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The antiviral role of CD8؉ cytotoxic T lymphocytes (CTLs) in human immunodeficiency virus type 1 (HIV-1) infection is poorly understood. Specifically, the degree to which CTLs reduce viral replication by killing HIV-1-infected cells in vivo is not known. Here we employ mathematical models of the infection process and CTL action to estimate the rate that CTLs can kill HIV-1-infected cells from in vitro and in vivo data. Our estimates, which are surprisingly consistent considering the disparities between the two experimental systems, demonstrate that on average CTLs can kill from 0.7 to 3 infected target cells per day, with the variability in this figure due to epitope specificity or other factors. These results are compatible with the observed decline in viremia after primary infection being primarily a consequence of CTL activity and have interesting implications for vaccine design.Evidence for the importance of cytotoxic T lymphocytes (CTLs) in retroviral infection includes the temporal association of the human immunodeficiency virus type 1 (HIV-1)-specific CTL response with reduction in viremia during primary infection (15) and the acute rise in viremia when simian immunodeficiency virus (SIV)-infected macaques (SIVmac) are CD8 ϩ cell depleted (12,19,27). These data have prompted many vaccinologists to focus on cellular immunity. Yet, despite clear evidence that CTLs have a crucial antiviral function, their impact in vivo remains obscure. This lack of understanding presents an obstacle to defining the requirements for a successful CTL-based vaccine. Mathematical modeling of the interaction of CTLs and HIV-1 is one approach to elucidating these requirements.For complicated biological processes, we often rely on mathematical models to explore mechanisms that are beyond direct experimental measurement. Most models require the representation of contributing processes by rate constants, to allow the evaluation of a mechanism of interest. Typically, some of these rate constants are estimated from the data used to build the model. But as model complexity increases, varying a large number of poorly defined parameters risks identifying the bestfitting wrong model. To avoid this pitfall, ideally rate constants should be derived from dedicated experiments, so that the "full model," when finally assembled, is not internally circular.A key parameter in such a model is the efficiency of CTLs in eliminating infected target cells. A direct estimate is derived from observing the impact of patient-derived HIV-1-specific CTLs on replication in HIV-1-infected cell lines in vitro. From titrations of CTL density against viral growth, we can derive the killing rate by fitting a simplified model. To confirm the relevance of these in vitro measurements using cell lines, we estimated the same parameter by analyzing data from an in vivo "adoptive transfer" experiment conducted by Brodie et al. in 1999 (6, 7). Our results provide similar independent estimates of this key parameter for modeling the impact of CTLs in HIV-1 pathogenesis. M...

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Recent devastating hurricanes demonstrated that extreme weather and climate change can jeopardize contaminated land remediation and harm public health and the environment. Since early 2016, the Sustainable Remediation Forum (SURF) has led research and organized knowledge exchanges to examine (1) the impacts of climate change and extreme weather events on hazardous waste sites, and (2) how we can mitigate these impacts and create value for communities. The SURF team found that climate change and extreme weather events can undermine the effectiveness of the approved site remediation, and can also affect contaminant toxicity, exposure, organism sensitivity, fate and transport, long-term operations, management, and stewardship of remediation sites. Further, failure to consider social vulnerability to climate change could compromise remediation and adaptation strategies. SURF's recommendations for resilient remediation build on resources and drivers from state, national, and international sources, and marry the practices of sustainable remediation and climate change adaptation. They outline both general principles and site-specific protocols and provide global examples of mitigation and adaptation strategies.Opportunities for synergy include vulnerability assessments that benefit and build on established hazardous waste management law, policy, and practices. SURF's recommendations can guide owners and project managers in developing a site resiliency strategy. Resilient remediation can help expedite cleanup and redevelopment, decrease public health risks, and create jobs, parks, wetlands, and resilient energy sources. Resilient remediation and redevelopment can also positively contribute to achieving international goals for sustainable land management, climate action, clean energy, and sustainable cities.

The disappointing outcomes of cellular immune-based vaccines against HIV-1 despite strong evidence for the protective role of CD8+ T lymphocytes (CTLs) has prompted revisiting the mechanisms of cellular immunity. Prior data from experiments examining the kinetics of Simian Immunodeficiency Virus (SIV) clearance in infected macaques with or without in vivo CD8 depletion were interpreted as refuting the concept that CTLs suppress SIV/HIV by direct killing of infected cells. Here we briefly review the biological evidence for CTL cytolytic activity in viral infections, and utilize biologically-directed modeling to assess the possibility of a killing mechanism for the antiviral effect of CTLs, taking into account the generation, proliferation, and survival of activated CD4+ and CD8+ T lymphocytes, as well as the life cycle of the virus. Our analyses of the published macaque data using these models support a killing mechanism, when one considers T lymphocyte and HIV-1 lifecycles, and factors such as the eclipse period before release of virions by infected cells, an exponential pattern of virion production by infected cells, and a variable lifespan for acutely infected cells. We conclude that for SIV/HIV pathogenesis, CTLs deserve their reputation as being cytolytic.