Understanding the role of cytotoxic T lymphocytes (CTLs) in controlling HIV-1 infection is vital for vaccine design. However, it is difficult to assess the importance of CTLs in natural infection. Different human leukocyte antigen (HLA) class I alleles are associated with different rates of progression to AIDS, indicating that CTLs play a protective role. Yet virus clearance rates following antiretroviral therapy are not impaired in individuals with advanced HIV disease, suggesting that weakening of the CTL response is not the major underlying cause of disease progression and that CTLs do not have an important protective role. Here we reconcile these apparently conflicting studies. We estimate the selection pressure exerted by CTL responses that drive the emergence of immune escape variants, thereby directly quantifying the efficiency of HIV-1–specific CTLs in vivo. We estimate that only 2% of productively infected CD4 + cell death is attributable to CTLs recognising a single epitope. We suggest that CTLs kill a large number of infected cells (about 10 7) per day but are not responsible for the majority of infected cell death.

Human immunodeficiency virus (HIV)-1 amino acid sequence polymorphisms associated with expression of specific human histocompatibility leukocyte antigen (HLA) class I alleles suggest sites of cytotoxic T lymphocyte (CTL)-mediated selection pressure and immune escape. The associations most frequently observed are between expression of an HLA class I molecule and variation from the consensus sequence. However, a substantial number of sites have been identified in which particular HLA class I allele expression is associated with preservation of the consensus sequence. The mechanism behind this is so far unexplained. The current studies, focusing on two examples of “negatively associated” or apparently preserved epitopes, suggest an explanation for this phenomenon: negative associations can arise as a result of positive selection of an escape mutation, which is stable on transmission and therefore accumulates in the population to the point at which it defines the consensus sequence. Such negative associations may only be in evidence transiently, because the statistical power to detect them diminishes as the mutations accumulate. If an escape variant reaches fixation in the population, the epitope will be lost as a potential target to the immune system. These data help to explain how HIV is evolving at a population level. Understanding the direction of HIV evolution has important implications for vaccine development.

Lion (Panthera leo) populations are in decline throughout most of Africa. The problem is particularly acute in southern Kenya, where Maasai pastoralists have been spearing and poisoning lions at a rate that will ensure near term local extinction. We investigated 2 approaches for improving local tolerance of lions: compensation payments for livestock lost to predators and Lion Guardians, which draws on local cultural values and knowledge to mitigate livestock-carnivore conflict and monitor carnivores. To gauge the overall influence of conservation intervention, we combined both programs into a single conservation treatment variable. Using 8 years of lion killing data, we applied Manski's partial identification approach with bounded assumptions to investigate the effect of conservation treatment on lion killing in 4 contiguous areas. In 3 of the areas, conservation treatment was positively associated with a reduction in lion killing. We then applied a generalized linear model to assess the relative efficacy of the 2 interventions. The model estimated that compensation resulted in an 87-91% drop in the number of lions killed, whereas Lion Guardians (operating in combination with compensation and alone) resulted in a 99% drop in lion killing.

The evolution of the human immunodeficiency virus (HIV-1) during chronic infection involves the rapid, continuous turnover of genetic diversity. However, the role of natural selection, relative to random genetic drift, in governing this process is unclear. We tested a stochastic model of genetic drift using partial envelope sequences sampled longitudinally in 28 infected children. In each case the Bayesian posterior (empirical) distribution of coalescent genealogies was estimated using Markov chain Monte Carlo methods. Posterior predictive simulation was then used to generate a null distribution of genealogies assuming neutrality, with the null and empirical distributions compared using four genealogy-based summary statistics sensitive to nonneutral evolution. Because both null and empirical distributions were generated within a coalescent framework, we were able to explicitly account for the confounding influence of demography. From the distribution of corrected P-values across patients, we conclude that empirical genealogies are more asymmetric than expected if evolution is driven by mutation and genetic drift only, with an excess of lowfrequency polymorphisms in the population. This indicates that although drift may still play an important role, natural selection has a strong influence on the evolution of HIV-1 envelope. A negative relationship between effective population size and substitution rate indicates that as the efficacy of selection increases, a smaller proportion of mutations approach fixation in the population. This suggests the presence of deleterious mutations. We therefore conclude that intrahost HIV-1 evolution in envelope is dominated by purifying selection against low-frequency deleterious mutations that do not reach fixation.

