Antiretroviral Treatment Start-Time during Primary SIVmac Infection in Macaques Exerts a Different Impact on Early Viral Replication and Dissemination

BACKGROUND: The time of infection is rarely known in human cases; thus, the effects of delaying the initiation of antiretroviral therapy (ART) on the peripheral viral load and the establishment of viral reservoirs are poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: Six groups of macaques, infected intravenously with SIV(mac251), were given placebo or antiretroviral therapy to explore reservoir establishment; macaques were treated for 2 weeks, with treatment starting 4 hours, 7 or 14 days after infection. Viral replication and dissemination were measured in the gut (rectum), in the lung and in blood and lymphoid tissues (peripheral lymph nodes), by quantifying viral RNA, DNA and 2LTR circles. We used immunohistochemistry (CD4 and CD68) to assess the impact of these treatments on the relative amount of virus target cells in tissue. Treatment that was started 4 hours post-infection (pi) decreased viral replication and dissemination in blood and tissue samples, which were assessed on day 14 (RNA/DNA/2LTR circles). The virus remained detectable and lymphoid tissues were activated in LN and the gut in both placebo- and ART-treated animals. Viral RNA in plasma continued to be lower in macaques treated seven days after infection; however, this was not the case for viral DNA in peripheral blood mononuclear cells. There was a small but significant difference in RNA and DNA levels in tissues between placebo- and ART-treated animals on day 21. When started 14 days after infection, treatment resulted in a limited decrease in the plasma viral load. CONCLUSIONS: Treatment that was started 4 hours after infection significantly reduced viral replication and dissemination. When started 7 days after infection, it was of slight virological benefit in peripheral blood and in tissues, and treatment was even less effective if started 14 days pi. These data favor starting ART no longer than one week after intravenous SIV(mac251) exposure

Inhaled Aerosol Dosimetry: Models, Implications and Impact: Proceedings of the Conference

The fourth conference, “Inhaled Aerosol Dosimetry: Advances, Applications and Impacts on Risk Assessments and Therapeutics”, was also held at “The Arnold and Mabel Beckman Center of the National Academies of Sciences and Engineering”, Irvine, California, October 16-18, 2024. It attracted 66 attendees including graduate students from seven nations (USA, Germany, France, India, the Netherlands, Switzerland, and S. Korea) and 52 papers and posters were presented. There were two highlighted sessions, number 5 and 6 in the program, on in vitro aerosol exposures and exposure systems. Keynote/Overview papers were delivered by Dr. Annie Jarabek (U.S. EPA), Dr. Gunter Oberdorster (U of Rochester), Dr. Jesssica Murray (U.S. EPA), Dr. Roger McClellan (Toxicology and Risk Analysis), Dr. Ross Walenga (U.S. FDA), and Dr. Ron Wolff (RK Wolff Safety Consulting, Inc.). See abstracts AB 52, 03, 04, 34 & 39, 50, and 41 respectively for these presentations. There were three awards to students for Outstanding Research, and a hosted luncheon where graduate students had open discussions with established scientists representing academia, government, pharmaceutical industry, and consultants. Discussions and written comments after the last session produced several recommendations that are to be published. And peer-reviewed papers from the conference are to be published in a Virtual Special Issue, “Inhaled Aerosol Dosimetry of the Journal of Aerosol Science, edited by Dr. Phalen (UC Irvine), Dr. Darquenne (UC San Diego), and Dr. Golshahi (Virginia Commonwealth University). The concluding open discussion addressed the need for another future conference and for the attendees to increase their collaborations. Sponsors NIH/NIEHS, U.S. EPA, ISAM, UC Irvine Advancement, and The Air Pollution Health Effects Laboratory, The Department of Environmental Health in The Joe C. Wen School of Population & Public Health, and the Department of Medicine, Division of Occupational and Environmental Health

Modelling the response to vaccine in non-human primates to define SARS-CoV-2 mechanistic correlates of protection

