Peripheral neuropathy is the most frequent neurological complication of HIV infection, affecting more than one-third of infected patients, including patients treated with antiretroviral therapy. ...Although emerging noninvasive techniques for corneal nerve assessments are increasingly being used to diagnose and monitor peripheral neuropathies, corneal nerve alterations have not been characterized in HIV. Here, to determine whether SIV infection leads to corneal nerve fiber loss, we immunostained corneas for the nerve fiber marker βIII tubulin. We developed and applied both manual and automated methods to measure nerves in the corneal subbasal plexus. These counting methods independently indicated significantly lower subbasal corneal nerve fiber density among SIV-infected animals that rapidly progressed to AIDS compared with slow progressors. Concomitant with decreased corneal nerve fiber density, rapid progressors had increased levels of SIV RNA and CD68-positive macrophages and expression of glial fibrillary acidic protein by glial satellite cells in the trigeminal ganglia, the location of the neuronal cell bodies of corneal sensory nerve fibers. In addition, corneal nerve fiber density was directly correlated with epidermal nerve fiber length. These findings indicate that corneal nerve assessment has great potential to diagnose and monitor HIV-induced peripheral neuropathy and to set the stage for introducing noninvasive techniques to measure corneal nerve fiber density in HIV clinical settings.
Abstract
Background
Although social distancing is a key public health response during viral pandemics, psychosocial stressors, such as social isolation, have been implicated in adverse health ...outcomes in general 1 and in the context of infectious disease, such as human immunodeficiency virus (HIV) 2, 3. A comprehensive understanding of the direct pathophysiologic effects of psychosocial stress on viral pathogenesis is needed to provide strategic and comprehensive care to patients with viral infection.
Methods
To determine the effect of psychosocial stress on HIV pathogenesis during acute viral infection without sociobehavioral confounders inherent in human cohorts, we compared commonly measured parameters of HIV progression between singly (n = 35) and socially (n = 41) housed simian immunodeficiency virus (SIV)-infected pigtailed macaques (Macaca nemestrina).
Results
Singly housed macaques had a higher viral load in the plasma and cerebrospinal fluid and demonstrated greater CD4 T-cell declines and more CD4 and CD8 T-cell activation compared with socially housed macaques throughout acute SIV infection.
Conclusions
These data demonstrate that psychosocial stress directly impacts the pathogenesis of acute SIV infection and imply that it may act as an integral variable in the progression of HIV infection and potentially of other viral infections.
This study demonstrates that psychosocial stress directly impacts the pathogenesis of acute SIV infection and implies that psychosocial stress may act as an integral variable in the progression of HIV infection and potentially of other viral infections.
Self-injurious behavior (SIB) occurs within laboratory-housed NHP at low frequency but can have a devastating effect on animal research and wellbeing. One barrier to the study and clinical management ...of these cases is the cost of equipment and personnel time to quantify the behavior
according to the current standard of observation and to score remotely obtained video recordings. In studies of human SIB, in which direct observation is difficult or prohibited, researchers have demonstrated that quantifying the tissue damage resulting from SIB can be a useful proxy to represent
the underlying behavior. We hypothesized that the nature of wounds resulting from SIB in NHP could be used in a similar manner to measure the abnormal behavior. Using a cohort of rhesus macaques with high-incidence SIB, we examined severity, distribution, and number of wounds and compared
them with observed incidences of SIB during a 12-wk experiment. We found that the number, severity, and distribution of physical wounds were associated with the incidences of biting behavior observed during the 2 wk prior to measurement. We also found that an increased number of wounds was
associated with increased severity. Animals with wounds of moderate severity were more likely to also have severe wounds than were macaques with wounds that were lower than moderate in severity. This work is the first representative study in NHP to find that behavioral SIB correlates with
physical wounding and that increases in the frequency and number of the body regions affected correlates with the severity of wounding.
Thrombocytopenia is a known consequence of HIV infection, and decreased production of platelets has been previously implicated in the pathogenesis of platelet decline during asymptomatic infection. ...Thrombopoietin (THPO) drives platelet production by stimulating the maturation of bone marrow megakaryocytes and can be transcriptionally downregulated by cytokines that are increased during infection such as transforming growth factor β (TGFβ) and platelet factor 4 (pf4).
To determine whether transcriptional downregulation of THPO contributed to decreased platelet production during asymptomatic infection in the simian immunodeficiency virus (SIV)/macaque model of HIV, we compared hepatic THPO mRNA levels to platelet number and megakaryocyte density. To identify potential inhibitory factors that decrease THPO transcription during asymptomatic infection, we measured TGFβ and pf4 plasma levels. To determine whether combined antiretroviral therapy (cART) could correct platelet decline by altering cytokine levels, we measured TGFβ and pf4 in cART-treated SIV-infected macaques and compared these values to cART-untreated SIV-infected macaques.
Hepatic THPO transcription was downregulated during asymptomatic SIV infection concurrent with platelet decline. Hepatic THPO mRNA levels correlated with bone marrow megakaryocyte density. In contrast, plasma TGFβ levels were inversely correlated with hepatic THPO transcription and bone marrow megakaryocyte density. With cART treatment, plasma TGFβ levels and platelet count returned to values similar to those in uninfected macaques.
TGFβ-mediated downregulation of hepatic THPO may lead to decline in platelet number during asymptomatic SIV infection, and cART may prevent platelet decline by normalizing plasma TGFβ levels.
