Biology subjects

Fuller, J. T.

Publications and source records attributed to Fuller, J. T..

3 recordsLinked to original sources

bioRxiv2021

Rapid progression is associated with lymphoid follicle dysfunction in SIV-infected infant rhesus macaques

HIV-infected infants are at an increased risk of progressing rapidly to AIDS in the first weeks of life. Here, we evaluated immunological and virological parameters in 25 SIV-infected infant rhesus macaques to understand the factors influencing a rapid disease outcome. Infant macaques were infected with SIVmac251 and monitored for 10 to 17 weeks post-infection. SIV-infected infants were divided into either typical (TypP) or rapid (RP) progressor groups based on levels of plasma anti-SIV antibody levels and SIV plasma viral load (with RP infants having low SIV-specific antibodies and high viral loads). Following SIV infection, 11 out of 25 infant macaques exhibited an RP phenotype, with 5 of these succumbing to AIDS-related infections. Interestingly, the TypP and RP infants were similar in their CD4 depletion and activation of CD8 T cells as measured by the levels of HLA-DR on the cell surface. However, differences between the two groups were identified in other immune cell populations, including a failure to expand activated memory (CD21-CD27+) B cells in peripheral blood in RP infant macaques, as well as reduced levels of germinal center (GC) B cells and T follicular helper (Tfh) cells in spleens (4- and 10-weeks post-SIV). Reduced B cell proliferation in splenic germinal GCs was associated with increased SIV+ cell density and follicular type 1 interferon (IFN)-induced immune activation. Further analyses determined that at 2-weeks post SIV infection TypP infants exhibited elevated levels of the GC-inducing chemokine CXCL13 in plasma, as well as significantly lower levels of viral envelope diversity compared to RP infants. Our findings provide evidence that early viral and immunologic events following SIV infection contributes to impairment of B cells, Tfh cells and germinal center formation, ultimately impeding the development of SIV-specific antibody responses in rapidly progressing infant macaques.

immunology↗

bioRxiv2020

Protection from viral rebound after therapeutic vaccination with an adjuvanted DNA vaccine is associated with SIV-specific polyfunctional CD8 T cells in the blood and mesenteric lymph nodes

A therapeutic vaccine that induces lasting control of HIV infection has the potential to eliminate the need for lifelong adherence to antiretroviral therapy (ART). This study investigated the efficacy of a therapeutic DNA vaccine delivered with a novel combination of adjuvants and immunomodulators to augment T cell immunity in the blood and gut-associated lymphoid tissue. In SIV-infected rhesus macaques, a DNA vaccine delivered by intradermal electroporation and expressing SIV Env, Gag, and Pol, and a combination of adjuvant plasmids expressing the catalytic A1 subunit of E. coli heat labile enterotoxin (LTA1), IL-12, IL-33, retinaldehyde dehydrogenase 2 and the immunomodulators soluble PD-1 and soluble CD80, significantly enhanced the breadth and magnitude of Gag-specific IFN-{gamma} T cell responses when compared to controls that were mock vaccinated or received the same DNA vaccine delivered by Gene Gun with a single adjuvant, the E. coli heat labile enterotoxin, LT. Notably, the DNA vaccine and adjuvant combination protected 3/5 animals from viral rebound, compared to only 1/4 mock vaccinated animals and 1/5 animals that received the DNA vaccine and LT. The lower viral burden among controllers during analytical treatment interruption significantly correlated with higher polyfunctional CD8+ T-cells (CD8+ T cells expressing 3 or more effector functions) in both mesenteric lymph nodes and blood measured during ART and analytical treatment interruption. Interestingly, controllers also had lower viral loads during acute infection and ART suggesting that inherent host-viral interactions induced prior to ART initiation likely influenced the response to therapeutic vaccination. These data indicate that gut mucosal immune responses combined with effective ART may play a key role in containing residual virus post-ART and highlight the need for therapeutic vaccines and adjuvants that can restore functional quality of peripheral and mucosal T cell responses before and during ART. Author SummaryHIV has caused significant human disease and mortality since its emergence in the 1980s. Furthermore, although antiretroviral therapy (ART) effectively reduces viral replication, stopping ART leads to increased viral loads and disease progression in most HIV-infected people. A therapeutic vaccine could enable HIV-infected people to control their infection without ART, but none of the vaccines that were tested in clinical trials so far have induced long-lasting control of virus replication. Here, we used the SIV rhesus macaque model to test a therapeutic vaccine consisting of DNA expressing SIV proteins and a novel combination of adjuvants to boost virus-specific immune responses. We found that our vaccine strategy significantly enhanced SIV-specific T cell responses when compared to controls and protected 3/5 animals from viral rebound. We determined that lower levels of virus replication post-ART were associated with enhanced T cell immunity in the gut-draining lymph nodes and blood. Our study highlights the critical role of T cell immunity for control of SIV and HIV replication and demonstrates that a successful therapeutic vaccine for HIV will need to elicit potent T cell responses in both the blood and gut-associated tissues.

microbiology↗

bioRxiv2020

Elicitation of potent neutralizing antibody responses by designed protein nanoparticle vaccines for SARS-CoV-2

A safe, effective, and scalable vaccine is urgently needed to halt the ongoing SARS-CoV-2 pandemic. Here, we describe the structure-based design of self-assembling protein nanoparticle immunogens that elicit potent and protective antibody responses against SARS-CoV-2 in mice. The nanoparticle vaccines display 60 copies of the SARS-CoV-2 spike (S) glycoprotein receptor-binding domain (RBD) in a highly immunogenic array and induce neutralizing antibody titers roughly ten-fold higher than the prefusion-stabilized S ectodomain trimer despite a more than five-fold lower dose. Antibodies elicited by the nanoparticle immunogens target multiple distinct epitopes on the RBD, suggesting that they may not be easily susceptible to escape mutations, and exhibit a significantly lower binding:neutralizing ratio than convalescent human sera, which may minimize the risk of vaccine-associated enhanced respiratory disease. The high yield and stability of the protein components and assembled nanoparticles, especially compared to the SARS-CoV-2 prefusion-stabilized S trimer, suggest that manufacture of the nanoparticle vaccines will be highly scalable. These results highlight the utility of robust antigen display platforms for inducing potent neutralizing antibody responses and have launched cGMP manufacturing efforts to advance the lead RBD nanoparticle vaccine into the clinic.

immunology↗