While the immune response to HIV is ultimately unsuccessful, its importance in restraining disease progression is clear. This is perhaps best exemplified in the tragic case of children infected with HIV perinatally, in whom the course of disease is much more fulminant than in adults. This reflects a poor immune response to the virus in the acute phase of infection due to immaturity of the neonatal immune system, as well as infection by a viral strain that has already evaded an immune system that is genetically close to that of the child. In essence, the poor immune response results in the lack of a latent phase, leading rapidly to AIDS.
13-32 Lymphoid tissue is the major reservoir of HIV infection.
In view of the active, ongoing immune response to HIV infections and the advent of antiretroviral therapies that efficiently blunt viral replication (see Section 1335), it is important to identify the reservoirs that allow the virus to persist. Although HIV load and turnover are usually measured in terms of the RNA present in virions in the blood, the major reservoir of HIV infection appears to be lymphoid tissue. Here, in addition to infected CD4 T cells, macrophages, and dendritic cells, HIV is also trapped in the form of immune complexes on the surface of follicular dendritic cells in germinal centers. These cells are not themselves infected but may act as a reservoir of infective virions that can persist for months, if not longer. Although tissue macrophages and dendritic cells seem able to harbor replicating HIV without being killed by it, these cells are shortlived and are not thought to be major reservoirs of latent infection. However, they appear to be important in spreading virus to other tissues, such as the brain, where infected cells in the central nervous system may contribute to the virus’s longterm persistence.
From studies of patients receiving antiretroviral treatment, it is estimated that more than 95% of the virus that can be detected in the plasma is derived from productively infected CD4 T cells that have a very short halflife—about 2 days. Virusproducing CD4 T cells are found in the Tcell areas of lymphoid tissues, and these T cells are thought to succumb to infection while being activated in an immune response. Latently infected CD4 memory T cells that become reactivated by antigen also produce virus that can spread to other activated CD4 T cells. In addition to cells that are productively or latently infected, a further large population of cells is infected by defective proviruses, which do not produce infectious virus. Unfortunately, latently infected CD4 memory T cells have an extremely long mean halflife of around 44 months. This means that drug therapy that effectively eliminates viral replication would have to be administered for over 70 years to completely clear the virus. Practically, then, infected patients will never be able to eliminate an HIV infection, and require treatment for life.
13-33 Genetic variation in the host can alter the rate of disease progression.