Detecting and controlling murine fur mites continues to be challenging. Here we compared the efficacy of fur-pluck, cage PCR, and fur PCR testing of mice naturally infested with Myocoptes musculinus ...and make recommendations regarding the application of these diagnostic strategies
in aged or treated mice. We compared all 3 diagnostic methods in groups of infested and noninfested control mice over time. For fur plucks, we used a scoring system to quantitatively compare mite infestations across ages. Mice that were 4 wk old had higher egg and mite scores than did older
mice, with average scores at 4 wk corresponding to 40 to 100 individual fur mites and eggs per sample. Furthermore, 15% and 20% of samples from infested mice at 24 and 28 wk of age, respectively, lacked all fur mites and eggs. Cage PCR results varied as mice grew older. Fur PCR testing was
the most sensitive and specific assay in untreated infested mice, particularly when mite densities were low. In addition, we compared fur-pluck and fur PCR tests for evaluating the efficacy of selamectin treatment. Two treatments with selamectin eliminated Myocoptes fur-mite infestations.
At 8 wk after treatment, all fur-pluck samples were negative, but one-third of treated infested cages remained positive by fur PCR assay; at 16 wk after treatment, all cages were negative by fur PCR assay. Because offspring of infested mice were invariably heavily infested, breeding of suspected
infested mice with subsequent testing of offspring was the definitive testing strategy when fur-pluck and PCR results conflicted.
To catalyze severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) research, including development of novel interventive and preventive strategies, the progression of disease was characterized ...in a robust coronavirus disease 2019 (COVID-19) animal model. In this model, male and female golden Syrian hamsters were inoculated intranasally with SARS-CoV-2 USA-WA1/2020. Groups of inoculated and mock-inoculated uninfected control animals were euthanized at 2, 4, 7, 14, and 28 days after inoculation to track multiple clinical, pathology, virology, and immunology outcomes. SARS-CoV-2–inoculated animals consistently lost body weight during the first week of infection, had higher lung weights at terminal time points, and developed lung consolidation per histopathology and quantitative image analysis measurements. High levels of infectious virus and viral RNA were reliably present in the respiratory tract at days 2 and 4 after inoculation, corresponding with widespread necrosis and inflammation. At day 7, when the presence of infectious virus was rare, interstitial and alveolar macrophage infiltrates and marked reparative epithelial responses (type II hyperplasia) dominated in the lung. These lesions resolved over time, with only residual epithelial repair evident by day 28 after inoculation. The use of quantitative approaches to measure cellular and morphologic alterations in the lung provides valuable outcome measures for developing therapeutic and preventive interventions for COVID-19 using the hamster COVID-19 model.
Amyloidosis is a progressive and ultimately fatal disease in which amyloid, an insoluble fibrillar protein, is deposited inappropriately in multiple organs, eventually leading to organ dysfunction. ...Although this condition commonly affects macaques, there is currently no reliable method
of early diagnosis. Changes in clinical pathology parameters have been associated with amyloidosis but occur in late stages of disease, are nonspecific, and resemble those seen in chronic, idiopathic enterocolitis. A review of animal records revealed that amyloidosis was almost always diagnosed
postmortem, with prevalences of 15% and 25% in our rhesus and pig-tailed macaque colonies, respectively. As a noninvasive, high-throughput diagnostic approach to improve antemortem diagnosis of amyloidosis in macaques, we evaluated serum amyloid A (SAA), an acute-phase protein and the precursor
to amyloid. Using necropsy records and ELISA analysis of banked serum, we found that SAA is significantly elevated in both rhesus and pig-tailed macaques with amyloid compared with those with chronic enterocolitis and healthy controls. At necropsy, 92% of rhesus and 83% of pig-tailed had amyloid
deposition in either the intestines or liver. Minimally invasive biopsy techniques including endoscopy of the small intestine, mucosal biopsy of the colon, and ultrasound-guided trucut biopsy of the liver were used to differentiate macaques in our colonies with similar clinical presentations
as either having amyloidosis or chronic, idiopathic enterocolitis. Our data suggest that SAA can serve as an effective noninvasive screening tool for amyloidosis and that minimally invasive biopsies can be used to confirm this diagnosis.
Background
Diastolic dysfunction is a highly prevalent cardiac abnormality in asymptomatic as well as ART‐treated human immunodeficiency virus (HIV) patients. Although the mechanisms underlying ...depressed cardiac function remain obscure, diastolic dysfunction in SIV‐infected rhesus macaques is highly correlated with myocardial viral load. As cardiomyocytes are not productively infected, damage may be an indirect process attributable to a combination of pro‐inflammatory mediators and viral proteins.
Methods and Results
Given the diverse roles of CCR5 in mediating recruitment of leukocytes to inflammatory sites and serving as a receptor for HIV entry into cells, we investigated the role of CCR5 in the SIV/macaque model of diastolic dysfunction. We found that in SIV‐infected macaques, CCR5 inhibition dramatically impacted myocardial viral load measured by qRT‐PCR and prevented diastolic dysfunction measured by echocardiography. Complementary in vitro experiments using fluorescence microscopy showed that CCR5 ligands impaired contractile function of isolated cardiomyocytes, thus identifying CCR5 signaling as a novel mediator of impaired cardiac mechanical function.
Conclusions
Together, these findings incriminate SIV/HIV gp120‐CCR5 as well as chemokine‐CCR5 interactions in HIV‐associated cardiac dysfunction. These findings also have important implications for the treatment of HIV‐infected individuals: in addition to antiviral properties and reduced chemokine‐mediated recruitment and activation of inflammatory cells, CCR5 inhibition may provide a cardioprotective benefit by preventing cardiomyocyte CCR5 signaling.
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