In humans, Streptococcus pneumoniae (SPN) is the leading cause of bacterial meningitis, a disease with high attributable mortality and frequent permanent neurological sequelae. The molecular mechanisms underlying the central nervous system tropism of SPN are incompletely understood, but include a primary interaction of the pathogen with the blood–brain barrier (BBB) endothelium. All SPN strains possess a gene encoding the surface-anchored sialidase (neuraminidase) NanA, which cleaves sialic acid on host cells and proteins. Here, we use an isogenic SPN NanA-deficient mutant and heterologous expression of the protein to show that NanA is both necessary and sufficient to promote SPN adherence to and invasion of human brain microvascular endothelial cells (hBMECs). NanA-mediated hBMEC invasion depends only partially on sialidase activity, whereas the N-terminal lectinlike domain of the protein plays a critical role. NanA promotes SPN–BBB interaction in a murine infection model, identifying the protein as proximal mediator of CNS entry by the pathogen.

HIV drug resistance acquired through superinfection significantly lowers the likelihood of successful antiretroviral therapy and undermines the clinical value of a patient's prior drug resistance testing and lack of prior antiretroviral use.

Background. Transmitted drug-resistant HIV slowly reverts in the blood to drug-sensitive virus. The environment of the male genital tract (MGT) may result in even slower rates of reversion to drug susceptibility.Methods. We measured the decay of resistance in longitudinally collected blood and semen samples from 5 individuals newly infected with HIV containing resistance mutations to nonnucleoside reverse-transcriptase inhibitors (NNRTIs). We also investigated the sexual transmission of HIV to and from these participants.Results. In 3 of the 5 individuals, NNRTI resistance persisted in blood and semen throughout follow-up (mean, 296 days after the estimated day of infection [EDI]). In the other 2 individuals, NNRTI resistance persisted in blood and semen for 871 and 1179 days after the EDI; however, even after NNRTI resistance had fully reverted in blood, it remained readily detectable in semen. Two transmission groups were identified among these participants-one as the recipient partner and the other as the source partner.Conclusions. Transmitted drug-resistant HIV, which persists in blood for years, may revert to wild type even more slowly in the MGT. This prolonged persistence in the MGT may contribute to the high prevalence rates of transmitted drug resistance.

ObjectiveCharacterize intra-individual HIV-1 subtype B pol evolution in antiretroviral naive individuals.DesignLongitudinal cohort study of individuals enrolled during primary infection.MethodsEligible individuals were antiretroviral naïve participants enrolled in the cohort from December 1997-December 2005 and having at least two blood samples available with the first one collected within a year of their estimated date of infection. Population-based pol sequences were generated from collected blood samples and analyzed for genetic divergence over time in respect to dual infection status, HLA, CD4 count and viral load.Results93 participants were observed for a median of 1.8 years (Mean = 2.2 years, SD = 1.9 years). All participants classified as mono-infected had less than 0.7% divergence between any two of their pol sequences using the Tamura-Nei model (TN93), while individuals with dual infection had up to 7.0% divergence. The global substitution rates (substitutions/nucleotide/year) for mono and dually infected individuals were significantly different (p<0.001); however, substitution rates were not associated with HLA haplotype, CD4 or viral load.ConclusionsEven after a maximum of almost 9 years of follow-up, all mono-infected participants had less than 1% divergence between baseline and longitudinal sequences, while participants with dual infection had 10 times greater divergence. These data support the use of HIV-1 pol sequence data to evaluate transmission events, networks and HIV-1 dual infection.