High Heritability Is Compatible with the Broad Distribution of Set Point Viral Load in HIV Carriers

Set point viral load in HIV patients ranges over several orders of magnitude and is a key determinant of disease progression in HIV. A number of recent studies have reported high heritability of set point viral load implying that viral genetic factors contribute substantially to the overall variation in viral load. The high heritability is surprising given the diversity of host factors associated with controlling viral infection. Here we develop an analytical model that describes the temporal changes of the distribution of set point viral load as a function of heritability. This model shows that high heritability is the most parsimonious explanation for the observed variance of set point viral load. Our results thus not only reinforce the credibility of previous estimates of heritability but also shed new light onto mechanisms of viral pathogenesis.     

Modeling the Genetic Control of HIV-1 Dynamics After Highly Active Antiretroviral Therapy

The progression of HIV disease has been markedly slowed by the use of highly active antiretroviral therapy (HAART). However, substantial genetic variation was observed to occur among different people in the decay rate of viral loads caused by HAART. The characterization of specific genes involved in HIV dynamics is central to design personalized drugs for the prevention of this disease, but usually cannot be addressed by experimental methods alone rather than require the help of mathematical and statistical methods. A novel statistical model has been recently developed to detect genetic variants that are responsible for the shape of HAART-induced viral decay curves. This model was employed to an HIV/AIDS trial, which led to the identification of a major genetic determinant that triggers an effect on HIV dynamics. This detected major genetic determinant also affects several clinically important parameters, such as half-lives of infected cells and HIV eradication times.Key Words: Hardy-weinberg equilibrium, bi-exponential function, quantitative trait loci, HIV dynamics, functional mapping.     

Hierarchical kernel mixture models for the prediction of AIDS disease progression using HIV structural gp120 profiles

Changes to the glycosylation profile on HIV gp120 can influence viral pathogenesis and alter AIDS disease progression. The characterization of glycosylation differences at the sequence level is inadequate as the placement of carbohydrates is structurally complex. However, no structural framework is available to date for the study of HIV disease progression. In this study, we propose a novel machine-learning based framework for the prediction of AIDS disease progression in three stages (RP, SP, and LTNP) using the HIV structural gp120 profile. This new intelligent framework proves to be accurate and provides an important benchmark for predicting AIDS disease progression computationally. The model is trained using a novel HIV gp120 glycosylation structural profile to detect possible stages of AIDS disease progression for the target sequences of HIV+ individuals. The performance of the proposed model was compared to seven existing different machine-learning models on newly proposed gp120-Benchmark_1 dataset in terms of error-rate (MSE), accuracy (CCI), stability (STD), and complexity (TBM). The novel framework showed better predictive performance with 67.82% CCI, 30.21 MSE, 0.8 STD, and 2.62 TBM on the three stages of AIDS disease progression of 50 HIV+ individuals. This framework is an invaluable bioinformatics tool that will be useful to the clinical assessment of viral pathogenesis.     

An HIV Epidemic Model Based on Viral Load Dynamics: Value in Assessing Empirical Trends in HIV Virulence and Community Viral Load

Trends in HIV virulence have been monitored since the start of the AIDS pandemic, as studying HIV virulence informs our understanding of HIV epidemiology and pathogenesis. Here, we model changes in HIV virulence as a strictly evolutionary process, using set point viral load (SPVL) as a proxy, to make inferences about empirical SPVL trends from longitudinal HIV cohorts. We develop an agent-based epidemic model based on HIV viral load dynamics. The model contains functions for viral load and transmission, SPVL and disease progression, viral load trajectories in multiple stages of infection, and the heritability of SPVL across transmissions. We find that HIV virulence evolves to an intermediate level that balances infectiousness with longer infected lifespans, resulting in an optimal SPVL∼4.75 log₁₀ viral RNA copies/mL. Adaptive viral evolution may explain observed HIV virulence trends: our model produces SPVL trends with magnitudes that are broadly similar to empirical trends. With regard to variation among studies in empirical SPVL trends, results from our model suggest that variation may be explained by the specific epidemic context, e.g. the mean SPVL of the founding lineage or the age of the epidemic; or improvements in HIV screening and diagnosis that results in sampling biases. We also use our model to examine trends in community viral load, a population-level measure of HIV viral load that is thought to reflect a population''s overall transmission potential. We find that community viral load evolves in association with SPVL, in the absence of prevention programs such as antiretroviral therapy, and that the mean community viral load is not necessarily a strong predictor of HIV incidence.     

