No abstract

ABSTRACT

PSC-RANTES binds to CCR5, inhibits human immunodeficiency virus type 1 (HIV-1) entry, and has been shown as a vaginal microbicide to protect rhesus macaques from a simian-human immunodeficiency virus chimera (SHIV SF162-p3 ) infection in a dose-dependent manner. In this study, env gene sequences from SHIV SF162-p3 -infected rhesus macaques treated with PSC-RANTES were analyzed for possible drug escape variants. Two specific mutations located in the V3 region of gp120 (K315R) and C-helical domain of gp41 (N640D) were identified in a macaque (m584) pretreated with a 100 M dose of PSC-RANTES. These two env mutations were found throughout infection (through week 77) but were found at only low frequencies in the inoculating SHIV SF162-p3 stock and in the other SHIV SF162-p3 -infected macaques. HIV-1 env genes from macaque m584 (env m584 ) and from inoculating SHIV SF162-p3 (env p3 ) were cloned into an HIV-1 backbone. Increases in 50% inhibitory concentrations to PSC-RANTES with env m584 were modest (sevenfold) and most pronounced in cells expressing rhesus macaque CCR5 as compared to human CCR5. Nonetheless, virus harboring env m584 , unlike inoculating virus env p3, could replicate even at the highest tissue culture PSC-RANTES concentrations (100 nM). Dual-virus competitions revealed a dramatic increase in fitness of chimeric virus containing env m584 (K315R/N640D) over that containing env p3 , but again, only in rhesus CCR5-expressing cells. This study is the first to describe the immediate selection and infection of a drug-resistant SHIV variant in the face of a protective vaginal microbicide, PSC-RANTES. This rhesus CCR5-specific/PSC-RANTES resistance selection is particularly alarming given the relative homogeneity of the SHIV SF162-p3 stock compared to the potential exposure to a heterogeneous HIV-1 population in human transmission.

These data support that CRSwNP and CRSsNP display alterations in systemic immune profiles. CRSwNP is characterized by significant elevations in circulating moDCs, which is associated with systemic Th2-biased inflammation. Circulating moDCs are associated with mucosal inflammation on CT imaging in CRSsNP. No association between moDCs and QoL is evident in either CRS subset.

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Conclusions are limited by the paucity of available data on the efficacy of IT for treating CRS-specific outcome measures. There is weak evidence to support the use of IT as an adjunctive treatment in CRS patients, particularly in the postoperative period.

The SN-5 tool provides a quick, safe, and reliable qualitative metric for monitoring sinonasal symptoms in young children with CF.

There is no clear evidence of avoidance of passive smoke exposure in the CRS population compared with controls. Passive smoke exposure also remained stable over time despite recent regional implementation of smoking bans. Given the constancy of exposure, it is critical that the impact of passive smoke on CRS exacerbation, outcomes, and pathophysiology be evaluated in large-scale clinical studies.