Loss of CD4+ T cells is mainly caused by the direct cytopathic effects of the replicating virus. In infected individuals, approximately 100 billion new viral particles are produced and 1 to 2 billion CD4+ T cells die each day. Death of these cells is a major cause of the relentless, and eventually profound, T cell immunodeficiency. Up to a point, the immune system can replace the dying T cells, but as the disease progresses, renewal of CD4+ T cells cannot keep up with their loss. Possible mechanisms by which the virus directly kills infected cells include increased plasma membrane permeability associated with budding of virus particles and defects in protein synthesis stemming from interference by viral proteins involved in viral replication.
In addition to direct killing of cells by the virus, other mechanisms may contribute to the loss or functional impairment of T cells. These include:
Chronic activation of uninfected cells, responding to HIV itself or to infections that are common in individuals with AIDS, leading to apoptosis of these cells.
HIV infection of cells in lymphoid organs (spleen, lymph nodes, tonsils) causing progressive destruction of the architecture and cellular composition of lymphoid tissues.
Fusion of infected and uninfected cells, leading to formation of syncytia (giant cells). In tissue culture the gp120 expressed on productively infected cells binds to CD4 molecules on uninfected T cells, followed by cell fusion. Fused cells usually die within a few hours.
Qualitative defects in T cell function. Even in asymptomatic HIV-infected individuals, defects have been reported, including a reduction in antigen-induced T cell proliferation, a decrease in TH1-type responses relative to the TH2 type, defects in intracellular signaling, and many more. The loss of TH1 responses results in a profound deficiency in cell-mediated immunity. There also is a selective loss of the memory subset of CD4+ helper T cells early in the course of disease, which explains poor recall responses to previously encountered antigens.
Low-level chronic or latent infection of T cells is an important feature of HIV infection. Integrated provirus, without viral gene expression (latent infection), can persist in cells for months or years. Even with potent antiviral therapy, which practically sterilizes the peripheral blood, latent virus lurks within CD4+ cells (both T cells and macrophages) in lymph nodes. According to some estimates, 0.05% of CD4+ T cells in the lymph nodes are latently infected. Because most of these CD4+ T cells are memory cells, they are long-lived, with a life span of months to years, and thus provide a persistent reservoir of virus.
HIV Infection of Non–T Immune Cells
In addition to infection and loss of CD4+ T cells, infection of macrophages and DCs also is important in the pathogenesis of HIV infection.
Macrophages. Similar to T cells, most macrophages infected by HIV are found in tissues, and in certain tissues, such as the lungs and brain, as many as 10% to 50% of macrophages are infected. Although cell division is required for nuclear entry and replication of most retroviruses, HIV-1 can infect and multiply in terminally differentiated nondividing macrophages, which may contain large numbers of virus particles. Even though macrophages allow viral replication, they are quite resistant to the cytopathic effects of HIV, in contrast to CD4+ T cells. Thus, macrophages may be reservoirs of infection, and in late stages of HIV infection, when CD4+ T-cell numbers decline greatly, macrophages may be an important site of continued viral replication.
Dendritic Cells. Mucosal DCs may be infected by the virus and transport it to regional lymph nodes, where the virus is transmitted to CD4+ T cells. Follicular DCs in the germinal centers of lymph nodes also are potential reservoirs of HIV. Although some follicular DCs may be susceptible to HIV infection, most virus particles are found on the surface of their dendritic processes.