Coinfection alters the playing field: herpesviruses induce acyclovir to inhibit HIV

The antiherpes drug acyclovir was found to inhibit HIV following its phosphorylation by human herpesviruses, providing a hypothesis to explain the observed beneficial effects of acyclovir therapy on HIV viral load and HIV disease progression. This report underscores the importance of studying HIV in the context of microbial copathogens.     

Sensitivity analysis for the assessment of causal vaccine effects on viral load in HIV vaccine trials

Vaccines with limited ability to prevent HIV infection may positively impact the HIV/AIDS pandemic by preventing secondary transmission and disease in vaccine recipients who become infected. To evaluate the impact of vaccination on secondary transmission and disease, efficacy trials assess vaccine effects on HIV viral load and other surrogate endpoints measured after infection. A standard test that compares the distribution of viral load between the infected subgroups of vaccine and placebo recipients does not assess a causal effect of vaccine, because the comparison groups are selected after randomization. To address this problem, we formulate clinically relevant causal estimands using the principal stratification framework developed by Frangakis and Rubin (2002, Biometrics 58, 21-29), and propose a class of logistic selection bias models whose members identify the estimands. Given a selection model in the class, procedures are developed for testing and estimation of the causal effect of vaccination on viral load in the principal stratum of subjects who would be infected regardless of randomization assignment. We show how the procedures can be used for a sensitivity analysis that quantifies how the causal effect of vaccination varies with the presumed magnitude of selection bias.     

The cytokine network of acute HIV infection: a promising target for vaccines and therapy to reduce viral set-point?

Cytokines play a central role in the pathogenesis of many diseases, including HIV infection. However, the role of the cytokine network in early HIV infection is only now starting to be elucidated. A number of studies conducted in recent years have indicated that cytokines of the acute/early stages of HIV and SIV infection can impact viral set-point months later, and this is of critical importance since viral set-point during chronic HIV infection affects virus transmission and disease progression. This raises the question whether modulating the cytokine environment during acute/early HIV infection can be a target for novel approaches to develop a vaccine and therapeutics. In this review we focus on the kinetics and function of cytokines during acute HIV and SIV infection and how these may impact viral set-point. We also discuss unresolved questions that are essential for our understanding of the role of acute infection cytokines in HIV infection and that, if answered, may suggest novel therapeutic and vaccine strategies to control the worldwide HIV pandemic.     

Mortality among Human Immunodeficiency Virus Type 2-Positive Villagers in Rural Guinea-Bissau Is Correlated with Viral Genotype

We present the results of a 6-year study of 131 human immunodeficiency virus (HIV) type 2 (HIV-2)-infected individuals from a rural population in Guinea-Bissau. Proviral DNA sequences 1.3 kb in length were obtained from each individual and, together with clinical data, including proviral load and CD4 and CD8 levels, were used to assess whether viral genotype influences clinical outcome. With a phylogenetic model, a correlation was found between viral genotype and mortality; this correlation was not due to confounding factors, such as age-specific viral strains or cohabitation of patients. The data provide strong evidence for the involvement of viral genetic factors in determining HIV disease progression in vivo. The pattern of association found suggests that virulence factors are multiple and scattered throughout the HIV-2 genome and can be rapidly gained or lost by the virus through a combination of mutation and recombination. These findings may lead to the identification of viral determinants of HIV disease progression.     

