HIV type 1 (HIV-1) persists within resting CD4 + T cells despite antiretroviral therapy (ART). To better understand the kinetics by which resting cell infection (RCI) is established, we developed a mathematical model that accurately predicts (r = 0.65, P = 2.5 × 10 −4 ) the initial frequency of RCI measured about 1 year postinfection, based on the time of ART initiation and the dynamic changes in viremia and CD4 + T cells. In the largest cohort of patients treated during acute seronegative HIV infection (AHI) in whom RCI has been stringently quantified, we found that early ART reduced the generation of latently infected cells. Although RCI declined after the first year of ART in most acutely infected patients, there was a striking absence of decline when initial RCI frequency was less than 0.5 per million. Notably, low-level viremia was observed more frequently as RCI increased. Together these observations suggest that (i) the degree of RCI is directly related to the availability of CD4 + T cells susceptible to HIV, whether viremia is controlled by the immune response and/or ART; and (ii) that two pools of infected resting CD4 + T cells exist, namely, less stable cells, observable in patients in whom viremia is not well controlled in early infection, and extremely stable cells that are established despite early ART. These findings reinforce and extend the concept that new approaches will be needed to eradicate HIV infection, and, in particular, highlight the need to target the extremely small but universal, long-lived latent reservoir.HIV latency | viral kinetics

Host-associated microbial communities are shaped by extrinsic and intrinsic factors to the holobiont organism. Environmental factors and microbe-microbe interactions act simultaneously on the microbial community structure, making the microbiome dynamics challenging to predict. The coral microbiome is essential to the health of coral reefs and sensitive to environmental changes. Here, we develop a dynamic model to determine the microbial community structure associated with the surface mucus layer (SML) of corals using temperature as an extrinsic factor and microbial network as an intrinsic factor. The model was validated by comparing the predicted relative abundances of microbial taxa to the relative abundances of microbial taxa from the sample data. The SML microbiome from Pseudodiploria strigosa was collected across reef zones in Bermuda, where inner and outer reefs are exposed to distinct thermal profiles. A shotgun metagenomics approach was used to describe the taxonomic composition and the microbial network of the coral SML microbiome. By simulating the annual temperature fluctuations at each reef zone, the model output is statistically identical to the observed data. The model was further applied to six scenarios that combined different profiles of temperature and microbial network to investigate the influence of each of these two factors on the model accuracy. The SML microbiome was best predicted by model scenarios with the temperature profile that was closest to the local thermal environment, regardless of the microbial network profile. Our model shows that the SML microbiome of P. strigosa in Bermuda is primarily structured by seasonal fluctuations in temperature at a reef scale, while the microbial network is a secondary driver. IMPORTANCE Coral microbiome dysbiosis (i.e., shifts in the microbial community structure or complete loss of microbial symbionts) caused by environmental changes is a key player in the decline of coral health worldwide. Multiple factors in the water column and the surrounding biological community influence the dynamics of the coral microbiome. However, by including only temperature as an external factor, our model proved to be successful in describing the microbial community associated with the surface mucus layer (SML) of the coral P. strigosa. The dynamic model developed and validated in this study is a potential tool to predict the coral microbiome under different temperature conditions.

Study objective -To determine the prevalence of rheumatic heart disease (RHD) and study the relationship of this disease to factors such as age, sex, housing, and socioeconomic status in Shimla town and the adjoining rural area. Design -A cross sectional survey, carried out by a specially trained examiner in cardiology. Setting -The study involved high risk school children (5-16 years of age) from Shimla town and the adjoining rural area of Kasumpti-Suni Block in the period 1992-93.Subjects -A total of 15 080 children on the school register (8120 boys and 6960 girls) were examined generally and specifically for evidence of RHD. Main results -Of the 15 080 children screened, the prevalence of rheumatic fever (RF)/RHD was 2-98 per thousand with no significant difference between the age groups of 5-10 and 11-16 years or in either sex (p>0'05). The prevalence was significantly greater in rural schools (4-8/ 1000) than in urban schools (1 98/1000) (p<0.05). There was overcrowding and poor housing in most cases. There were fewer cases of RHD with severe valvular lesions in the younger age group than in the older children. The mitral valve was the valve most commonly affected by RFI RHD.Conclusions -RHD continues to be a serious health problem. Regular surveys are needed to identify cases early and to ensure secondary prophylaxis with penicillin is given thereby preventing recurrence of RF and progression ofthe severity of the valvular lesion. Echocardiography is necessary to identify cases ofRF/RHD. Strategies for preventing RHD should involve primary prevention to avert the first attack of carditis and strengthening of secondary prophylaxis through improved education and motivation of patients, parents, and physicians.

