HIV/AIDS: in search of an animal model

AIDS is among the most devastating diseases of our time, claiming the lives of approximately 3 million people per year. The primary cause of AIDS, human immunodeficiency virus type 1 (HIV-1), is a pathogen that is highly specific for humans and generally does not infect or cause disease in other species. This property complicates the generation of animal models that are urgently needed to test new antiretroviral therapies and vaccines. The most practical animal models developed to date consist of infection of rhesus macaques with a simian immunodeficiency virus (SIV) or chimeric HIV/SIV viruses. Although these models are useful for particular applications, the fact that SIV is a distinct virus compared with HIV-1 represents a significant limitation to their use. Here, we discuss the uses and limitations of existing models and recent advances that might lead to better animal models for HIV/AIDS.     

Allocating HIV prevention funds in the United States: recommendations from an optimization model

The Centers for Disease Control and Prevention (CDC) had an annual budget of approximately $327 million to fund health departments and community-based organizations for core HIV testing and prevention programs domestically between 2001 and 2006. Annual HIV incidence has been relatively stable since the year 2000 and was estimated at 48,600 cases in 2006 and 48,100 in 2009. Using estimates on HIV incidence, prevalence, prevention program costs and benefits, and current spending, we created an HIV resource allocation model that can generate a mathematically optimal allocation of the Division of HIV/AIDS Prevention's extramural budget for HIV testing, and counseling and education programs. The model's data inputs and methods were reviewed by subject matter experts internal and external to the CDC via an extensive validation process. The model projects the HIV epidemic for the United States under different allocation strategies under a fixed budget. Our objective is to support national HIV prevention planning efforts and inform the decision-making process for HIV resource allocation. Model results can be summarized into three main recommendations. First, more funds should be allocated to testing and these should further target men who have sex with men and injecting drug users. Second, counseling and education interventions ought to provide a greater focus on HIV positive persons who are aware of their status. And lastly, interventions should target those at high risk for transmitting or acquiring HIV, rather than lower-risk members of the general population. The main conclusions of the HIV resource allocation model have played a role in the introduction of new programs and provide valuable guidance to target resources and improve the impact of HIV prevention efforts in the United States.     

A new animal model of Bordetella pertussis infection and immunity

Bordetella pertussis is a strictly human pathogen. Experimental infection of other animals can occur with large inoculating doses; rat, mice and primate models have been used to study pathogenesis and immunity. Recently, it was shown that newborn piglets are susceptible to B. pertussis. Lung pathophysiology of infected piglets was similar to that of human infants that develop bronchopneumonia. Piglets and infants are anatomically similar and maternal antibodies are transferred and secreted by a similar mechanism. This model could be valuable for studying the roles of passively and actively acquired immunity against B. pertussis.     

Endemic threshold results in an age-duration-structured population model for HIV infection

In this paper we consider an age-duration-structured population model for HIV infection in a homosexual community. First we investigate the invasion problem to establish the basic reproduction ratio R(0) for the HIV/AIDS epidemic by which we can state the threshold criteria: The disease can invade into the completely susceptible population if R(0)>1, whereas it cannot if R(0)<1. Subsequently, we examine existence and uniqueness of endemic steady states. We will show sufficient conditions for a backward or a forward bifurcation to occur when the basic reproduction ratio crosses unity. That is, in contrast with classical epidemic models, for our HIV model there could exist multiple endemic steady states even if R(0) is less than one. Finally, we show sufficient conditions for the local stability of the endemic steady states.     

RNA-based gene therapy for the treatment and prevention of HIV: from bench to bedside

Gene therapy is considered a feasible approach for the treatment and prevention of HIV/AIDS. Targeting both viral genes and host dependency factors can interfere with the viral lifecycle and prevent viral replication. A number of approaches have been taken to target these genes, including ribozymes, aptamers, and RNAi based therapies. A number of these therapies are now beginning to make their way into clinical trials and providing proof of principle that gene therapy is a safe and realistic option for treating HIV. Here, we focus on those therapies that have progressed along the pipeline to preclinical and clinical testing.     