Autonomous targeting of infectious superspreaders using engineered transmissible therapies

Infectious disease treatments, both pharmaceutical and vaccine, face three universal challenges: the difficulty of targeting treatments to high-risk 'superspreader' populations who drive the great majority of disease spread, behavioral barriers in the host population (such as poor compliance and risk disinhibition), and the evolution of pathogen resistance. Here, we describe a proposed intervention that would overcome these challenges by capitalizing upon Therapeutic Interfering Particles (TIPs) that are engineered to replicate conditionally in the presence of the pathogen and spread between individuals--analogous to 'transmissible immunization' that occurs with live-attenuated vaccines (but without the potential for reversion to virulence). Building on analyses of HIV field data from sub-Saharan Africa, we construct a multi-scale model, beginning at the single-cell level, to predict the effect of TIPs on individual patient viral loads and ultimately population-level disease prevalence. Our results show that a TIP, engineered with properties based on a recent HIV gene-therapy trial, could stably lower HIV/AIDS prevalence by ～30-fold within 50 years and could complement current therapies. In contrast, optimistic antiretroviral therapy or vaccination campaigns alone could only lower HIV/AIDS prevalence by <2-fold over 50 years. The TIP's efficacy arises from its exploitation of the same risk factors as the pathogen, allowing it to autonomously penetrate superspreader populations, maintain efficacy despite behavioral disinhibition, and limit viral resistance. While demonstrated here for HIV, the TIP concept could apply broadly to many viral infectious diseases and would represent a new paradigm for disease control, away from pathogen eradication but toward robust disease suppression.     

Primary HIV infection in infants: impact of highly active antiretroviral therapy on the natural course

In the absence of any antiretroviral therapy, about one-third of infants with perinatally acquired HIV infection develop AIDS within the first months of life, while the remainder show slower disease progression. As the rate of viral replication during the first 3 months of life is strictly correlated with and predictive of disease outcome, any treatment that keeps the virus at low levels during primary infection might substantially modify the natural history of infection. Emerging data show that some infants treated early with highly active antiretroviral therapy have persistenty undetectable levels of HIV, and lack an HIV-specific immune response, despite preservation of immune functions. These findings strongly suggest that early therapeutic intervention might lead to a long-term suppression of viral replication.     

High resolution hemodynamic profiling of murine arteriovenous fistula using magnetic resonance imaging and computational fluid dynamics

The progression of Human Immunodeficiency Virus (HIV) within host includes typical stages and the Antiretroviral Therapy (ART) is shown to be effective in slowing down this progression. There are great challenges in describing the entire HIV disease progression and evaluating comprehensive effects of ART on life expectancy for HIV infected individuals on ART. We develop a novel summative treatment benefit index (TBI), based on an HIV viral dynamics model and linking the infection and viral production rates to the Weibull function. This index summarizes the integrated effect of ART on the life expectancy (LE) of a patient, and more importantly, can be reconstructed from the individual clinic data. The proposed model, faithfully mimicking the entire HIV disease progression, enables us to predict life expectancy and trace back the timing of infection. We fit the model to the longitudinal data in a cohort study in China to reconstruct the treatment benefit index, and we describe the dependence of individual life expectancy on key ART treatment specifics including the timing of ART initiation, timing of emergence of drug resistant virus variants and ART adherence. We show that combining model predictions with monitored CD4 counts and viral loads can provide critical information about the disease progression, to assist the design of ART regimen for maximizing the treatment benefits.     

Immunopathogenesis of HIV infection.

The ultimate consequence of infection with HIV is profound immunosuppression that is the result of both quantitative and qualitative abnormalities of the helper/inducer subset of T lymphocytes. The initial pathogenic event in HIV infection is binding of the envelope glycoprotein of HIV to the CD4 receptor molecule present on the surface of CD4+ T lymphocytes and monocyte/macrophages. In vivo the reservoir for HIV infection in the peripheral blood is the CD4+ T cell, whereas in other tissues the monocyte/macrophage may play a substantial role. As disease progresses in HIV-infected individuals, the viral burden in the peripheral blood CD4+ T cells increases. An understanding of the mechanisms involved in the transition from an initially low viral burden during the asymptomatic phase of HIV infection to the higher levels of virus expression detected in late stage disease is being investigated intensively. A number of potential agents that may influence regulation of HIV expression have been identified including mitogens, antigens, heterologous viruses, cytokines, and physical factors. The pathogenic mechanisms of HIV-induced neurologic abnormalities and the potential role of HIV in a number of other clinical manifestations of HIV infection are also discussed.     

