Microbial Mechanisms to Escape the Immune System 3
|In previous posts (1,2) we discussed the mechanisms by which Gram positive and Gram negative bacteria evade the host immune response. Today, I would like to discuss some of the mechanisms that viruses use to escape the immune system. Bacteria and viruses employ very different strategies to avoid being targeted by the immune system. These two pathogens are very different, and even today there may be some controversy regarding if a virus is a living entity or not. The reason for that is that viruses need a host to replicate themselves.|
|One of the viruses that pose a significant human public health issue is HIV. HIV stands for Human Immunodeficiency Virus and the disease it causes is known as AIDS, which stands for Acquired Immunodeficiency Syndrome. Not everyone infected with HIV develops AIDS, which is the final stage of the infection. Patients at this stage have a severely damaged immune system, making them an easy target for opportunistic infections. These infections are not frequent in healthy individuals as opportunistic pathogens proliferate in patients with a weakened immune system.||
by Thomas Splettstoesser
|HIV is mainly a sexually transmitted disease. However, if blood of an infected person gets into the bloodstream of a healthy individual, there is a risk of infection. This is the case for disease transmission through sharing contaminated needles. The virus belongs to the Retroviridae family, which replicates through reverse transcription. In this process, instead of the classical DNA -> RNA -> protein synthesis pathway, the genomic material of the virus is stored in an RNA molecule, which is reverse transcribed to a DNA molecule that inserts itself into the host DNA. After that, the virus DNA uses the host molecular machinery to produce the proteins needed for self-replication. In this mechanism, the sequence goes as RNA -> DNA -> RNA -> protein.|
|Regarding the above sequence of events, it supports the hypothesis that RNA was the first molecule capable of storing genetic information, rather than today’s dominant DNA. In any case, modern therapy targeting HIV replication can efficiently inhibit the virus’ replication. This therapy, known as ART (anti-retroviral therapy), can reduce the infection to a chronic state with very low levels of viral titer. So, without any therapy, how does HIV manage to escape the immune system?||
What came first: the DNA or the RNA?
|The interaction of HIV with host cells is complex, but several details have been unveiled. HIV has a notorious T cell tropism; that is, the virus preferentially infects CD4+ T cells. As the virus persists and hides within memory T cells, it uses the same cells of the immune system designed to defend our body from pathogens. This is the pathogenic evolution of an evil genius, as it targets our main defense system. Thus, some of the warriors of our defense system actually become Trojan Horses that may destroy the whole system.|
|The virus enters macrophages and CD4 T cells by the adsorption of glycoproteins on its surface to specific receptors on these cells. This involves the CD4 molecule itself, along with a chemokine receptor, commonly CXCR4 and/or CCR5. A different viral glycoprotein binds to integrin α4β7, activating LFA-1, the central integrin involved in the establishment of virological synapses, which facilitate efficient cell-to-cell spreading of the virus. The virus can hide in the T cells for a long time, and a normal T cell response can’t be developed, so it escapes elimination.||
Okaaay, let’s see what we've got here...
|Mechanism of Viral Entry/Membrane Fusion
|Nonetheless, even before the virus reaches the T cells, it already starts showing its capacity to hijack the immune system. As it primarily enters the body through the genital mucosa, it has developed mechanisms to successfully cross this barrier. One of the proposed mechanisms is that the virus crosses the mucosa by transcytosis or by adhering to the dendrites of intraepithelial dendritic cells.
After penetrating the mucosal barrier, the virus can bind elements of the complement cascade, and induce downregulation of host complement receptors that impair monocyte chemotactic responses to inflammatory stimuli. In addition to this, HIV can also mimic or modulate certain pro-inflammatory cytokines and use the cytokine network to promote its own replication and survival.
|However, it is at the molecular level where the strongest weapon of HIV lies: its capacity to mutate. The HIV-1 RNA genome mutates randomly at a high rate which helps the virus to evade immune recognition by the host. The high mutation rate of the virus is facilitated by the activity of error prone viral reverse transcriptase that lacks proofreading activity. By constantly changing its appearance, the virus avoids recognition by the immune system.||
I ain't afraid of no tiger!
As seen on www.genius.com
|HIV is one the biggest challenges mankind has faced in terms of public health. Although there is no cure in sight, modern anti-retroviral therapy can keep the replication of the virus at very low or even undetectable levels. There are also many scientific labs working on preventing and even curing the disease, but until then, it’s best to be aware of the virus and the disease, and use preventative measures as necessary.|
|To learn more about HIV infection and its consequences we recommend the following reading:|
|Contributed by Miguel Tam, PhD|