Naveen K. Vaidya

Immediate antiviral therapy appears to restrict resting CD4+ cell HIV-1 infection without accelerating the decay of latent infection

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.

Controlling Co-Epidemics: Analysis of HIV and Tuberculosis Infection Dynamics

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.

Viral Dynamics during Primary Simian Immunodeficiency Virus Infection: Effect of Time-Dependent Virus Infectivity

ABSTRACT 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 ∼8-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 ∼16 times slower than in ramp-up plasma virus recipient animals and ∼6 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.

HIV epidemic in Far-Western Nepal: effect of seasonal labor migration to India

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.

Treatment-Mediated Alterations in HIV Fitness Preserve CD4+ T Cell Counts but Have Minimal Effects on Viral Load

For most HIV-infected patients, antiretroviral therapy controls viral replication. However, in some patients drug resistance can cause therapy to fail. Nonetheless, continued therapy with a failing regimen can preserve or even lead to increases in CD4+ T cell counts. To understand the biological basis of these observations, we used mathematical models to explain observations made in patients with drug-resistant HIV treated with enfuvirtide (ENF/T-20), an HIV-1 fusion inhibitor. Due to resistance emergence, ENF was removed from the drug regimen, drug-sensitive virus regrown, and ENF was re-administered. We used our model to study the dynamics of plasma-viral RNA and CD4+ T cell levels, and the competition between drug-sensitive and resistant viruses during therapy interruption and re-administration. Focusing on resistant viruses carrying the V38A mutation in gp41, we found ENF-resistant virus to be 17±3% less fit than ENF-sensitive virus in the absence of the drug, and that the loss of resistant virus during therapy interruption was primarily due to this fitness cost. Using viral dynamic parameters estimated from these patients, we show that although re-administration of ENF cannot suppress viral load, it can, in the presence of resistant virus, increase CD4+ T cell counts, which should yield clinical benefits. This study provides a framework to investigate HIV and T cell dynamics in patients who develop drug resistance to other antiretroviral agents and may help to develop more effective strategies for treatment.

HIV-1 gp120 induces type-1 programmed cell death through ER stress employing IRE1α, JNK and AP-1 pathway

The ER stress-mediated apoptosis has been implicated in several neurodegenerative diseases; however, its role in HIV/neuroAIDS remains largely unexplored. The present study was undertaken to assess the involvement and detailed mechanism of IRE1α pathway in HIV-1 gp120-mediated ER stress and its possible involvement in cell death. Various signaling molecules for IRE1α pathway were assessed using SVGA cells, primary astrocytes and gp120 transgenic mice, which demonstrated gp120-mediated increase in phosphorylated JNK, XBP-1 and AP-1 leading to upregulation of CHOP. Furthermore, HIV-1 gp120-mediated activation of IRE1α also increased XBP-1 splicing. The functional consequence of gp120-mediated ER stress was determined via assessment of gp120-mediated cell death using PI staining and MTT assay. The gp120-mediated cell death also involved caspase-9/caspase-3-mediated apoptosis. These findings were confirmed with the help of specific siRNA for IRE1α, JNK, AP-1, BiP and CHOP showing significant reduction in gp120-mediated CHOP expression. Additionally, silencing all the intermediates also reduced the gp120-mediated cell death and caspase-9/caspase-3 activation at differential levels. This study provides ER-stress as a novel therapeutic target in the management of gp120-mediated cell death and possibly in the treatment of neuroAIDS.

