ABSTRACT
Previous studies on horseshoe bats (Rhinolophus spp.) have described many coronaviruses related to SARS-CoV (SARSCoVr) in China and only a few coronaviruses related to SARS-CoV-2 (SARSCoV2r) in Yunnan (southern China), Cambodia, Laos and Thailand. Here, we report the results of several field missions carried out in 2017, 2021 and 2022 across Vietnam during which 1218 horseshoe bats were sampled from 19 locations. Sarbecoviruses were detected in 11% of faecal RNA extracts, with much more positives among Rhinolophus thomasi (46%). We assembled 38 Sarbecovirus genomes, including 32 SARSCoVr, four SARSCoV2r, and two recombinants of SARSCoVr and SARSCoV2r (RecSar), one showing a Spike protein very similar to SARS-CoV-2. We detected a bat co-infected with four coronaviruses, including two sarbecoviruses. Our analyses revealed that Sarbecovirus genomes evolve in Vietnam under strong geographical and host constraints. First, we found evidence for a deep separation between viruses from northern Vietnam and those from central and southern Vietnam. Second, we detected only SARSCoVr in Rhinolophus thomasi, both SARSCoVr and SARSCoV2r in Rhinolophus affinis, and only RecSar in Rhinolophus pusillus captured close to the border with China. Third, the bias in favour of Uracil in synonymous third codon positions of SARSCoVr extracted from R. thomasi showed a negative correlation with latitudes. Our results also provided support for an emergence of SARS-CoV in horseshoe bats from northern Yunnan and emergence of SARS-CoV-2 in horseshoe bats from northern Indochina subtropical forests (southern Yunnan, northern Laos and north-western Vietnam).
ABSTRACT
BACKGROUND: HIV-infected patients under antiretroviral therapy that includes HIV protease inhibitors (PIs) are prone to develop a complex metabolic syndrome including insulin resistance, lipodystrophy and hypertension. Whether hypertension and cardiovascular events could result from the adipocyte renin angiotensin system (RAS) overactivation has never been investigated. METHODS: Primary human adipocytes and 3T3-F442A murine adipocytes were incubated with lopinavir or atazanavir boosted with ritonavir, with or without the angiotensin II type-1 receptor (AT1R) blockers (ARBs), irbesartan or telmisartan, and the peroxysome proliferator-activated receptor-gamma (PPAR-gamma) regulators, rosiglitazone and GW9662. Adipose RAS activation and adipocyte functions were evaluated. RESULTS: The ritonavir-boosted PIs activated the adipose RAS in human and murine adipocytes as shown by the overexpression of AT1R protein, angiotensinogen messenger RNA and the amplified effect of angiotensin II on extracellular signal-regulated kinase 1/2 activity. ARBs prevented the PI effect on RAS activation (AT1R overexpression and signalling) and adipocyte functions (dedifferentiation, insulin resistance, oxidative stress and inflammation). Consistent with a role of PPAR-gamma signalling in PI-induced RAS activation, the PPAR-gamma agonist (rosiglitazone) normalized PI-induced AT1R overexpression and adipocyte dysfunction. Conversely, the PPAR-gamma antagonist (GW9662) induced AT1R overexpression and reduced the beneficial effect of telmisartan on PI toxicity. CONCLUSIONS: We report that two frequently prescribed PI combinations could activate the adipose RAS in cultured cells, in part through a PPAR-gamma-dependant signalling pathway. Our data suggest a role for the adipose RAS in the development of hypertension in HIV-infected patients under PI treatment, and point out the potential use of ARBs to decrease PI adverse effects.