Can herpes simplex virus type 2 suppression slow HIV disease progression: a study protocol for the VALacyclovir In Delaying Antiretroviral Treatment Entry (VALIDATE) trial

<p>Abstract</p> <p>Background</p> <p>Although highly active antiretroviral therapy (HAART) has dramatically decreased HIV-related morbidity and mortality, the associated costs, toxicities, and resistance risks make the potential delay of HAART initiation an attractive goal. Suppression of herpes simplex virus type 2 (HSV-2) may be a novel strategy for achieving this goal because HSV-2 is associated with clinically significant increases in HIV viral load, the primary driver of HIV disease progression.</p> <p>Methods/Design</p> <p>The VALacyclovir In Delaying Antiretroviral Treatment Entry (VALIDATE) trial is a multicentre, randomized, fully blinded, clinical trial of twice daily valacyclovir 500 mg versus placebo for delaying the need for initiating HAART among HIV-1, HSV-2 co-infected HAART-naïve adults. 480 participants from Canada, Brazil and Argentina will undergo quarterly clinical follow-up until reaching the composite primary endpoint of having a CD4+ T-cell count ≤ 350 cells/mm³or initiation of HAART for any reason, whichever occurs first. The primary analysis will use a proportional hazards model, stratified by site, to estimate the relative risk of progression to this endpoint associated with valacyclovir. Secondary analyses will compare the rates of change in CD4 count, median log₁₀HIV viral load, drug-related adverse events, frequency of HSV reactivations, rate of acyclovir-resistant HSV, and quality of life between study arms.</p> <p>Discussion</p> <p>Although HIV treatment guidelines continue to evolve, with some authorities recommending earlier HAART among asymptomatic individuals, the potential delay of HAART remains a clinically relevant goal for many. If shown to be of benefit, implementation of the VALIDATE intervention will require careful consideration of both individual patient-level and public health implications.</p> <p>Trial Registration</p> <p>Current Controlled Trials ISRCTN66756285</p> <p>ClinicalTrials.gov NCT00860977</p

Early Life Events Carry Over to Influence Pre-Migratory Condition in a Free-Living Songbird

Conditions experienced during development can have long-term consequences for individual success. In migratory songbirds, the proximate mechanisms linking early life events and survival are not well understood because tracking individuals across stages of the annual cycle can be extremely challenging. In this paper, we first use a 13 year dataset to demonstrate a positive relationship between 1st year survival and nestling mass in migratory Savannah sparrows (Passerculus sandwichensis). We also use a brood manipulation experiment to show that nestlings from smaller broods have higher mass in the nest relative to individuals from larger broods. Having established these relationships, we then use three years of field data involving multiple captures of individuals throughout the pre-migratory period and a multi-level path model to examine the hypothesis that conditions during development limit survival during migration by affecting an individual's ability to accumulate sufficient lean tissue and fat mass prior to migration. We found a positive relationship between fat mass during the pre-migratory period (Sept–Oct) and nestling mass and a negative indirect relationship between pre-migratory fat mass and fledging date. Our results provide the first evidence that conditions during development limit survival during migration through their effect on fat stores. These results are particularly important given recent evidence showing that body condition of songbirds at fledging is affected by climate change and anthropogenic changes to landscape structure

DNA Fingerprinting Reveals Female Preference for Male Parental Care in Savannah Sparrows

According to sexual selection theory, females choose mates to ensure access to high quality resources, male parental care, or good genes. This last hypothesis has been hotly debated on both theoretical and empirical grounds. In contrast, female preference for male parental care has received less attention, primarily because the potential benefits of paternal effort seem obvious. The fitness relations are less clear in double-brood species, however, because females can base mating decisions on their prior experience with male parental care. Here, the extent of male parental care delivered to first-brood offspring may indicate male genetic quality and/or be the target of female manipulation via her subsequent mating fidelity. In Savannah Sparrows (Passerculus sandwichensis), multi-locus DNA fingerprinting of 203 adults and young revealed substantial female infidelity in first and second broods: overall, 24 of 80 first-brood young (30%) and 13 of 80 second-brood young (16.3%) were the product of extra-pair fertilizations. Among 12 females altering fidelity between broods, absolute male feeding rate to first-brood offspring was a strong, positive predictor of change in female fidelity. Because the extent of male parental care reflects a male\u27s viability, the data support a \u27good-genes\u27 interpretation

Microgeographic Patterns of Genetic and Morphological Variation in Savannah Sparrows (Passerculus sandwichensis)

Surveys of genetic population structure are often limited to large geographic scales because geographically close populations are indistinguishable. Genetic uniformity across adjacent demes can be interpreted as evidence for cohesion (panmixia) or recent divergence. However, poor genetic resolution at microgeographic scales can also arise from the use of overly conservative (slowly evolving) markers. This study examines the ability of hypervariable, minisatellite loci to discriminate among geographically close populations of Savannah sparrows (Passerculus sandwichensis) and to track morphological differentiation at a microgeographic scale (interregional distance \u3c 55 km). Savannah sparrows breeding at five island and two mainland sites in the Bay of Fundy, New Brunswick, Canada, show concordant patterns of variation in external morphology (seven characters) and multilocus DNA fingerprinting profiles (S,y): island sparrows are phenotypically larger and genetically more similar to each other than they are to mainland sparrows. This pattern of variation is consistent with both adaptive (natural selection) and nonadaptive (genetic drift) mechanisms of population divergence. Based on minisatellite diversity, the effective size of both island and mainland populations is 37, an estimate substantially lower than census population sizes. These data are discordant with observations of sparrow vagility and abundance and suggest a closer examination of microgeographic patterns in avian systems

