Increased plasmacytoid dendritic cell maturation and natural killer cell activation in HIV-1 exposed, uninfected intravenous drug users.

BACKGROUND: Increased natural killer (NK) activation has been associated with resistance to HIV-1 infection in several cohorts of HIV-1 exposed, uninfected individuals. Inheritance of protective NK receptor alleles (KIR3DS1 and KIR3DL1) has also been observed in a subset of HIV-1 exposed, uninfected individuals. However, the exact mechanism contributing to NK activation in HIV-1 exposed, uninfected intravenous drug users (EU-IDU) remains to be elucidated. OBJECTIVE: We investigated the role of both host genotype and pathogen-induced dendritic cell modulation of NK activation during high-risk activity in a cohort of 15 EU-IDU individuals and 15 control, uninfected donors from Philadelphia. DESIGN: We assessed the activation status of NK cells and dendritic cells by flow cytometry and utilized functional assays of NK-DC cross-talk to characterize the innate immune compartment in EU-IDU individuals. RESULTS: As previously reported, NK cell activation (CD69) and/or degranulation (CD107a) was significantly increased in EU-IDU individuals compared with control uninfected donors (P = 0.0056, n = 13). Genotypic analysis indicated that the frequency of protective KIR (KIR3DS1) and HLA-Bw4*80I ligands was not enriched in our cohort of EU-IDU individuals. Rather, plasmacytoid dendritic cells (PDC) from EU-IDU exhibited heightened maturation (CD83) compared with control uninfected donors (P = 0.0011, n = 12). When stimulated in vitro, both PDCs and NK cells from EU-IDU individuals maintained strong effector cell function and did not exhibit signs of exhaustion. CONCLUSION: Increased maturation of PDCs is associated with heightened NK activation in EU-IDU individuals suggesting that both members of the innate compartment may contribute to resistance from HIV-1 infection in EU-IDU.

Scale-dependence of Cope's rule in body size evolution of Paleozoic brachiopods.

The average body size of brachiopods from a single habitat type increased gradually by more than two orders of magnitude during their initial Cambrian-Devonian radiation. This increase occurred nearly in parallel across all major brachiopod clades (classes and orders) and is consistent with Cope's rule: the tendency for size to increase over geological time. The increase is not observed within small, constituent clades (represented here by families), which underwent random, unbiased size changes. This scale-dependence is caused by the preferential origination of new families possessing initially larger body sizes. However, this increased family body size does not confer advantages in terms of greater geological duration or genus richness over families possessing smaller body sizes. We suggest that the combination of size-biased origination of families and parallel size increases among major, more inclusive brachiopod clades from a single habitat type is best explained by long-term, secular environmental changes during the Paleozoic that provided opportunities for body size increases associated with major morphological evolution.