptive immune responses in 56 healthy volunteers who received two doses of the BNT162b2 vaccination. Here, we analyzed antibody responses to the homologous Wu strain as well as several variants of concern, including the emerging Mu (B.1.621) variant, and T cell responses in a subset of these volunteers at six months (day 210 post-primary vaccination) after the second dose. Our data demonstrate a substantial waning of antibody responses and T cell immunity to SARS-CoV-2 and its variants, at 6 months following the second immunization with the BNT162b2 vaccine. Notably, a significant proportion of vaccinees have neutralizing titers below the detection limit, and suggest a 3rd booster immunization might be warranted to enhance the antibody titers and T cell responses.

immunology↗

bioRxiv2021

Evaluation of mRNA-1273 against SARS-CoV-2 B.1.351 Infection in Nonhuman Primates

BackgroundVaccine efficacy against the B.1.351 variant following mRNA-1273 vaccination in humans has not been determined. Nonhuman primates (NHP) are a useful model for demonstrating whether mRNA-1273 mediates protection against B.1.351. MethodsNonhuman primates received 30 or 100 {micro}g of mRNA-1273 as a prime-boost vaccine at 0 and 4 weeks, a single immunization of 30 {micro}g at week 0, or no vaccine. Antibody and T cell responses were assessed in blood, bronchioalveolar lavages (BAL), and nasal washes. Viral replication in BAL and nasal swabs were determined by qRT-PCR for sgRNA, and histopathology and viral antigen quantification were performed on lung tissue post-challenge. ResultsEight weeks post-boost, 100 {micro}g x2 of mRNA-1273 induced reciprocal ID50 neutralizing geometric mean titers against live SARS-CoV-2 D614G and B.1.351 of 3300 and 240, respectively, and 430 and 84 for the 30 {micro}g x2 group. There were no detectable neutralizing antibodies against B.1351 after the single immunization of 30 {micro}g. On day 2 following B.1.351 challenge, sgRNA in BAL was undetectable in 6 of 8 NHP that received 100 {micro}g x2 of mRNA-1273, and there was a [~]2-log reduction in sgRNA in NHP that received two doses of 30 {micro}g compared to controls. In nasal swabs, there was a 1-log10 reduction observed in the 100 {micro}g x2 group. There was limited inflammation or viral antigen in lungs of vaccinated NHP post-challenge. ConclusionsImmunization with two doses of mRNA-1273 achieves effective immunity that rapidly controls lower and upper airway viral replication against the B.1.351 variant in NHP.

immunology↗

bioRxiv2021

Analysis of HIV Reservoirs in Cellular Conjugates from Peripheral Blood

Defining distinctive attributes of HIV-infected cells will inform development of HIV cure-directed therapies. Prior ex vivo studies of blood and tissue have suggested that some HIV-infected CD4 T cells are found in conjugates with other cell types. Here, we analyzed levels and sequences of HIV nucleic acids in sorted cellular conjugates from PBMC. Compared to single CD4 T cells, conjugates containing CD4 T cells showed no enrichment for HIV DNA or RNA. However, in several HIV controllers, HIV DNA sequences from sorted conjugates were enriched for sequences closely related to plasma viruses. In ART-treated people, although subgenomic HIV DNA sequences in sorted conjugates and single cells were genetically intermingled, intact proviruses were more frequent in whole blood cells than in magnetically-purified CD4 T cells. We conclude that some HIV-infected cells have attributes that predict preferential loss during sample processing, and that may also reflect vulnerability to therapeutic targeting in vivo.

immunology↗