Introduction
The Acquired Immunodeficiency Syndrome (AIDS) is the disease caused by in infection with Human Immunodeficiency Virus (HIV). The disease is categorized by profound immunosuppression with associated opportunistic infections and malicious tumors, degenerative, central nervous system (CNS) deterioration. The virus of HIV infects a variety of human cells of the immune system, including CD4+ helper T cells (CD4 are a type white blood cells), macrophages and dendritic cells. HIV epidemic was first identified in the 1980s and evolved as human pathogen. About 84.2 million people have been infected by HIV and more than 40.1 million adults and children are died due to HIV. Approximately 38.4 million people are living with HIV infection and AIDS of which approximately 70% are in Africa and 20% in Asia and almost 2 million people die of the disease every year. The disease is especially devastating because about half of the approximately 3 million new cases every year occur in young adults (15 to 24 years old). AIDS has left approximately 14 million orphans and resulted in the death of approximately 30 million people. Currently there is no effective vaccine or cure for AIDS, but quite effective antiretroviral therapies have been developed.
How HIV causes
Immunodeficiency in Human?
The function of both the
adaptive and innate immune system become ultimately impaired after the
infection of HIV. The HIV can be attributed to several mechanisms, the most
common defects are in cell mediated immunity which includes its direct
cytopathic effect and indirect effects.
In HIV infected people the
direct cytopathic effect of infection of CD4+ T cells by HIV is a major reason
behind the loss of these cell. The production of HIV in CD4+ T Cells is ultimately
resulted into their death and decline in the number of these cell in human
body. Following are major serious effect of HIV on infected CD4+ cells:-
1. The permeability of plasma membrane is increased and as well as increase in entry of fatal amount of calcium due to production of virus with expression of gp41 in the plasma membrane and budding of viral particles. This encourages apoptosis, or osmotic lysis of the cell caused by the inflow of water.
2. The Cell died due to interference in
synthesis of cellular protein by the production of virus.
3. Multinucleated giant cells or syncytia are
formed due to fusion of plasma membranes of HIV-infected T cells with
uninfected CD4+ T cells by virtue of gp120-CD4 interactions. This formation of
HIV-induced syncytia is toxic to both HIV-infected T cells as well as for
uninfected CD4+ T cell that fuse to the infected cells.
4. In HIV-infected individuals the production
of virus in infected CD4+ T cells also ultimately lead to the depletion and
loss of function of these cells.
The one way that has been finally lead to immunodeficiency
that are common in HIV-infected patients is chronic activation of uninfected T
cells or also by production of cytokines as a result of these infections which
ultimately rise apoptosis of the cells. Resultantly the numbers of HIV-infected
cells are highly increased due to the apoptotic death of activated lymphocytes
or the loss of CD4+ T cells. Many patients of AIDS possess HIV-specific cell
mediated cytotoxicity because the antibodies against HIV envelope proteins may
bind to HIV-infected CD4+ T cells. The cells become incapable of responding to
antigenic stimulation due to blockage in cell surface expression of CD4 caused
by interference with normal protein processing in the endoplasmic reticulum as
a result of binding of gp120 to newly synthesized intracellular CD4.
Depletion of CD4+ T cells causes defects in the function of immune system and intensify the immune deficiency in HIV infected individuals. These defects in the function include a decrease in T cell responses to antigens and weak humoral immune responses. These defects can be caused due to the effect of HIV infection on CD4+ T cells as well as effect of soluble gp120 released from infected cells binding to uninfected cells. For example, CD4 which has bond gp120 might not be available to interact with class II MHC molecules on APCs and hence inhibited the responses T cell to antigens. On the other hand, helper T cell function downregulated due to signals delivered by gp120 binding to CD4. The T cells infected with HIV being incapable to form tight synapses with APCs and this may also restrict T cell activation.
In the pathogenesis of immunodeficiency caused by HIV, the
Tat protein may play some role. The Tat within T cells can interact with a
variety of regulatory proteins and resultantly inhibited normal T cell
functions such as production of cytokine. This Tat can escape across the plasma
membrane and enter neighboring cells thus effect the activation of uninfected T
cells in a paracrine style.
Abnormalities in macrophages dendritic cells and follicular
dendritic cells due to infection of HIV also contribute to the development of
immunodeficiency.
As compare to helper T lymphocytes, macrophages express much lower levels of CD4 but macrophages can express CCR5 co-receptors and can causes HIV infection. Macrophages, however are comparatively resistant to the HIV-cytopathic effects.
A gp120/gp41-independent route may also infect macrophages. For example, Fc receptor-mediated endocytosis of antibody-coated HIV virions or phagocytosis of other infected cells. This is because generally macrophages may be infected by the virus instead of killed and become a base ground for the virus. As the number of macrophage linked with HIV exceeds T cell linked with virus in most tissues of AIDS patients including the brain and lungs. Macrophages infected with HIV may reduce antigen presentation functions and cytokine secretion.
1. HIV may also infect dendritic cells and as compare to macrophages, HIV infection does not directly damage the dendritic cells. But during the process of antigen presentation dendritic cells develops close connection with naïve T cells. It is suggested that during this process naïve T cells may be infected by dendritic cell and become as significant passage for the injury T cells.
2. FDCs (Follicular Dendritic Cells) present
in the germinal centers of lymph nodes and the spleen trap large amount of HIV
on their surfaces partially by Fc receptor-mediated binding of antibody-coated
virus. However, follicular dendritic cell are not efficiently infected but
provoked the pathogenesis of the HIV-linked immunodeficiency in following two
ways:-
a. The follicular dendritic cells surface is a
reservoir for HIV that can infect macrophages as well as CD4+ T cells in the
lymph nodes.
b.
The normal functions of follicular dendritic cells in immune responses are
reduced and may finally be demolished by the virus. The net result of loss of
the follicular dendritic cell network in the lymph nodes and spleen is a
profound dissolution of the architecture of the peripheral lymphoid
system.