Modeling malaria and typhoid fever co-infection dynamics

Malaria and typhoid are among the most endemic diseases, and thus, of major public health concerns in tropical developing countries. In addition to true co-infection of malaria and typhoid, false diagnoses due to similar signs and symptoms and false positive results in testing methods, leading to improper controls, are the major challenges on managing these diseases. In this study, we develop novel mathematical models describing the co-infection dynamics of malaria and typhoid. Through mathematical analyses of our models, we identify distinct features of typhoid and malaria infection dynamics as well as relationships associated to their co-infection. The global dynamics of typhoid can be determined by a single threshold (the typhoid basic reproduction number, R0(T)) while two thresholds (the malaria basic reproduction number, R0(M), and the extinction index, R0(MM)) are needed to determine the global dynamics of malaria. We demonstrate that by using efficient simultaneous prevention programs, the co-infection basic reproduction number, R0, can be brought down to below one, thereby eradicating the diseases. Using our model, we present illustrative numerical results with a case study in the Eastern Province of Kenya to quantify the possible false diagnosis resulting from this co-infection. In Kenya, despite having higher prevalence of typhoid, malaria is more problematic in terms of new infections and disease deaths. We find that false diagnosis-with higher possible cases for typhoid than malaria-cause significant devastating impacts on Kenyan societies. Our results demonstrate that both diseases need to be simultaneously managed for successful control of co-epidemics.

Transmission dynamics of the recently-identified BYD virus causing duck egg-drop syndrome.

Baiyangdian (BYD) virus is a recently-identified mosquito-borne flavivirus that causes severe disease in ducks, with extremely rapid transmission, up to 15% mortality within 10 days and 90% reduction in egg production on duck farms within 5 days of infection. Because of the zoonotic nature of flaviviruses, the characterization of BYD virus and its epidemiology are important public health concerns. Here, we develop a mathematical model for the transmission dynamics of this novel virus. We validate the model against BYD outbreak data collected from duck farms in Southeast China, as well as experimental data obtained from an animal facility. Based on our model, the basic reproductive number of BYD virus is high (R 0 = 21) indicating that this virus is highly transmissible, consistent with the dramatic epidemiology observed in BYDV-affected duck farms. Our results indicate that younger ducks are more vulnerable to BYD disease and that ducks infected with BYD virus reduce egg production (to about 33% on average) for about 3 days post-infection; after 3 days infected ducks are no longer able to produce eggs. Using our model, we predict that control measures which reduce contact between mosquitoes and ducks such as mosquito nets are more effective than insecticides.

Impact of early treatment programs on HIV epidemics: An immunity-based mathematical model

While studies on pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) have demonstrated substantial advantages in controlling HIV transmission, the overall benefits of the programs with early initiation of antiretroviral therapy (ART) have not been fully understood and are still on debate. Here, we develop an immunity-based (CD4+ T cell count based) mathematical model to study the impacts of early treatment programs on HIV epidemics and the overall community-level immunity. The model is parametrized using the HIV prevalence data from South Africa and fully analyzed for stability of equilibria and infection persistence criteria. Using our model, we evaluate the effects of early treatment on the new infection transmission, disease death, basic reproduction number, HIV prevalence, and the community-level immunity. Our model predicts that the programs with early treatments significantly reduce the new infection transmission and increase the community-level immunity, but the treatments alone may not be enough to eliminate HIV epidemics. These findings, including the community-level immunity, might provide helpful information for proper implementation of HIV treatment programs.

Impact of Tenofovir gel as a PrEP on HIV infection: a mathematical model.

Pre-exposure prophylaxis (PrEP) has been considered as one of the promising interventions for HIV infection as experiments on various groups and sites have reported its significant effectiveness. This study evaluates the effectiveness of Tenofovir gel, one of the widely used PrEPs for women, through a mathematical model. Our model has excellent agreement with the experimental data on the use of Tenofovir gel as a PrEP in South African women. Using our model, we estimate both male-to-female and female-to-male transmission rates with and without Tenofovir gel protection. Through these estimates we demonstrate that the use of Tenofovir gel as a PrEP can significantly reduce the reproduction numbers, new infections, and HIV prevalence in South Africa. Our results further show that the effectiveness of Tenofovir gel largely depends on the level of adherence to the gel and the proportion of women under gel coverage. Even though Tenofovir gel alone may not be able to eradicate the disease as indicated by our estimates of the reproduction numbers, together with other interventions, such as condom use, it can serve as a strong weapon to fight against HIV epidemics.