Extra-pair paternity in monogamous and polygynous Savannah sparrows

Extra-pair paternity can influence mating systems by affecting the fitness costs associated with polygyny. Polygyny is disadvantageous to males when the time and energetic demands of multiple pairings decrease either a male\u27s success at gaining extra-pair fertilizations or his ability to ensure paternity among harem members. In Savannah sparrows,Passerculus sandwichensison Kent Island, New Brunswick, Canada, multilocus DNA fingerprinting of 136 adults and young revealed substantial female infidelity: overall, 31 of 92 young (33.7%) in 15 of 24 nests (62.5%) were the product of extra-pair fertilizations. Male mating status was a strong predictor of paternity. Each of seven monogamous females produced at least one extra-pair offspring, but only six of 11 primary females (54.5%) and two of six secondary females (33.3%) were unfaithful. As a result, nearly 80% of the young in nests of polygynous males resulted from within-pair fertilizations, compared with only 40% of the young in nests of monogamous males. Kent Island Savannah sparrows are simultaneously polygynous, and the absence of paternity costs associated with polygyny is surprising. The observed pattern of paternity suggests the operation of female choice, although male control of parentage cannot be excluded. Extra-pair paternity in monogamous and polygynous Savannah sparrows, Passerculus sandwichensis - ResearchGate. Available from: http://www.researchgate.net/publication/248591455_Extra-pair_paternity_in_monogamous_and_polygynous_Savannah_sparrows_Passerculus_sandwichensis [accessed Sep 30, 2015]

Fitness Consequences of Male Parental Care in Savannah Sparrows

The fitness consequences of male parental care are central to life-history models of reproductive effort and the evolution of social and genetic mating system However in a 4-year study (1992–1995) of Savannah sparrows (Parsserculs sandwichensis) nesting on Kent Island, New Brunswick, Canada, male parental care during the nestling stage was only weakly related to offspring quality and survivorship. Females compensated for poor paternal performance by elevating their feeding rates, and they thus ameliorated selection on male parental care. The likelihood and size of subsequent broods was also unrelated to male feeding effort, suggesting the absence of some indirect (or ‘female-mediated’) benefits. These results were confirmed by an experiment in which male removal resulted in increased female feeding rates but had little effect on the number or quality of young. In contrast, previous research with multilocus DNA fingerpnnting revealed a strong, positive relationship between a male\u27s parental effort and his subsequent fertilization success. Together, this research suggests that the proximate and ultimate targets of male feeding effort can be disiinct traditional assumptions regarding the function of male parental care in birds may therefore be incomplete

An Experimental Test of the Testosterone Mediated Oxidation Handicap Hypothesis in a Wild Bird

The oxidation handicap hypothesis (OHH) proposed that honesty in sexual signals is maintained when testosterone simultaneously promotes the development of elaborate signals and imposes an oxidative cost. Although there is evidence that testosterone enhances display traits in some cases, relatively few studies have tested the prediction that testosterone generates oxidative costs. We tested this prediction experimentally by administering testosterone (n=14) and control (n=14) implants to free-living common yellowthroat warblers (Geothlypis trichas) and quantifying testosterone and oxidative state before and 35±15days after implantation. We interpreted our experimental results in the context of a larger database of 83 unmanipulated males observed over five breeding seasons. In our observational data, testosterone was related to aspects of the carotenoid-based bib, but these relationships were age-dependent. Bib coloration was related to testosterone only for first time breeders, while bib size was positively and negatively associated with testosterone among experienced and inexperienced breeders, respectively. Two measures of oxidative metabolism-damage to DNA and total antioxidant capacity (TAC)-were unrelated to endogenous testosterone. Despite the correlation between endogenous testosterone and plumage, our experimental results failed to support the key prediction of the OHH. Testosterone treated males had higher levels of TAC upon recapture, but oxidative damage to DNA did not differ from controls. Because antioxidants can protect against the harmful effects of oxidative stress, one interpretation of our results is that males physiologically compensated for elevated testosterone, avoiding the honesty enforcing mechanism of the OHH. Taken together, our results suggest that testosterone is not a direct mediator of honest signaling in yellowthroats via its effects on oxidative stress

Data from: Age and infection history are revealed by different ornaments in a warbler

Female preference for older or more disease-resistant males are both possible outcomes of parasite-mediated sexual selection, but the extent to which infection alters the development of ornaments to yield signals of male age and health has rarely been explored. In a longitudinal study of 61 male common yellowthroats (Geothlypis trichas), age-related increases in the size of the melanin-based mask and carotenoid-based bib were not correlated among young males, likely owing to differences in how blood parasites affect ornament development. Infection with trypanosomes and hemosporidians in a male’s first breeding season was associated with slower growth of the mask; uninfected males attained large masks in their second breeding season, while infected males attained large masks in their third breeding season. In contrast, the bib size of males increased every year regardless of infection. As a consequence, different populations of males are identified by the largest ornaments – older males in the case of bib and a combination of older males and young, uninfected males in the case of mask. Although mask is thus the more informative trait with respect to male health, females prefer large bibs in our population. If infection is opportunistic, young, uninfected males may not possess good genes for parasite resistance but simply good luck, and it may benefit females to prefer older males who are more likely to have withstood prior episodes of selection. A “pure” signal of age may be a more reliable signal of resistance to parasites than an ornament whose expression is modulated by infection