In Vitro and Animal Models of Human Immunodeficiency Virus Infection of the Central Nervous System

Initially, progressive dementia affected a large percentage (15 to 20%) of adults infected with human immunodeficiency virus (HIV). However, with the present use of potent antiretroviral therapies, its incidence has been reduced to approximately 8 to 12%. This dementia, known as HIV-associated dementia (HAD) or AIDS dementia complex, is characterized by a progressive deterioration of affective, cognitive, and motor skills. Patients show loss of the ability to concentrate. They also lose fine motor coordination and may display changes in behavior and personality. These symptoms become more pronounced in patients with end-stage disease, often progressing to memory loss, apathy, personality changes, and social withdrawal. Although potent antiretroviral therapies have significantly reduced other complications of HIV infections (e.g., opportunistic infections), the associated decrease in HAD has been proportionately less. Consequently HAD is becomingly a relatively more important complication of HIV infection. HIV-infected children are also susceptible to HAD, with as many as 30 to 50% of this group displaying signs and symptoms of HAD (71). Unlike in adults, HAD in children is often an early event, manifest by microencephaly, failure to achieve both cognitive and motor developmental milestones, and/or frank regression of milestones once achieved. Indeed, it has been reported that children are more likely to develop dementia than to develop opportunistic infections (31). Since the initial reports of AIDS in 1981, much time and energy has been devoted to determining how HIV enters the body, gains entry into cells, replicates, and then causes the immunosuppresion that is the hallmark of this disease. However, when we look specifically at the case of HIV and the central nervous system, it is obvious that there are important questions that remain to be definitively answered. For instance, how soon after infection does HIV enter the central nervous system (CNS)? It is believed to enter early after infection, but is this on the scale of hours or days? How does HIV cross the blood-brain barrier (BBB)? What is the mechanism by which cells in the brain are damaged? Why do not all HIV-infected patients develop HAD, and why do those that develop HAD display a wide range of symptoms? Why do some patients with extremely high viral loads in the CNS not develop HAD and others with relatively low viral loads develop frank dementia? Unfortunately, these types of questions are not easily answered. Ascertaining the answers to these and other similar questions would require access to tissues from individuals who have been very recently infected with HIV and from individuals at various points along the pathway to dementia. Recently infected individuals are very difficult to identify, and even when this is possible, only some types of samples are available for analysis. Brain tissue is generally unavailable unless the acutely infected patient dies by some other means shortly after infection. Another factor to consider is that individuals react differently to HIV infection. The pattern of disease in one person is often substantially different from that in the next. Although the end point is the same, progression to that point may follow markedly different paths. To overcome problems such as these, the research community must rely primarily on various in vitro and animal systems to model aspects of HIV infection of the CNS. There are a number of in vitro systems and animal models that are being used to investigate aspects of HIV infection in the CNS. Each model has unique strengths and weaknesses. The purpose of this review is to briefly explain the most popular model systems and comment on the utility of each system with respect to CNS AIDS and HAD.