A recent experiment involving simian immunodeficiency virus (SIV) infection of macaques revealed that the infectivity of this virus decreased over the first few months of infection. Based on this observation, we introduce a viral dynamic model in which viral infectivity varies over time. The model is fit to viral load data from eight (donor) monkeys infected by intravaginal inoculation of SIVmac251, three monkeys infected by intravenous inoculation of virus isolated from the donors during the ramp-up phase of acute infection, and three monkeys infected by intravenous inoculation of virus isolated at the viral set-point. Although we only analyze data from 14 monkeys, the new model with time-dependent infectivity seems to fit the data significantly better than a widely used model with constant infectivity (P ‫؍‬ 2.44 ؋ 10 ؊11 ). Our results indicate that plasma virus infectivity on average decays ϳ8-fold (95% confidence interval [CI] ‫؍‬ 5.1 to 10.3) over the course of acute infection, with the decay occurring exponentially with an average rate of 0.28 day ؊1 (95% CI ‫؍‬ 0.14 to 0.42 day ؊1 ). The decay rate in set point plasma virus recipient animals is ϳ16 times slower than in ramp-up plasma virus recipient animals and ϳ6 times slower than in donor animals. Throughout acute infection up to the set-point, the infection rate is higher in ramp-up plasma virus recipient animals than in set-point plasma virus recipient animals. These results show that the infectivity depends upon the source of viral infection.During primary human immunodeficiency virus type 1 (HIV-1) infection, the number of virus particles in plasma increases rapidly, reaches a peak, and then declines until it reaches a set-point level (i.e., a quasi-steady state) (9, 43). During the first 1 to 3 weeks of a typical HIV infection the viral load remains below the limit of detection of conventional assays (12). This period, known as the eclipse phase, is followed by a 2-to 4-week ramp-up period, during which rapid (exponential) viral replication takes place, resulting in high plasma viral RNA levels and significant depletion of CCR5 ϩ CD4 ϩ T cells (12,24,31,47).A recent experiment indicates that the infectivity of SIV changes over time during primary infection (26). Ma et al. (26) infected macaques with SIV isolated either during ramp-up or at set-point. They found that early-stage plasma containing 20 SIV RNA copies could successfully infect animals, while with set-point plasma ϳ1,500 SIV RNA copies were needed to establish infection. As suggested by Ma et al. (26), the highly infectious virus during the early phase compared to the chronic phase could be due to (i) insufficient rounds of replication during the early phase to produce enough noninfectious viral genomes; (ii) coating of the set-point phase plasma virions with antibodies that interfere with infectivity; and/or (iii) efficient elimination during early-phase infection of less-infectious genomes. Preliminary data comparing the ratio of the 50% tissue culture infectious dose (TCID 50 ) wit...

An important question, of whether the initiation of HIV treatment during ongoing TB treatment for HIV-TB co-infected individuals is appropriate, still remains unanswered; initiating HIV treatment at or soon after the start of the TB treatment course has some advantages including fewer HIV-related deaths and a lower risk of HIV transmission as well as some disadvantages including occurrence of Immune Reconstitution Inflammatory Syndrome (IRIS) due to a high pill burden. In this study, we develop a mathematical model to explore the effects of early and late HIV treatment, during the TB treatment course, on new HIV infections, HIV-related deaths, and IRIS cases. Mathematical analyses of our model indicate that co-infection treatment programs alone cannot eradicate the diseases; additional interventions and/or treatments targeting individuals infected with a single disease are necessary for successful disease eradication. Numerical computations of the model solution demonstrate that outcomes of the treatment programs aiming to reduce the total burden of this co-infection depend highly on both the strength and initiation timing of antiretroviral therapy (ART). Based on our model, we also formulate an optimal control problem and solve it using Pontryagin's Maximum Principle and an efficient numerical iterative method. Our numerical results of an optimal HIV-TB treatment protocol that yields a minimum burden from this co-infection indicates that each of the new HIV infections, HIV-related deaths and IRIS cases is important for achieving optimal benefits from the co-infection treatment programs.

