Characteristics of HIV-1 Discordant Couples Enrolled in a Trial of HSV-2 Suppression to Reduce HIV-1 Transmission: The Partners Study

Background: The Partners HSV-2/HIV-1 Transmission Study (Partners Study) is a phase III, placebo-controlled trial of daily acyclovir for genital herpes (HSV-2) suppression among HIV-1/HSV-2 co-infected persons to reduce HIV-1 transmission to their HIV-1 susceptible partners, which requires recruitment of HIV-1 serodiscordant heterosexual couples. We describe the baseline characteristics of this cohort. Methods: HIV-1 serodiscordant heterosexual couples, in which the HIV-1 infected partner was HSV-2 seropositive, had a CD4 count ≥250 cells/mcL and was not on antiretroviral therapy, were enrolled at 14 sites in East and Southern Africa. Demographic, behavioral, clinical and laboratory characteristics were assessed. Results: Of the 3408 HIV-1 serodiscordant couples enrolled, 67% of the HIV-1 infected partners were women. Couples had cohabitated for a median of 5 years (range 2–9) with 28% reporting unprotected sex in the month prior to enrollment. Among HIV-1 susceptible participants, 86% of women and 59% of men were HSV-2 seropositive. Other laboratory-diagnosed sexually transmitted infections were uncommon (500 relative to <350, respectively, p<0.001). Conclusions: The Partners Study successfully enrolled a cohort of 3408 heterosexual HIV-1 serodiscordant couples in Africa at high risk for HIV-1 transmission. Follow-up of this cohort will evaluate the efficacy of acyclovir for HSV-2 suppression in preventing HIV-1 transmission and provide insights into biological and behavioral factors determining heterosexual HIV-1 transmission. Trial Registration ClinicalTrials.gov NCT0019451

Effect of nano-confinement on the kinetics of an interfacial click chemistry reaction

In semiconductor manufacturing of 3-D nano-transistors, modified kinetics have been encountered for the aqueous chemical etching of thin films in 1-D and 2-D nano-confined volumes, either delayed or accelerated [1,2]. Deviations from kinetics observed on planar substrates were attributed to the overlap of electrostatic double layers (EDL) on opposite walls and the consequent depletion or enrichment of reactive ions in the nano-space. These explanations stem from studies on nanofluidic systems, where however electrostatic effects cannot explain all observations [3]. The study of the mechanisms in play in the etching of thin films is hampered by the complexity of the reaction schemes. On the other hand, biorthogonal click chemistry provides kinetically simple reactions in aqueous solutions, which are also being used in the binding of biological molecules such as DNA to the active surface of biosensors. In this last purpose, the surface is covered with a SAM ending with one of the reactants. Reactions at the surface of highly organized monomolecular layers, such as SAMs, are typically retarded compared to those in solution [4]. In nanofluidic devices, kinetics will be affected by both the confinement in the SAM and in the nano-channels. We studied the cycloaddition of dibenzylcyclooctyne-PEG3-alcohol (DBCO) to a linear azide-terminated SAM in ultra-pure water, a second order strain-promoted azide-alkyne click chemistry reaction with no side reaction when performed in solution. Kinetics were monitored in-situ using ATR-FTIR. For this purpose, double-side polished silicon wafers without and with 320nm deep nanochannels of varying width (32-64nm) were cleaved and polished to make ATR crystals that were mounted in a flow cell [5]. The cycloaddition in presence of an excess DBCO could be described as a pseudo-first-order reaction in all cases, in agreement with literature on similar reactions in solution [6,7]. However, the rate constant for the reaction with the SAM was higher by about 3 orders of magnitude compared to those of similar reactions in solution [6,7]. The interactions of the rather hydrophobic SAM surface (water contact angle of 84°) with the hydrophobic head of the DBCO molecule, together with the orientation of the azide groups at the surface of the SAM were likely responsible for the faster reaction with the DBCO molecule. On the other hand, the rate constant for the SAM in the nanochannels was about 4 times smaller than that for the planar surface. Here an explanation was sought in the overlap of the EDLs of the polarized SAM surfaces and its influence on the orientation of the polar-tailed DBCO molecule inside the channels. In support of this interpretation, changes in electrical potential inside the channels were probed using pH measurements with fluorescein, as described in [8].status: publishe