BackgroundGenetic diversity of the human immunodeficiency virus type 1 (HIV-1) population within an individual is lost during transmission to a new host. The demography of transmission is an important determinant of evolutionary dynamics, particularly the relative impact of natural selection and genetic drift immediately following HIV-1 infection. Despite this, the magnitude of this population bottleneck is unclear.ResultsWe use coalescent methods to quantify the bottleneck in a single case of homosexual transmission and find that over 99% of the env and gag diversity present in the donor is lost. This was consistent with the diversity present at seroconversion in nine other horizontally infected individuals. Furthermore, we estimated viral diversity at birth in 27 infants infected through vertical transmission and found there to be no difference between the two modes of transmission.ConclusionAssuming the bottleneck at transmission is selectively neutral, such a severe reduction in genetic diversity has important implications for adaptation in HIV-1, since beneficial mutations have a reduced chance of transmission.

The outcome of human immunodeficiency virus type 1 (HIV-1) infection is related to the set-point plasma virus load (pVL) that emerges after primary HIV-1 infection (PHI). This set-point pVL generally remains stable but eventually increases with progression to disease. However, the events leading to loss of viremic control are poorly understood. Here, we describe an individual who presented with symptomatic PHI and subsequently progressed rapidly, after an initial period of 1 year during which viral replication was well controlled. Escalation of viral replication in this atypical case was preceded by the emergence of escape variants in many epitopes targeted by dominant CD8 + T cell responses and a marked decrease in HIV-1-specific CD4 + and CD8 + T cell frequencies. There were no changes in viral tropism, replication kinetics, or neutralizing antibody titers. These findings demonstrate the temporal relationship between viral escape from CD8 + T cell activity, decrease in HIV-1-specific T cell frequencies, and loss of control of viral replication.Substantial evidence indicates that the adaptive immune system plays a major role in containing viral replication during HIV-1 infection [1,2]. In particular, HIV-1-specific CD8 + T cell responses are thought to mediate the decrease in the initial viremia during primary HIV-1 infection (PHI) [3,4]. After PHI, a setpoint plasma virus load (pVL) emerges that, in general, remains relatively stable throughout the chronic asymptomatic phase of infection. The magnitude of this setpoint pVL, which is likely determined by early interactions between the virus and the immune system, is inversely related to the rate of progression to AIDS [5]. However, the factors that are responsible for the maintenance of the established set-point pVL are less well defined, and it is not clear which events eventually lead to loss of control of viremia. Identification of such events requires longitudinal and comprehensive analysis of adaptive immune responses and viral evolution in patients with untreated HIV-1 infection.Here, we studied the natural course of HIV-1 infection over a period of 2 years in an individual who presented with symptomatic PHI. Initially, viral replication

On 1 and 2 June 2010, an international meeting was held at the University of Paris Sud XI, France, organized within the framework of the EU FP7 consortium project HUNT, to bring together fisheries and conservation scientists to discuss a unified framework for the future of management strategies for harvested species.

Novel features associated with multiterawatt laser interactions with solid targets at incident irradiances in the range (1. 0-12.0) X 10' W cm are presented. Collimation of the plasma How normal to the target surface has been observed in time-integrated x-ray images and ion-velocity measurements. Ions emitted from the target have a characteristic energy of typically 100 keV. The ion spectrum extends to 1.5 MeV. Calculations are presented that suggest the observed collimation is due to a large magnetic field pinching the plasma.