Type III CRISPR–Cas systems make use of a multi-subunit effector complex to target foreign (m)RNA transcripts complementary to the guide/CRISPR RNA (crRNA). Base-pairing of the target RNA with specialized regions in the crRNA not only triggers target RNA cleavage, but also activates the characteristic Cas10 subunit and sets in motion a variety of catalytic activities that starts with the production of cyclic oligoadenylate (cOA) second messenger molecules. These messenger molecules can activate an extensive arsenal of ancillary effector proteins carrying the appropriate sensory domain. Notably, the CARF and SAVED effector proteins have been responsible for renewed interest in type III CRISPR–Cas due to the extraordinary diversity of defenses against invading genetic elements. Whereas only a handful of CARF and SAVED proteins have been studied so far, many of them seem to provoke abortive infection, aimed to kill the host and provide population-wide immunity. A defining feature of these effector proteins is the variety of in silico-predicted catalytic domains they are fused to. In this mini-review, we discuss all currently characterized type III-associated CARF and SAVED effector proteins, highlight a few examples of predicted CARF and SAVED proteins with interesting predicted catalytic activities, and speculate how they could contribute to type III immunity.
The Philippines has had a rapidly growing HIV epidemic with a shift in the prevalent subtype from B to CRF01_AE. However, the phylodynamic history of CRF01_AE in the Philippines has yet to be reconstructed. We conducted a descriptive retrospective study reconstructing the history of HIV-1 CRF01_AE transmissions in the Philippines through molecular epidemiology. Partial polymerase sequences (n = 1429) collected between 2008 and 2018 from 13 Philippine regions were collated from the RITM drug resistance genotyping database. Subsampling was performed on these Philippine and Los Alamos National Laboratory HIV international sequences followed by estimation of the time to the most recent common ancestor (tMRCA), effective reproductive number (Re), effective viral population size (Ne), relative migration rates and geographic spread of CRF01_AE with BEAST. Re and Ne were compared between CRF01_AE and B. Most CRF01_AE sequences formed a single clade with a tMRCA of 1999 [95% HPD: 1996, 2001]. Exponential growth of Ne was observed from 1999 to 2013. The Re reached peaks of 3.71 [95% HPD: 1.71, 6.14] in 2009 and 2.87 [95% HPD: 1.78, 4.22] between 2012 and 2015. A transient decrease to 0.398 [95% HPD: 0.0105, 2.28] occurred between 2010 and 2012. The epidemic most likely started in Luzon in the National Capital Region, which then spread diffusely to the rest of the country. Both CRF01_AE and subtype B exhibited similar but unsynchronized patterns of Re over time. These results characterize the subtype-specific phylodynamic history of the CRF01_AE epidemic in the Philippines, which contextualizes and may inform past, present, and future public health measures toward controlling the HIV epidemic in the Philippines.
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