Effect of 1-D Nano-Confinement on the Kinetics of a Click-Chemistry Surface Reaction Used in Biosensors

© 2018 Trans Tech Publications, Switzerland. In semiconductor manufacturing of 3-D nano-structures, modified kinetics have been encountered for the aqueous chemical etching of thin films in nano-confined spaces. A popular explanation relies on changes in reactant concentration from the overlap of electrostatic double layers (EDL) on opposite walls of the nano-structures. In this study, the cycloaddition of dibenzylcyclooctyne-PEG3-alcohol (DBCO) to a linear azide-terminated SAM was performed in nanochannels of width varying from 62 to 32 nm. ATR-FTIR was used to monitor the reaction kinetics, characterize water structuring and determine the pH in nanochannels. Reaction kinetics were slower in nanochannels as compared to a planar surface, while pH shifts were observed in absence of EDL overlap, with a significant influence of channel width. Actually only the overall decrease in reaction rate could be explained by EDL overlap. The discussion shows that the water structuring measured in nanochannels may play a significant role in the observed phenomena.status: publishe

Correction: Whole genome sequencing of extreme phenotypes identifies variants in CD101 and UBE2V1 associated with increased risk of sexually acquired HIV-1.

[This corrects the article DOI: 10.1371/journal.ppat.1006703.]

Whole genome sequencing of extreme phenotypes identifies variants in CD101 and UBE2V1 associated with increased risk of sexually acquired HIV-1.

Host genetic variation modifying HIV-1 acquisition risk can inform development of HIV-1 prevention strategies. However, associations between rare or intermediate-frequency variants and HIV-1 acquisition are not well studied. We tested for the association between variation in genic regions and extreme HIV-1 acquisition phenotypes in 100 sub-Saharan Africans with whole genome sequencing data. Missense variants in immunoglobulin-like regions of CD101 and, among women, one missense/5' UTR variant in UBE2V1, were associated with increased HIV-1 acquisition risk (p = 1.9x10-4 and p = 3.7x10-3, respectively, for replication). Both of these genes are known to impact host inflammatory pathways. Effect sizes increased with exposure to HIV-1 after adjusting for the independent effect of increasing exposure on acquisition risk.Trial registrationClinicalTrials.gov NCT00194519; NCT00557245

Effect of Condom Use on Per-act HSV-2 Transmission Risk in HIV-1, HSV-2-discordant Couples.

BACKGROUND: The efficacy of condoms for protection against transmission of herpes simplex virus type 2 (HSV-2) has been examined in a variety of populations with different effect measures. Often the efficacy has been assessed as change in hazard of transmission with consistent vs inconsistent use, independent of the number of acts. Condom efficacy has not previously measured on a per-act basis. METHODS: We examined the per-act HSV-2 transmission rates with and without condom use among 911 African HSV-2 and human immunodeficiency virus type 1 (HIV-1) serodiscordant couples followed for an average of 18 months in an HIV prevention study. Infectivity models were used to associate the log10 probability of HSV-2 transmission over monthly risk periods with reported numbers of protected and unprotected sex acts. Condom efficacy was computed as the proportionate reduction in transmission risk for protected relative to unprotected sex acts. RESULTS: Transmission of HSV-2 occurred in 68 couples, including 17 with susceptible women and 51 with susceptible men. The highest rate of transmission was from men to women: 28.5 transmissions per 1000 unprotected sex acts. We found that condoms were differentially protective against HSV-2 transmission by sex; condom use reduced per-act risk of transmission from men to women by 96% (P < .001) and marginally from women to men by 65% (P = .060). CONCLUSIONS: Condoms are recommended as an effective preventive method for heterosexual transmission of HSV-2

Dose-response models (protection index (PI) × genetic variant interaction models) using the augmented sample.

<p>Dose-response models (protection index (PI) × genetic variant interaction models) using the augmented sample.</p