Bacterial Vaginosis Associated with Increased Risk of Female-to-Male HIV-1 Transmission: A Prospective Cohort Analysis among African Couples

Background

Bacterial vaginosis (BV), a disruption of the normal vaginal flora, has been associated with a 60% increased risk of HIV-1 acquisition in women and higher concentration of HIV-1 RNA in the genital tract of HIV-1–infected women. However, whether BV, which is present in up to half of African HIV-1–infected women, is associated with an increase in HIV-1 transmission to male partners has not been assessed in previous studies.

Methods and Findings

We assessed the association between BV on female-to-male HIV-1 transmission risk in a prospective study of 2,236 HIV-1–seropositive women and their HIV-1 uninfected male partners from seven African countries from a randomized placebo-controlled trial that enrolled heterosexual African adults who were seropositive for both HIV-1 and herpes simplex virus (HSV)-2, and their HIV-1–seronegative partners. Participants were followed for up to 24 months; every three months, vaginal swabs were obtained from female partners for Gram stain and male partners were tested for HIV-1. BV and normal vaginal flora were defined as a Nugent score of 7–10 and 0–3, respectively. To reduce misclassification, HIV-1 sequence analysis of viruses from seroconverters and their partners was performed to determine linkage of HIV-1 transmissions. Overall, 50 incident HIV-1 infections occurred in men in which the HIV-1–infected female partner had an evaluable vaginal Gram stain. HIV-1 incidence in men whose HIV-1–infected female partners had BV was 2.91 versus 0.76 per 100 person-years in men whose female partners had normal vaginal flora (hazard ratio 3.62, 95% CI 1.74–7.52). After controlling for sociodemographic factors, sexual behavior, male circumcision, sexually transmitted infections, pregnancy, and plasma HIV-1 RNA levels in female partners, BV was associated with a greater than 3-fold increased risk of female-to-male HIV-1 transmission (adjusted hazard ratio 3.17, 95% CI 1.37–7.33).

Conclusions

This study identified an association between BV and increased risk of HIV-1 transmission to male partners. Several limitations may affect the generalizability of our results including: all participants underwent couples HIV counseling and testing and enrolled in an HIV-1 prevention trial, and index participants had a baseline CD4 count ≥250 cells/mm³ and were HSV-2 seropositive. Given the high prevalence of BV and the association of BV with increased risk of both female HIV-1 acquisition and transmission found in our study, if this association proves to be causal, BV could be responsible for a substantial proportion of new HIV-1 infections in Africa. Normalization of vaginal flora in HIV-1–infected women could mitigate female-to-male HIV-1 transmission. Trial Registration: ClinicalTrials.com {"type":"clinical-trial","attrs":{"text":"NCT00194519","term_id":"NCT00194519"}}NCT00194519 Please see later in the article for the Editors'' Summary     

The Glycobiome of the Rumen Bacterium Butyrivibrio proteoclasticus B316T Highlights Adaptation to a Polysaccharide-Rich Environment

Determining the role of rumen microbes and their enzymes in plant polysaccharide breakdown is fundamental to understanding digestion and maximising productivity in ruminant animals. Butyrivibrio proteoclasticus B316^T is a Gram-positive, butyrate-forming rumen bacterium with a key role in plant polysaccharide degradation. The 4.4Mb genome consists of 4 replicons; a chromosome, a chromid and two megaplasmids. The chromid is the smallest reported for all bacteria, and the first identified from the phylum Firmicutes. B316 devotes a large proportion of its genome to the breakdown and reassembly of complex polysaccharides and has a highly developed glycobiome when compared to other sequenced bacteria. The secretion of a range of polysaccharide-degrading enzymes which initiate the breakdown of pectin, starch and xylan, a subtilisin family protease active against plant proteins, and diverse intracellular enzymes to break down oligosaccharides constitute the degradative capability of this organism. A prominent feature of the genome is the presence of multiple gene clusters predicted to be involved in polysaccharide biosynthesis. Metabolic reconstruction reveals the absence of an identifiable gene for enolase, a conserved enzyme of the glycolytic pathway. To our knowledge this is the first report of an organism lacking an enolase. Our analysis of the B316 genome shows how one organism can contribute to the multi-organism complex that rapidly breaks down plant material in the rumen. It can be concluded that B316, and similar organisms with broad polysaccharide-degrading capability, are well suited to being early colonizers and degraders of plant polysaccharides in the rumen environment.     

