Blood Lactate Kinetics Established Through Polynomial Line of Best Fit

PURPOSE: The purpose of this research is to determine a consistent line of best fit to mathematically define blood lactate kinetics during an incremental test to volitional fatigue. METHODS: There were 28 male and 10 female (n=38) subjects. Prior to testing, subjects signed an informed consent approved by the Institutional Review Board (IRB) for humans as subjects at Midwestern State University. Resting measures include: age (y), height (cm), weight (kg), body fat (%). The exercise measures of heart rate (HR, b*min.-1), minute volume of oxygen consumption (VO2, mL*kg-1*min.-1) and blood lactate (BLa, mM) were taken during a maximal cycle ergometer (VelotronTM) test utilizing the Australian Institute of Sport (AIS) cycle ergometer protocol. The aforementioned measures were taken each minute during the test until volitional fatigue. Statistical measures included means (standard deviation, SD) for group analysis. Trend line analysis was utilized to determine the line of best fit for BLa kinetic analysis. A coefficient of determination was used to establish level of association between the line of best fit and BLa kinetics. RESULTS: Group means (SD) for measures were the following for male and female subjects, respectively: age (y), 28.9 (12.2), 22.3 (5.3); height (cm), 177.3 (5.5), 167.7 (6.3); weight (kg), 75.8 (7.4), 63.5 (10.2); body fat (%), 10.01 (4.2), 22.9 (3.6); maximal VO2 (mL*kg-1*min.-1), 84.9 (4.6), 63.1 (14.1), peak BLa (mM), 12.7 (2.8), 9.3 (0.71). Third (3) order polynomial line of best fit was established for male and female BLa kinetics during the cycle ergometer test. Male and female polynomial equations with coefficient of determination (R2) are the following, respectively: Male, y = -(7 x 10-7) x3 + 0.0007x2 - 0.2104x + 19.917, R² = 0.9982; Female, y=-(2 x 10-6) x3 + 0.0012x2 - 0.2452x + 18.268, R² = 0.9892. CONCLUSION: Within the sample tested, blood lactate kinetics showed a consistent kinetic pattern with male and female cyclists. Trend line analysis indicates a 3rd order polynomial line of best fit was highly associated with BLa kinetics

A Comparison of Heart Rate Variability Between High Fit and Recreational Fit Cyclists

Download PD

A Comparison of Heart Rate Slope Between High Fit and Recreational Fit Cyclists

Download PD

A Comparison of Heart Rate Threshold Points Between High Fit and Recreational Fit Cyclists

Download PD

Laparoscopic Technique for Serial Collection of Liver and Mesenteric Lymph Nodes in Macaques

The mesenteric lymph nodes (MLN) and the liver are exposed to microbes and microbial products from the gastrointestinal (GI) tract, making them immunologically unique. The GI tract and associated MLN are sites of early viral replication in human immunodeficiency virus (HIV) infection and the MLN are likely important reservoir sites that harbor latently-infected cells even after prolonged antiretroviral therapy (ART). The liver has been shown to play a significant role in immune responses to lentiviruses and appears to play a significant role in clearance of virus from circulation. Nonhuman primate (NHP) models for HIV and Acquired Immunodeficiency Syndrome (AIDS) closely mimic these aspects of HIV infection and serial longitudinal sampling of primary sites of viral replication and the associated immune responses in this model will help to elucidate critical events in infection, pathogenesis, and the impact of various intervention strategies on these events. Current published techniques to sample liver and MLN together involve major surgery and/or necropsy, which limits the ability to investigate these important sites in a serial fashion in the same animal. We have previously described a laparoscopic technique for collection of MLN. Here, we describe a minimally invasive laparoscopic technique for serial longitudinal sampling of liver and MLN through the same two port locations required for the collection of MLN. The use of the same two ports minimizes the impact to the animals as no additional incisions are required. This technique can be used with increased sampling frequency compared to major abdominal surgery and reduces the potential for surgical complications and associated local and systemic inflammatory responses that could complicate interpretation of results. This procedure has potential to facilitate studies involving NHP models while improving animal welfare

Early cellular innate immune responses drive Zika viral persistence and tissue tropism in pigtail macaques