Synonymous substitution rates predict HIV disease progression as a result of underlying replication dynamics

Upon HIV transmission, some patients develop AIDS in only a few months, while others remain disease free for 20 or more years. This variation in the rate of disease progression is poorly understood and has been attributed to host genetics, host immune responses, co-infection, viral genetics, and adaptation. Here, we develop a new “relaxed-clock” phylogenetic method to estimate absolute rates of synonymous and nonsynonymous substitution through time. We identify an unexpected association between the synonymous substitution rate of HIV and disease progression parameters. Since immune activation is the major determinant of HIV disease progression, we propose that this process can also determine viral generation times, by creating favourable conditions for HIV replication. These conclusions may apply more generally to HIV evolution, since we also observed an overall low synonymous substitution rate for HIV-2, which is known to be less pathogenic than HIV-1 and capable of tempering the detrimental effects of immune activation. Humoral immune responses, on the other hand, are the major determinant of nonsynonymous rate changes through time in the envelope gene, and our relaxed-clock estimates support a decrease in selective pressure as a consequence of immune system collapse.     

Impact of cytokines on replication in the thymus of primary human immunodeficiency virus type 1 isolates from infants

Early infection of the thymus with the human immunodeficiency virus (HIV) may explain the more rapid disease progression among children infected in utero than in children infected intrapartum. Therefore, we analyzed infection of thymocytes in vitro by HIV type 1 primary isolates, obtained at or near birth, from 10 children with different disease outcomes. HIV isolates able to replicate in the thymus and impact thymopoiesis were present in all infants, regardless of the timing of viral transmission and the rate of disease progression. Isolates from newborns utilized CCR5, CXCR4, or both chemokine receptors to enter thymocytes. Viral expression was observed in discrete thymocyte subsets postinfection with HIV isolates using CXCR4 (X4) and isolates using CCR5 (R5), despite the wider distribution of CXCR4 in the thymus. In contrast to previous findings, the X4 primary isolates were not more cytopathic for thymocytes than were the R5 isolates. The cytokines interleukin-2 (IL-2), IL-4, and IL-7 increased HIV replication in the thymus by inducing differentiation and expansion of mature CD27(+) thymocytes expressing CXCR4 or CCR5. IL-2 and IL-4 together increased expression of CXCR4 and CCR5 in this population, whereas IL-4 and IL-7 increased CXCR4 but not CCR5 expression. IL-2 plus IL-4 increased the viral production of all pediatric isolates, but IL-4 and IL-7 had a significantly higher impact on the replication of X4 isolates compared to R5 isolates. Our studies suggest that coreceptor use by HIV primary isolates is important but is not the sole determinant of HIV pathogenesis in the thymus.     

Rodent cells support key functions of the human immunodeficiency virus type 1 pathogenicity factor Nef

After infection with human immunodeficiency virus (HIV), progression toward immunodeficiency is governed by a complex interplay of viral and host determinants. The viral accessory protein Nef is a key factor for the development of AIDS. Strains of HIV and simian immunodeficiency virus that lack functional nef genes either do not induce AIDS or do so only after a significant delay. The validity of a transgenic-small-animal model for de novo infection by HIV will depend on its ability to recapitulate the actions of critical factors of viral pathogenicity, such as Nef. We assessed the ability of rat, mouse, and hamster cells to support key effector functions of Nef. In cell lines from rodents, the subcellular distribution of wild-type HIV type 1 strain SF2 Nef and mutants was comparable to that in human cells. Nef downregulated human CD4 from the cell surface, was associated with p21-activated kinase activity, and enhanced the infectivity of HIV-1 virions. Importantly, these Nef-induced effects, as well as the downregulation of rat CD4 and major histocompatibility complex class I molecules, could also be demonstrated in primary T lymphocytes and macrophages from human CD4-transgenic rats. Thus, HIV-1 Nef exerts key functions in rodent cells. In line with our ongoing efforts to establish a transgenic-rat model of HIV disease, these results indicate that important aspects of viral pathogenesis could be addressed in a transgenic-rodent model permissive for de novo infection and that such a model would be valuable for evaluating the function of Nef in vivo.     

