We have previously demonstrated that CD4+CD25+ Treg cells activated during the course of FIV infection suppress CD8+ CTL function in a TGFβ-dependent fashion, inhibiting IFNγ and IL2 production, and inducing G1 cell cycle arrest. Here, we describe the molecular events occurring at the IL2 promoter leading to suppression of IL2 production. These experiments demonstrate that FoxP3 induced by lentivirus-activated Treg cells in the CD8+ target cells binds to the IL2 promoter, actively repressing IL2 transcription. We further demonstrate that the chronic activation of CD8+ T cells during FIV infection results in chromatin remodeling at the IL2 promoter, specifically, demethylation of CpG residues. These DNA modifications occur during active transcription and translation of IL2; however, these changes render the IL2 promoter permissive to FoxP3-induced transcriptional repression. These data help explain, in part, the seemingly paradoxical observations that CD8+ T cells displaying an activation phenotype exhibit altered antiviral function. Further, we demonstrate that blocking demethylation of CpG residues at the IL2 promoter inhibits FoxP3 binding, suggesting a potential mechanism for rescue and / or reactivation of CD8+ T cells. Using the FIV model for lentiviral persistence, these studies provide a framework for understanding how immune activation combined with Treg cell-mediated suppression may affect CD8+ T cell IL2 transcription, maturation, and anti-viral function.
The growth rate of new HIV infections in the Philippines was the fastest of any countries in the Asia-Pacific region between 2010 and 2016. To date, HIV-1 subtyping results in the Philippines have been determined by characterizing only partial viral genome sequences. It is not known whether recombination occurs in the majority of unsequenced genome regions. Nearfull-length genome (NFLG) sequences were obtained by amplifying two overlapping half genomes from plasma samples collected between 2015 and 2017 from 23 newly diagnosed infected individuals in the Philippines. Phylogenetic analysis showed that the newly characterized sequences were CRF01_AE (14), subtype B (3), CRF01/B recombinants (5) and a CRF01/CRF07/B recombinant (1). All 14 CRF01_AE formed a tight cluster, suggesting that they were derived from a single introduction. The time to the most recent common ancestor (tMRCA) for CRF01_AE in the Philippines was 1995 (1992-1998), about 10-15 years later than that of CRF01_AE in China and Thailand. All five CRF01/B recombinants showed distinct recombination patterns, suggesting ongoing recombination between the two predominant circulating viruses. The identification of partial CRF07_BC sequences in one CRF01/CRF07/B recombinant, not reported previously in the Philippines, indicated that CRF07_BC may have been recently introduced into that country from China, where CRF07_BC is prevalent. Our results show that the major epidemic strains may have shifted to an increased predominance of CRF01_AE and its recombinants, and that other genotypes such as CRF07_BC may have been introduced into the Philippines.
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