Irreversible depletion of intestinal CD4+ T cells is associated with T cell activation during chronic HIV infection

HIV infection in the human gastrointestinal (GI) tract is thought to be central to HIV progression, but knowledge of this interaction is primarily limited to cohorts within Westernized countries. Here, we present a large cohort recruited from high HIV endemic areas in South Africa and found that people living with HIV (PLWH) presented at a younger age for investigation in the GI clinic. We identified severe CD4(+) T cell depletion in the GI tract, which was greater in the small intestine than in the large intestine and not correlated with years on antiretroviral treatment (ART) or plasma viremia. HIV-p24 staining showed persistent viral expression, particularly in the colon, despite full suppression of plasma viremia. Quantification of mucosal antiretroviral (ARV) drugs revealed no differences in drug penetration between the duodenum and colon. Plasma markers of gut barrier breakdown and immune activation were elevated irrespective of HIV, but peripheral T cell activation was inversely correlated with loss of gut CD4(+) T cells in PLWH alone. T cell activation is a strong predictor of HIV progression and independent of plasma viral load, implying that the irreversible loss of GI CD4(+) T cells is a key event in the HIV pathogenesis of PLWH in South Africa, yet the underlying mechanisms remain unknown

HIV infection drives interferon signaling within intestinal SARS-CoV-2 target cells

SARS-CoV-2 infects epithelial cells of the human gastrointestinal (GI) tract and causes related symptoms. HIV infection impairs gut homeostasis and is associated with an increased risk of COVID-19 fatality. To investigate the potential link between these observations, we analyzed singlecell transcriptional profiles and SARS-CoV-2 entry receptor expression across lymphoid and mucosal human tissue from chronically HIV-infected individuals and uninfected controls. Absorptive gut enterocytes displayed the highest coexpression of SARS-CoV-2 receptors ACE2, TMPRSS2, and TMPRSS4, of which ACE2 expression was associated with canonical interferon response and antiviral genes. Chronic treated HIV infection was associated with a clear antiviral response in gut enterocytes and, unexpectedly, with a substantial reduction of ACE2 and TMPRSS2 target cells. Gut tissue from SARS-CoV-2-infected individuals, however, showed abundant SARS-CoV-2 nucleocapsid protein in both the large and small intestine, including an HIV-coinfected individual. Thus, upregulation of antiviral response genes and downregulation of ACE2 and TMPRSS2 in the GI tract of HIV-infected individuals does not prevent SARS-CoV-2 infection in this compartment. The impact of these HIVassociated intestinal mucosal changes on SARS-CoV-2 infection dynamics, disease severity, and vaccine responses remains unclear and requires further investigation

Towards housing first and harm reduction : addressing opioid dependence and homelessness in Tshwane during the COVID-19 pandemic

Pandemics can increase mortality and drug-related harms among people experiencing homelessness. The Housing First approach prioritises housing and service access. Harm reduction, a principle of Housing First, minimises the consequences of drug use. This chapter presents lessons learnt from the application of Housing First and harm reduction principles with homeless people in Tshwane, South Africa, between April 2020 and March 2021. Quantitative service delivery data were retrospectively reviewed and analysed using descriptive statistics. Accounts by authors who participated in the COVID-19 response were collectively discussed in relation to the Housing First and harm reduction actors and process. Issues were synthesised in relation to two six-month periods. A task team was established to co-ordinate Tshwane’s response. In the first six months, 1 440 temporary bed-spaces were created at 25 shelters, and 2 066 people at shelters received food, social support and on-site healthcare services. Across shelters, 1 076 residents were started on methadone to manage opioid withdrawal. By the second six-month period, many gains were lost. Changes in political leadership stalled plans to reintegrate people housed in temporary shelters, and reduced funding led to shelter closures. By April 2021, more shelters operated than in pre-COVID-19 times, harm reduction capacitation for shelter staff continued, and local government committed to establish a street homelessness unit.Through a combination of funding and collaboration, progress was made towards Housing First and harm reduction for homeless people in Tshwane. A national policy on homelessness should be developed, funded and implemented. This should be informed by additional research, developed in partnership with affected populations, and built on a common understanding of Housing First and harm reduction.http://www.journals.co.za/content/journal/healthrFamily Medicin

Obstructive jaundice: Studies on predictors of biliary infection and microbiological analysis in an HIV setting

Background. Early diagnosis of biliary infection is critical for timely antimicrobial therapy and biliary drainage. HIV infection may influence the spectrum and severity of biliary infection in an environment with a high HIV prevalence. Charcot’s triad has low sensitivity and higher specificity for biliary infection, and more sensitive markers are required.Objectives. To investigate possible predictors of biliary infection (bacteriobilia) and identify the microbiological spectrum in patients presenting with biliary obstruction to a tertiary institute in an environment with a high prevalence of HIV.Methods. Bile was assessed for infection at endoscopic retrograde cholangiopancreatography, percutaneous transhepatic cholangiography and surgery, and the roles of clinical/haematological factors, C-reactive protein (CRP) and procalcitonin (PCT) in determining biliary infection were evaluated. Results: One hundred and six patients with obstructive jaundice had a mean age of 52 years (range 21 - 58); most were female (74%), and 36 (34%) were infected with HIV, with a mean CD4 count of 495 cells/µL. Choledocholithiasis (53%), biliary strictures (21%) and head of pancreas tumour (8%) were the main aetiopathologies. Bile was obtained for microbial culture from 104 patients (98%), and 56 (54%) were infected. Gram-negative bacteria were most frequent (58%), and 2 HIV-infected patients had fungal infections (Candida albicans and Aspergillus fumigatus). Screening for endoscopy-associated infections revealed Pseudomonas aeruginosa. PCT was a poor predictor of bacterial infection, whereas CRP was a fair predictor.Conclusions. The majority of bacteria cultured were sensitive to ciprofloxacin or amoxicillin-clavulanate. Duodenoscopes were a potential source of Pseudomonas infection

Phosphorodiamidates as a Promising New Phosphate Prodrug Motif for Antiviral Drug Discovery: Application to Anti-HCV Agents

We herein report phosphorodiamidates as a significant new phosphate prodrug motif. Sixty-seven phosphorodiamidates are reported of two 6-O-alkyl 2′-C-methyl guanosines, with significant variation in the diamidate structure. Both symmetrical and asymmetric phosphorodiamidates are reported, derived from various esterified amino acids, both d and l, and also from various simple amines. All of the compounds were evaluated versus hepatitis C virus in replicon assay, and nanomolar activity levels were observed. Many compounds were noncytotoxic at 100 μM, leading to high antiviral selectivities. The agents are stable in acidic, neutral, and moderately basic media and in selected biological media but show efficient processing by carboxypeptidases and efficiently yield the free nucleoside monophosphate in cells. On the basis of in vitro data, eight leads were selected for additional in vivo evaluation, with the intent of selecting one candidate for progression toward clinical studies. This phosphorodiamidate prodrug method may have broad application outside of HCV and antivirals as it offers many of the advantages of phosphoramidate ProTides but without the chirality issues present in most cases