Modulation of apoptosis by HIV protease inhibitors

Advances in treatment have transformed the Human Immunodeficiency Virus (HIV) infection from a progressive and ultimately fatal disease to one that can be managed effectively by chronic suppressive antiretroviral therapy. The drugs now used to treat HIV infection not only inhibit viral replication but also have effects on cellular metabolism and homeostasis. Of particular interest to cellular immunologists, members of the HIV Protease Inhibitor (PI) class of antiretroviral agents possess intrinsic immunomodulatory and antiapoptotic properties. This review focuses on the development and use of PI together with their impact on HIV disease, immunity, and apoptosis.     

Dynamic imaging of cell-free and cell-associated viral capture in mature dendritic cells

Dendritic cells (DCs) capture human immunodeficiency virus (HIV) through a non-fusogenic mechanism that enables viral transmission to CD4(+) T cells, contributing to in vivo viral dissemination. Although previous studies have provided important clues to cell-free viral capture by mature DCs (mDCs), dynamic and kinetic insight on this process is still missing. Here, we used three-dimensional video microscopy and single-particle tracking approaches to dynamically dissect both cell-free and cell-associated viral capture by living mDCs. We show that cell-free virus capture by mDCs operates through three sequential phases: virus binding through specific determinants expressed in the viral particle, polarized or directional movements toward concrete regions of the cell membrane and virus accumulation in a sac-like structure where trapped viral particles display a hindered diffusive behavior. Moreover, real-time imaging of cell-associated viral transfer to mDCs showed a similar dynamics to that exhibited by cell-free virus endocytosis leading to viral accumulation in compartments. However, cell-associated HIV type 1 transfer to mDCs was the most effective pathway, boosted throughout enhanced cellular contacts with infected CD4(+) T cells. Our results suggest that in lymphoid tissues, mDC viral uptake could occur either by encountering cell-free or cell-associated virus produced by infected cells generating the perfect scenario to promote HIV pathogenesis and impact disease progression.     

The role of antigenic stimulation and cytotoxic T cell activity in regulating the long-term immunopathogenesis of HIV: mechanisms and clinical implications

This paper develops a predictive mathematical model of cell infection, host immune response and viral replication that reproduces observed long-term trends in human immunodeficiency virus (HIV) pathogenesis. Cell activation induced by repeated exposure to many different antigens is proposed as the principal mechanism of providing target cells for HIV infection and, hence, of CD4+ T cell depletion, with regulation of the overall T cell pool size causing concomitant CD8 pool increases. The model correctly predicts the cross-patient variability in disease progression, the rate of which is found to depend on the efficacy of anti-HIV cytotoxic T lymphocyte responses, overall viral pathogenicity and random effects. The model also predicts a variety of responses to anti-viral therapy, including episodic residual viral replication and discordant responses and we find that such effects can be suppressed by increasing the potency of treatment.     

The use of a method for the quantitative determination of HIV-1 RNA for assessing the severity and prognosis of the development of the disease

The informatory role of a new marker of HIV infection, characterizing the content of HIV-1 RNA in the biological fluids of the patient's body, is evaluated. The quantitative determination of HIV-1 RNA, carried out in a single assay, was made in the blood of 25 HIV-infected patients. These studies confirmed that the determination of the level of RNA in the plasma (viral load) was a reliable criterion indicating the severity and progress of the disease. The viral load of more than 100,000 copies/ml was a sign prognosticating the future pronounced progress of the disease in spite of moderate clinical manifestations and relatively high values of CD4 cells in the patient's blood at the moment of testing.