The immune response to Zika virus is required to curtail the infection and avoid immunopathology, but may be involved in the associated pathophysiology. Here the authors show that viral persistence and tissue tropism is shaped by an early innate immune response in a pigtail macaque model of infection

A Gut Reaction to SIV and SHIV Infection: Lower Dysregulation of Mucosal T Cells during Acute Infection Is Associated with Greater Viral Suppression during cART

Selection of a pre-clinical non-human primate (NHP) model is essential when evaluating therapeutic vaccine and treatment strategies for HIV. SIV and SHIV-infected NHPs exhibit a range of viral burdens, pathologies, and responses to combinatorial antiretroviral therapy (cART) regimens and the choice of the NHP model for AIDS could influence outcomes in studies investigating interventions. Previously, in rhesus macaques (RMs) we showed that maintenance of mucosal Th17/Treg homeostasis during SIV infection correlated with a better virological response to cART. Here, in RMs we compared viral kinetics and dysregulation of gut homeostasis, defined by T cell subset disruption, during highly pathogenic SIVΔB670 compared to SHIV-1157ipd3N4 infection. SHIV infection resulted in lower acute viremia and less disruption to gut CD4 T-cell homeostasis. Additionally, 24/24 SHIV-infected versus 10/19 SIV-infected animals had sustained viral suppression <100 copies/mL of plasma after 5 months of cART. Significantly, the more profound viral suppression during cART in a subset of SIV and all SHIV-infected RMs corresponded with less gut immune dysregulation during acute SIV/SHIV infection, defined by maintenance of the Th17/Treg ratio. These results highlight significant differences in viral control during cART and gut dysregulation in NHP AIDS models and suggest that selection of a model may impact the evaluation of candidate therapeutic interventions for HIV treatment and cure strategies

Simian-Human Immunodeficiency Virus SHIV.CH505 Infection of Rhesus Macaques Results in Persistent Viral Replication and Induces Intestinal Immunopathology

Simian-human immunodeficiency viruses (SHIVs) have been utilized to test vaccine efficacy and characterize mechanisms of viral transmission and pathogenesis. However, the majority of SHIVs currently available have significant limitations in that they were developed using sequences from chronically HIV-infected individuals or uncommon HIV subtypes or were optimized for the macaque model by serially passaging the engineered virus or Recently, a newly developed SHIV, SHIV.C.CH505.375H.dCT (SHIV.CH505), which incorporates vpu-env (gp140) sequences from a transmitted/founder HIV-1 subtype C strain, was shown to retain attributes of primary HIV-1 strains. However, a comprehensive analysis of the immunopathology that results from infection with this virus, especially in critical tissue compartments like the intestinal mucosa, has not been completed. In this study, we evaluated the viral dynamics and immunopathology of SHIV.CH505 in rhesus macaques. In line with previous findings, we found that SHIV.CH505 is capable of infecting and replicating efficiently in rhesus macaques, resulting in peripheral viral kinetics similar to that seen in pathogenic SIV and HIV infection. Furthermore, we observed significant and persistent depletions of CCR5 and CCR6 CD4 T cells in mucosal tissues, decreases in CD4 T cells producing Th17 cell-associated cytokines, CD8 T cell dysfunction, and alterations of B cell and innate immune cell function, indicating that SHIV.CH505 elicits intestinal immunopathology typical of SIV/HIV infection. These findings suggest that SHIV.CH505 recapitulates the early viral replication dynamics and immunopathogenesis of HIV-1 infection of humans and thus can serve as a new model for HIV-1 pathogenesis, treatment, and prevention research. The development of chimeric SHIVs has been instrumental in advancing our understanding of HIV-host interactions and allowing for testing of novel treatments. However, many of the currently available SHIVs have distinct drawbacks and are unable to fully reflect the features characteristic of primary SIV and HIV strains. Here, we utilize rhesus macaques to define the immunopathogenesis of the recently developed SHIV.CH505, which was designed without many of the limitations of previous SHIVs. We observed that infection with SHIV.CH505 leads to peripheral viral kinetics and mucosal immunopathogenesis comparable with those caused by pathogenic SIV and HIV. Overall, these data provide evidence of the value of SHIV.CH505 as an effective model of SIV/HIV infection and an important tool that can be used in future studies, including preclinical testing of new therapies or prevention strategies

Simian-Human Immunodeficiency Virus SHIV.CH505 Infection of Rhesus Macaques Results in Persistent Viral Replication and Induces Intestinal Immunopathology.