The application of phosphoramidate ProTide technology to the potent anti-HCV compound 4′-azidocytidine (R1479)

We report the design, synthesis and evaluation of a family of ca 50 phosphoramidate ProTides of the potent anti-HCV compound 4′-azidocytidine (R1479), with variation on the ester, amino acid and aryl moiety of the ProTide. Sub-μM inhibitors of HCV emerge. The compounds are all non-cytotoxic in the replicon assay. We herein report detailed SARs for each of the regions of the ProTide.     

Regional differences in prevalence of HIV-1 discordance in Africa and enrollment of HIV-1 discordant couples into an HIV-1 prevention trial

Background

Most HIV-1 transmission in Africa occurs among HIV-1-discordant couples (one partner HIV-1 infected and one uninfected) who are unaware of their discordant HIV-1 serostatus. Given the high HIV-1 incidence among HIV-1 discordant couples and to assess efficacy of interventions for reducing HIV-1 transmission, HIV-1 discordant couples represent a critical target population for HIV-1 prevention interventions and prevention trials. Substantial regional differences exist in HIV-1 prevalence in Africa, but regional differences in HIV-1 discordance among African couples, has not previously been reported.

Methodology/Principal Findings

The Partners in Prevention HSV-2/HIV-1 Transmission Trial (“Partners HSV-2 Study”), the first large HIV-1 prevention trial in Africa involving HIV-1 discordant couples, completed enrollment in May 2007. Partners HSV-2 Study recruitment data from 12 sites from East and Southern Africa were used to assess HIV-1 discordance among couples accessing couples HIV-1 counseling and testing, and to correlate with enrollment of HIV-1 discordant couples. HIV-1 discordance at Partners HSV-2 Study sites ranged from 8–31% of couples tested from the community. Across all study sites and, among all couples with one HIV-1 infected partner, almost half (49%) of couples were HIV-1 discordant. Site-specific monthly enrollment of HIV-1 discordant couples into the clinical trial was not directly associated with prevalence of HIV-1 discordance, but was modestly correlated with national HIV-1 counseling and testing rates and access to palliative care/basic health care (r = 0.74, p = 0.09).

Conclusions/Significance

HIV-1 discordant couples are a critical target for HIV-1 prevention in Africa. In addition to community prevalence of HIV-1 discordance, national infrastructure for HIV-1 testing and healthcare delivery and effective community outreach strategies impact recruitment of HIV-1 discordant couples into HIV-1 prevention trials.     

Molecular phylogeography of the Amazonian Chagas disease vectors Rhodnius prolixus and R. robustus

The phylogeographical structure of the closely related species Rhodnius prolixus and R. robustus is presented based on a 663-base pair (bp) fragment of the mitochondrial cytochrome b gene. Twenty haplotypes were recovered from 84 samples examined, representing 26 populations from seven Latin American countries. The resulting phylogenetic tree is composed of five major reciprocally monophyletic clades, one representing R. prolixus and four representing R. robustus. While R. prolixus is a very homogeneous assemblage, R. robustus has deeper clades and is paraphyletic, with the clade comprising R. robustus from Venezuela (Orinoco region) more closely related to the R. prolixus clade than to the other R. robustus populations from the Amazon region. The R. robustus paraphyly was supported further by the analysis of a nuclear gene (D2 region of the 28S RNA) for a subset of specimens. The data support the view that R. robustus represents a species complex. Levels of sequence divergence between clades within each region are compatible with a Pleistocene origin. Nucleotide diversity (pi) for all R. prolixus populations was extremely low (0.0008), suggesting that this species went through a recent bottleneck, and was subsequently dispersed by man.     