Early HIV infection in vivo: branching-process model for studying timing of immune responses and drug therapy

We propose a stochastic, branching-process model of early events in vivo in human or simian immunodeficiency virus (HIV or SIV) infection and study the influence that the time of appearance of virus-specific antibodies or cytotoxic cells, or of administration of antiretroviral drugs, has on the probability of progression to a chronic infection. In some biological scenarios, our model predicts that a few days' delay in response or intervention would make little difference, while in others it would be highly deleterious. We show that prophylactic efficacy does not require perfect efficiency at neutralizing infectious virus. Data from a trial of PMPA, a potent antiretroviral drug, as post-exposure therapy for SIV infection in macaques, reported by C.-C. Tsai, P. Emau, K.E. Follis, T.W. Beck, R. E. Beneveniste, N. Bischofberger, J.D. Lifson, W.R. Morton (J. Virol. 72 (1998) 4265), provides a test of the model. We show that their observations are consistent with a branching-process without invoking supplementary viral- or host-variability. Finally, most animal trials of antiviral drugs or vaccines use very high viral inoculums; our model demonstrates that in such experiments we risk greatly underestimating the efficacy of these agents.     

Language emergence: clues from a new bedouin sign

A sign language has emerged among three generations of deaf people and their families in a Bedouin community in the Negev desert. This newly reported case sheds light on the minimal environmental social factors required to generate a language.     

Gene therapy of T helper cells in HIV infection: Mathematical model of the criteria for clinical effect

The paper presents a mathematical analysis of the criteria for gene therapy of T helper cells to have a clinical effect on HIV infection. The analysis indicates that for such a therapy to be successful, it must protect the transduced cells against HIV-induced death. The transduced cells will not survive as a population if the gene therapy only blocks the spread of virus from transduced cells that become infected. The analysis also suggests that the degree of protection against disease-related cell death provided by the gene therapy is more important than the fraction of cells that is initially transduced. If only a small fraction of the cells can be transduced, transduction of T helper cells and transduction of haematopoietic progenitor cells will result in the same steady-state level of transduced T helper cells. For gene therapy to be efficient against HIV infection, our analysis suggests that a 100% protection against viral escape must be obtained. The study also suggests that a gene therapy against HIV infection should be designed to give the transduced cells a partial but not necessarily total protection against HIV-induced cell death, and to avoid the production of viral mutants insensitive to the gene therapy.     

Passive immunization for the treatment and prevention of HIV infection.

Passive immunization using serum or immunoglobulin preparations has been used in the prophylaxis and treatment of many bacterial and viral diseases. Preliminary attempts to use these methods to prevent HIV infection in chimpanzees have been promising. With the identification of polyclonal and monoclonal antibodies with protective activity against HIV in in vitro systems, the possibility of using these reagents in vivo takes on new relevance. The potential and problems of using passively administered anti-HIV antibodies for HIV prophylaxis and treatment are discussed, as well as the relative merits of polyclonal versus monoclonal reagents.     

Cyclosporine A-induced autoimmunity: an animal model for human scleroderma

Animal models have been shown to be very valuable in the elucidation of pathologic mechanisms in complex human diseases. However, conscientious comparison with the human disease is required to define to what extend the respective model is relevant for the human situation. In this study we have compared Cyclosporine A-induced autoimmunity in the rat with human scleroderma and hereby we have taken into account the histo- and immunopathology, the presence of vascular abnormalities, and the occurrence of circulating autoantibodies. Altogether, the macroscopical and histopathological similarities are the most important characteristics for considering Cyclosporine A-induced autoimmunity as an experimental model for human scleroderma. Furthermore, the presence of T cells and macrophages in the lesions, as well as the peripheral immune deviation within the CD4 T cell compartment are two other common factors and they justify the use of the animal model Cyclosporine A-induced autoimmunity in further studies on the role of T cells in the pathogenesis of scleroderma.