The pathogenesis of HIV-1 infection is very complex, but the following factors are likely to be important in the disease-causing process.
The initial target of HIV-1 is CD4 molecules, particularly on the surface of CD4 helper T + lymphocytes, monocytes, and macrophages. The virus can also infect other human cells expressing CD4, and a wide range of CD4 negative cells, including renal and gastrointesti-nal epithelium and brain astrocytes. The mechanism for infection of non – CD4-bearing cells is unknown but may involve other receptors or fusion with cells already infected with HIV. The virus replicates in macrophages, and these cells could serve as a reservoir for continued expansion of the infection to other cell types by cell-to-cell fusion, which allows the virus to spread without being exposed to neutralizing antibody. Infected macrophages may participate in breakdown of the blood – brain barrier, allowing enhanced exposure of the central nervous system (CNS). Although CNS and intestinal disturbances are a promi-nent part of fully developed AIDS, it is not clear whether they are a direct result of infec-tion of these cells or mediated by cytokines from infected macrophages and T lympho-cytes.
Kinetic studies of changes in viral load with antiviral therapy demonstrated the half-life of HIV in plasma is 5 to 6 hours. In other words, more than 50% of the viral load measured on any given day has been produced in the past 24 hours. Because 99% of the viral load is produced by cells that were infected within the past 48 to 72 hours, cell turnover must be equally rapid. Indeed, when similar kinetic studies are performed on changes in CD4 cell counts, it is estimated that up to 1 billion CD4 cells are produced per day in response to the infection and that the half-life of these cells is only 1.6 days.
The long asymptomatic period following HIV infection (clinical latency) occurs despite active virus replication in the host. Several factors can terminate the long latent period of HIV-1. Mutations occur during viral replication that appear to enhance induction of viru-lent forms of the virus, with increased cytopathic capacity and altered cell tropisms. Thus, the mutated forms of HIV-1 isolated from later stages of disease infect a broader range of cell types and grow more rapidly than those isolated in the asymptomatic period. Initially, it was believed that little or no viral replication occurred during this latent period, but studies of lymph nodes of individuals with early asymptomatic disease have shown in-tense immunologic reactions within the lymphoid tissue at early stages of disease. This implies that the immune system is capable of controlling the virus to some degree early in the course of disease, an ability that is later lost as the disease progresses over time.
Recent studies of HIV infection have shown that the level of free virus in the plasma increases in direct relation to the stage of disease. Individuals with early-stage disease have less than 10 infectious virions/mL of plasma, whereas those in late-stage disease have between 100 and 1000 infectious virions/mL of plasma. These studies imply either that viral replication was increasing during later stages of disease due to more virulent mutations and/or the immune system had lost its ability to clear free virus as the disease progresses.
The primary immune defect in AIDS results from the reduction in the numbers and effec-tiveness of CD4+ helper-inducer T lymphocytes, both in absolute numbers and relative to CD8+ suppressor T lymphocytes. This is due to direct killing of CD4+ T lympho-cytes by the virus but may also involve other mechanisms as well. These include sec-ondary killing of uninfected (bystander) cells during cell fusion, autoimmune processes that lead to the elimination of CD4+ T lymphocytes by opsonophagocytosis, and anti-body-dependent cell-mediated cytotoxicity (ADCC) directed at gp120 expressed on the CD4+ cell surface. There are also functional defects in CD4+ T lymphocytes affecting lymphokine production and leading to inhibition of some macrophage functions.
Effects on CD4+ T lymphocytes thus lead to a generalized failure of cell-mediated immune responses, but there is also an effect on antibody production due to polyclonal activation of B cells, possibly associated with other viral infections of these cells. This overwhelms the capacity of infected individuals to respond to specific antigens. The end result of these processes is a disturbance of immune balance that can give rise to malig-nancies as well as the susceptibility of AIDS patients to a range of opportunistic viral, fungal, and bacterial infections.
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