The definition of correlates of protection is critical for the development of next-generation SARS-CoV-2 vaccine platforms. Here, we propose a model-based approach for identifying mechanistic correlates of protection based on mathematical modelling of viral dynamics and data mining of immunological markers. The application to three different studies in non-human primates evaluating SARS-CoV-2 vaccines based on CD40-targeting, two-component spike nanoparticle and mRNA 1273 identifies and quantifies two main mechanisms that are a decrease of rate of cell infection and an increase in clearance of infected cells. Inhibition of RBD binding to ACE2 appears to be a robust mechanistic correlate of protection across the three vaccine platforms although not capturing the whole biological vaccine effect. The model shows that RBD/ACE2 binding inhibition represents a strong mechanism of protection which required significant reduction in blocking potency to effectively compromise the control of viral replication.Initiative for the creation of a Vaccine Research InstituteInfrastructure nationale pour la modélisation des maladies infectieuses humaine

Administration of airborne pathogens in non-human primates

International audienc

Isolation and phenotypic characterization of human and nonhuman primate intestinal lamina propria mononuclear cells

International audienc

Loss of reactivity of vaccine-induced CD4 T cells in immunized monkeys after SIV/HIV challenge.

International audienceBACKGROUND: Immunization protocols involving priming with DNA and boosting with recombinant live virus vectors such as recombinant modified Vaccinia Ankara (rMVA) are considered as vaccine candidates against HIV. Such protocols improve the outcome of simian/human immunodeficiency virus (SHIV) pathogenic challenge in Rhesus monkeys. OBJECTIVES: To investigate the fate of vaccine-induced T cells after a mucosal SHIV challenge. METHODS: We immunized Rhesus monkeys (Macaca mulatta) by DNA priming followed by rMVA boost. After intrarectal challenge with SHIV 89.6P, immunized animals demonstrated early control of viral replication and stable CD4 T-cell counts. We monitored T-cell responses by measuring IFN-gamma secretion and proliferation. RESULTS: Immunization induced strong and sustained SHIV-specific CD4 and CD8 T-cell responses. CD8 T-cell responses were recalled during acute infection, whereas none of the vaccine-induced SHIV-specific CD4 T-cell responses were recalled. Moreover, most of the CD4 T-cell responses became undetectable in peripheral blood or lymph nodes even after in-vitro peptide stimulation. In contrast, we persistently detected CD4 T-cell responses specific for control recall antigens in infected animals. CONCLUSION: SHIV 89.6P challenge results in a lack of reactivity of vaccine-induced SHIV-specific CD4 T cells. These results may have important implications in the AIDS vaccine field, especially for the evaluation of new vaccine candidates, both in preventive and therapeutic trials

Changes in Soluble Factor-Mediated CD8(+) Cell-Derived Antiviral Activity in Cynomolgus Macaques Infected with Simian Immunodeficiency Virus SIVmac251: Relationship to Biological Markers of Progression

Cross-sectional studies have shown that the capacity of CD8(+) cells from human immunodeficiency virus (HIV)-infected patients and simian immunodeficiency virus (SIV) SIVmac-infected macaques to suppress the replication of human and simian immunodeficiency viruses in vitro depends on the clinical stage of disease, but little is known about changes in this antiviral activity over time in individual HIV-infected patients or SIV-infected macaques. We assessed changes in the soluble factor-mediated noncytolytic antiviral activity of CD8(+) cells over time in eight cynomolgus macaques infected with SIVmac251 to determine the pathophysiological role of this activity. CD8(+) cell-associated antiviral activity increased rapidly in the first week after viral inoculation and remained detectable during the early phase of infection. The net increase in antiviral activity of CD8(+) cells was correlated with plasma viral load throughout the 15 months of follow-up. CD8(+) cells gradually lost their antiviral activity over time and acquired virus replication-enhancing capacity. Levels of antiviral activity correlated with CD4(+) T-cell counts after viral set point. Concentrations of β-chemokines and interleukin-16 in CD8(+) cell supernatants were not correlated with this antiviral activity, and α-defensins were not detected. The soluble factor-mediated antiviral activity of CD8(+) cells was neither cytolytic nor restricted to major histocompatibility complex. This longitudinal study strongly suggests that the increase in noncytolytic antiviral activity from baseline and the maintenance of this increase over time in cynomolgus macaques depend on both viral replication and CD4(+) T cells