Simian-human immunodeficiency viruses (SHIVs) have been utilized to test vaccine efficacy and characterize mechanisms of viral transmission and pathogenesis. However, the majority of SHIVs currently available have significant limitations in that they were developed using sequences from chronically HIV-infected individuals or uncommon HIV subtypes or were optimized for the macaque model by serially passaging the engineered virus or Recently, a newly developed SHIV, SHIV.C.CH505.375H.dCT (SHIV.CH505), which incorporates vpu-env (gp140) sequences from a transmitted/founder HIV-1 subtype C strain, was shown to retain attributes of primary HIV-1 strains. However, a comprehensive analysis of the immunopathology that results from infection with this virus, especially in critical tissue compartments like the intestinal mucosa, has not been completed. In this study, we evaluated the viral dynamics and immunopathology of SHIV.CH505 in rhesus macaques. In line with previous findings, we found that SHIV.CH505 is capable of infecting and replicating efficiently in rhesus macaques, resulting in peripheral viral kinetics similar to that seen in pathogenic SIV and HIV infection. Furthermore, we observed significant and persistent depletions of CCR5 and CCR6 CD4 T cells in mucosal tissues, decreases in CD4 T cells producing Th17 cell-associated cytokines, CD8 T cell dysfunction, and alterations of B cell and innate immune cell function, indicating that SHIV.CH505 elicits intestinal immunopathology typical of SIV/HIV infection. These findings suggest that SHIV.CH505 recapitulates the early viral replication dynamics and immunopathogenesis of HIV-1 infection of humans and thus can serve as a new model for HIV-1 pathogenesis, treatment, and prevention research. The development of chimeric SHIVs has been instrumental in advancing our understanding of HIV-host interactions and allowing for testing of novel treatments. However, many of the currently available SHIVs have distinct drawbacks and are unable to fully reflect the features characteristic of primary SIV and HIV strains. Here, we utilize rhesus macaques to define the immunopathogenesis of the recently developed SHIV.CH505, which was designed without many of the limitations of previous SHIVs. We observed that infection with SHIV.CH505 leads to peripheral viral kinetics and mucosal immunopathogenesis comparable with those caused by pathogenic SIV and HIV. Overall, these data provide evidence of the value of SHIV.CH505 as an effective model of SIV/HIV infection and an important tool that can be used in future studies, including preclinical testing of new therapies or prevention strategies

Effects of persistent modulation of intestinal microbiota on SIV/HIV vaccination in rhesus macaques

An effective vaccine to prevent HIV transmission has not yet been achieved. Modulation of the microbiome via probiotic therapy has been suggested to result in enhanced mucosal immunity. Here, we evaluated whether probiotic therapy could improve the immunogenicity and protective efficacy of SIV/HIV vaccination. Rhesus macaques were co-immunized with an SIV/HIV DNA vaccine via particle-mediated epidermal delivery and an HIV protein vaccine administered intramuscularly with Adjuplex™ adjuvant, while receiving daily oral Visbiome probiotics. Probiotic therapy alone led to reduced frequencies of colonic CCR5 and CCR6  CD4  T cells. Probiotics with SIV/HIV vaccination led to similar reductions in colonic CCR5  CD4 T cell frequencies. SIV/HIV-specific T cell and antibody responses were readily detected in the periphery of vaccinated animals but were not enhanced with probiotic treatment. Combination probiotics and vaccination did not impact rectal SIV/HIV target populations or reduce the rate of heterologous SHIV acquisition during the intrarectal challenge. Finally, post-infection viral kinetics were similar between all groups. Thus, although probiotics were well-tolerated when administered with SIV/HIV vaccination, vaccine-specific responses were not significantly enhanced. Additional work will be necessary to develop more effective strategies of microbiome modulation in order to enhance mucosal vaccine immunogenicity and improve protective immune responses