A co-epidemic arises when the spread of one infectious disease stimulates the spread of another infectious disease. Recently, this has happened with human immunodeficiency virus (HIV) and tuberculosis (TB). We develop two variants of a co-epidemic model of two diseases. We calculate the basic reproduction number (R(0)), the disease-free equilibrium, and the quasi-disease-free equilibria, which we define as the existence of one disease along with the complete eradication of the other disease, and the co-infection equilibria for specific conditions. We determine stability criteria for the disease-free and quasi-disease-free equilibria. We present an illustrative numerical analysis of the HIV-TB co-epidemics in India that we use to explore the effects of hypothetical prevention and treatment scenarios. Our numerical analysis demonstrates that exclusively treating HIV or TB may reduce the targeted epidemic, but can subsequently exacerbate the other epidemic. Our analyses suggest that coordinated treatment efforts that include highly active antiretroviral therapy for HIV, latent TB prophylaxis, and active TB treatment may be necessary to slow the HIV-TB co-epidemic. However, treatment alone may not be sufficient to eradicate both diseases. Increased disease prevention efforts (for example, those that promote condom use) may also be needed to extinguish this co-epidemic. Our simple model of two synergistic infectious disease epidemics illustrates the importance of including the effects of each disease on the transmission and progression of the other disease.

BackgroundBecause of limited work opportunities in Nepal and the open-border provision between Nepal and India, a seasonal labor migration of males from Far-Western Nepal to India is common. Unsafe sexual activities of these migrants in India, such as frequent visits to brothels, lead to a high HIV prevalence among them and to a potential transmission upon their return home to Nepal. The present study aims to evaluate the role of such seasonal labor-migration to India on HIV transmission in Far-Western Nepal and to assess prevention programs.MethodsAn HIV epidemic model was developed for a population in Far-Western Nepal. The model was fitted to the data to estimate the back and forth mobility rates of labor-migrants to India, the HIV prevalence among migrants and the HIV transmission rate in Far-Western Nepal. HIV prevalence, new infections, disease deaths and HIV infections recruited from India were calculated. Prevention programs targeting the general population and the migrants were evaluated.ResultsWithout any intervention programs, Far-Western Nepal will have about 7,000 HIV infected individuals returning from India by 2015, and 12,000 labor-migrants living with HIV in India. An increase of condom use among the general population from 39% to 80% will reduce new HIV infections due to sexual activity in Far-Western Nepal from 239 to 77. However, such a program loses its effectiveness due to the recruitment of HIV infections via returning migrants from India. The reduction of prevalence among migrants from 2.2% to 1.1% can bring general prevalence down to 0.4% with only 3,500 recruitments of HIV infections from India.ConclusionRecruitment of HIV infections from India via seasonal labor-migrants is the key factor contributing to the HIV epidemic in Far-Western Nepal. Prevention programs focused on the general population are ineffective. Our finding highlights the urgency of developing prevention programs which reduce the prevalence of HIV among migrants for a successful control of the HIV epidemic in Far-Western Nepal.

Cocaine, a commonly used drug of abuse, has been shown to cause neuropathological dysfunction and damage in the human brain. However, the role of autophagy in this process is not defined. Autophagy generally protective in nature, can also be destructive leading to autophagic cell death. This study was designed to investigate whether cocaine induces autophagy in the cells of CNS origin. We employed astrocyte, the most abundant cell in the CNS, to define the effects of cocaine on autophagy. We measured levels of the autophagic marker protein LC3II in SVGA astrocytes after exposure with cocaine. The results showed that cocaine caused an increase in LC3II level in a dose- and time-dependent manner, with the peak observed at 1 mM cocaine after 6 hours exposure. This result was also confirmed by detecting LC3II in SVGA astrocytes using confocal microscopy and transmission electron microscopy. Next, we sought to explore the mechanism by which cocaine induces the autophagic response. We found that cocaine-induced autophagy was mediated by sigma 1 receptor, and autophagy signaling proteins p-mTOR, Atg5, Atg7 and p-Bcl-2/Beclin-1 were also involved and this was confirmed by using selective inhibitors and siRNAs. In addition, we found that chronic treatment with cocaine resulted in cell death, which is caspase-3 independent, and can be ameliorated by autophagy inhibitor. Therefore, this study demonstrated that cocaine induces autophagy in astrocytes and is associated with autophagic cell death.