Immunopathogenesis of HIV Infection
المؤلف:
Baijayantimala Mishra
المصدر:
Textbook of Medical Virology
الجزء والصفحة:
2nd Edition , p253-254
2025-12-06
70
Progressive deterioration of CD4+ T cells associated with a persistent state of immune activation is the hallmark of HIV infection.
The effects on CD4 cells, CD8 cells and B cells are described below.
CD4+ T cells: The progressive immunodeficiency during the course of HIV infection can be attributed to various degrees of immune dysfunction and immune activation. Multiple mechanisms of CD4+ T lymphocyte destruction (both structural as well as functional) have been observed in various stages of the disease.
During the early (primary) phase of infection, intense HIV replication occurs in gut associated lymphoid tissue (GALT) and the CD4+ Th17 cells which are the prime target of HIV and also abundant in the GALT. Depletion of CD4+ Th17 cells, which are important for defense against extracellular bacteria, leads to increased gut microbial translocation, and a state of persistent immune activation. Another subset of CD4+ T helper cells, called follicular helper CD4+ T cells, present in the germinal centers of lymphoid follicles are also believed to be early targets of HIV during initial infection.
As the disease progresses, there occurs a range of functional abnormalities of CD4+ T helper cells which include reduced impaired expression of IL7 and IL2 receptors, and decreased production of CD28 expressing cells. Cells without CD28 expression respond suboptimally to activation signals. Antibody dependent cell-mediated cytotoxicity also contributes to overall decrease in number of CD4+ T helper cells by causing destruction of uninfected CD4+ T helper cells also known as innocent bystander lysis.
The progressive decrease in the number of CD4+ T helper cells occurs due to a combination of plasma membrane disruption due to viral budding, Fas dependent and Fas independent apoptosis, and syncytia formation.
HIV gene products like env, tat and vpr enhance apoptosis. Recently, an inflammatory mode of cell death pyroptosis, involving caspase 1 and IL1b has been postulated in HIV mediated CD4 cell destruction.
CXCR-4 tropic HIV isolates induce fusion between adjacent T cell membranes to form a giant multinucleate cell called syncytium. Cell death of both HIV infected as well as uninfected T helper is accelerated during syncytia formation. The rate of destruction of CD4+ T helper cells exceeds the rate of reconstitution of CD4+ T helper cells pool. This is due to a number of factors like destruction of the fibroblastic reticular cell network, collagen deposition, and reduced utilization of the T cell survival factor interleukin 7 in the lymphoid tissue which ultimately leads to a state when CD4+ T helper cells count drops below critical level.
CD8+ T cells: HIV specific CD8+ CTL (cytotoxic T lymphocyte) response is able to contain the replication of virus only for a brief period. As the disease progresses, number of escape mutants keeps increasing which enables HIV to evade CTL response.
There are a lot of functional abnormalities of CD8+ T cells occur during the course of HIV infection like expression of activation markers HLA DR, upregulation of inhibitory receptors PD-1, reduced expression of IL-2 receptor (CD25), IL-7 receptor (CD127), and CD28. These functional abnormalities result in less secretion of CC chemokines such as RANTES (regulated on activation, normal T cell expressed and secreted) or chemokine (C-C motif) ligand 5 (CCCL5), macrophage inflammatory proteins (MIP) 1a and b. These CC chemokines inhibit viral replication. As functional abnormalities of CD8+ T cells ensue, there is less secretion of chemokines and subsequently viral replication goes unchecked. Also the quantitative as well as qualitative decline in CD4+ T helper cells adversely affects CD8+ T cells.
B cells: In HIV infection, there is aberrant B cell activation which leads to hypergammaglobulinemia. Over the period of the disease, there is production of aberrant memory B cells with reduced expression of CD21, and upregulation of inhibitory receptors. All these eventually lead to functional exhaustion of B cells. Neutralizing antibodies directed against envelop glycoproteins gp120 and gp41 are able to neutralize HIV during early course of infection. Subsequently, due to lack of proof-reading capacity of the viral reverse transcriptase (RT) enzyme, there is generation of high degree of viral diversity, which accounts for escape mutants which escape the neutralizing antibodies. Although some individuals mount broadly neutralizing antibody response, capable of recognizing highly diverse stains, these antibodies develop very late in the course of the disease and their clinical significance is not very clear.
Protective antibodies raised against HIV are also implicated in disease progression. It has been shown that antibodies against gp41 facilitate infection of new cells through Fc receptors (anti body enhancement). Anti- gp120 antibodies also participate in ADCC (antibody-dependent cell-mediated cytotoxicity) and destroy uninfected CD 4 cells by bystander killing.
The pathogenesis of HIV is a complex interplay of viral and host immunologic events and varies during different stages of the disease process. The typical course of an untreated HIV-infected individual can be broadly subdivided into primary infection, clinical latency and finally advanced disease. The pathogenic events during various stages of the disease are described below.
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