IRAK-2 participates in multiple toll-like receptor signaling pathways to NFkappaB via activation of TRAF6 ubiquitination

Toll-like receptor (TLR) signaling is known to involve interleukin-1 receptor-associated kinases (IRAKs), however the particular role of IRAK-2 has remained unclear. Further, although IRAK-1 was originally thought to be central for the TLR-NFkappaB signaling axis, recent data have shown that it is dispensable for NFkappaB activation for some TLRs and demonstrated an alternative role for it in interferon regulatory factor activation. Here we show that IRAK-2 is critical for the TLR-mediated NFkappaB activation pathway. The poxviral TLR antagonist A52 inhibited NFkappaB activation by TLR2, -3, -4, -5, -7, and -9 ligands, via its interaction with IRAK-2, while not affecting interferon regulatory factor activation. Knockdown of IRAK-2 expression by small interfering RNA suppressed TLR3, TLR4, and TLR8 signaling to NFkappaB in human cell lines, and importantly, TLR4-mediated chemokine production in primary human cells. IRAK-2 usage by different TLRs was distinct, because it acted downstream of the TLR adaptors MyD88 and Mal but upstream of TRIF. Expression of IRAK-2, but not IRAK-1, led to TRAF6 ubiquitination, an event critical for NFkappaB activation. Further, IRAK-2 loss-of-function mutants, which could not activate NFkappaB, were incapable of promoting TRAF6 ubiquitination. Thus we propose that IRAK-2 plays a more central role than IRAK-1 in TLR signaling to NFkappaB.     

The early‐life environment and individual plasticity in life‐history traits

We tested whether the early‐life environment can influence the extent of individual plasticity in a life‐history trait. We asked: can the early‐life environment explain why, in response to the same adult environmental cue, some individuals invest more than others in current reproduction? Moreover, can it additionally explain why investment in current reproduction trades off against survival in some individuals, but is positively correlated with survival in others? We addressed these questions using the burying beetle, which breeds on small carcasses and sometimes carries phoretic mites. These mites breed alongside the beetle, on the same resource, and are a key component of the beetle's early‐life environment. We exposed female beetles to mites twice during their lives: during their development as larvae and again as adults during their first reproductive event. We measured investment in current reproduction by quantifying average larval mass and recorded the female's life span after breeding to quantify survival. We found no effect of either developing or breeding alongside mites on female reproductive investment, nor on her life span, nor did developing alongside mites influence her size. In post hoc analyses, where we considered the effect of mite number (rather than their mere presence/absence) during the female's adult breeding event, we found that females invested more in current reproduction when exposed to greater mite densities during reproduction, but only if they had been exposed to mites during development as well. Otherwise, they invested less in larvae at greater mite densities. Furthermore, females that had developed with mites exhibited a trade‐off between investment in current reproduction and future survival, whereas these traits were positively correlated in females that had developed without mites. The early‐life environment thus generates individual variation in life‐history plasticity. We discuss whether this is because mites influence the resources available to developing young or serve as important environmental cues.     

The mammalian Golgi regulates numb signaling in asymmetric cell division by releasing ACBD3 during mitosis

Mammalian neural progenitor cells divide asymmetrically to self-renew and produce a neuron by segregating cytosolic Numb proteins primarily to one daughter cell. Numb signaling specifies progenitor over neuronal fates but, paradoxically, also promotes neuronal differentiation. Here we report that ACBD3 is a Numb partner in cell-fate specification. ACBD3 and Numb proteins interact through an essential Numb domain, and the respective loss- and gain-of-function mutant mice share phenotypic similarities. Interestingly, ACBD3 associates with the Golgi apparatus in neurons and interphase progenitor cells but becomes cytosolic after Golgi fragmentation during mitosis, when Numb activity is needed to distinguish the two daughter cells. Accordingly, cytosolic ACBD3 can act synergistically with Numb to specify cell fates, and its continuing presence during the progenitor cell cycle inhibits neuron production. We propose that Golgi fragmentation and reconstitution during cell cycle differentially regulate Numb signaling through changes in ACBD3 subcellular distribution and represent a mechanism for coupling cell-fate specification and cell-cycle progression.     

Synthesis and characterisation of phenanthroline-oxazine ligands and their Ag(I), Mn(II) and Cu(II) complexes and their evaluation as antibacterial agents

BioMetals - A series of phenanthroline-oxazine ligands were formed by a cyclisation reaction between L-tyrosine amino acid esters and 1,10-phenanthroline-5,6-dione (phendione). The methyl...