Human Immunodeficiency virus is a
retrovirus. Retroviruses have an enzyme,
reverse transcriptase that can transcribe RNA into DNA. HIV has been shown to have a profound effect
on the brain of patients infected by the virus.
It causes HAD (HIV associated dementia) in Aids patients. The damage to the brain from this virus is
caused by the virus crossing through the blood brain barrier (BBB). The blood brain barrier is a barrier
composed of epithelial cells that are tightly connected by proteins forming
tight junction complexes. Early in the
onset of AIDS, HIV is thought to use activated monocytes to infect cells in the
brain. The virus supposedly uses regular
biological mechanisms for crossing the blood brain barrier.
In the later stages of AIDS the
blood brain barrier (BBB) is mechanically altered, thus allowing for an
increase in infected monocyte and macrophage to invade the brain. Many mechanisms have been proposed for how HIV
is able to alter the blood brain barrier.
One mechanism is that cytokines released by infected cells or activated
epithelial cells disrupts the BBB allowing for infected cells to infiltrate
into the brain. Cytokines
(cell-signaling proteins) can cause epithelial cells to secrete proteins that
thin the basal lamina (the lining of proteins between the epithelial cells and
other cells in the blood). Another
mechanism proposed is the viral protein such as Tat and gp120 are secreted from
infected cells could alter the blood brain barrier. Tat has been shown in animal
models to cause disorganization of the tight junction complexes in the blood
brain barrier. Also, gp120 has been shown in animal models to cause degradation of
both the basal lamina and the protein that makes up the tight junction complexes
between the epithelial cells. Another
belief in the research community is HIV can infect the endothelial cells in the
blood brain barrier leading to infection in the brain. If the endothelial cells can be infected with
HIV, the cells could secrete Tat or other proteins that could cause the
degradation of the basal lamina and tight junctions. The epithelial cells could also die due to
infection leading to the infiltration of infected cells into the brain.
After the blood brain barrier has
been altered infected monocytes and macrophages can enter the brain at a higher
rate. As more monocytes (t-cells) enter
the brain they recruit macrophages by secreting cytokines activating more cells
which leads to inflammation and oxidative stress in the brain. The microglia and astrocytes (brain cells) become
infected and can replicate the virus to infect more cells in the brain. All these events contribute to the cause of
HAD.
One question that arises from my
research done on this topic is: what would be the target for drug treatment to
prevent the progression of HAD?
References:
Grass G and Kaul M. Molecular Mechanisms of neuroinvasion by
monocytes-macrophages in HIV-1 infection.
Retrovirology 2010. 7:30.
Miller F, Afonso P, Gessain A and
Ceccaldi P. Blood-brain barrier and retroviral
infections. Virulence 2012. 3:222-229.
Valcour V, Shiramizu B and
Shikuma C. HIV DNA in circulating
monocytes as a mechanism to dementia and other complication. Journal of Leukocyte Biology 2010.
87:621-626.
Having studied HIV many times in the past, it is known that HIV has a slow progression where the immune system becomes noticeably compromised around 10 years after initial infection. This is when damage to the host is noticeable and the host is susceptible to a wide range of secondary infections. It is interesting to learn that one destructive mechanism of the HIV virus that is noticeable is its ability to influence the permeability of the BBB and thus activating monocytes to turn into macrophages that cause motor and cognitive damage in the brain, since HIV targets CD4+ cells. However, I did not know that the actual gp120 protein can be secreted from HIV infected cells that increases the permeability of the BBB. I’ve learned that the gp120 spike on the HIV virus is involved in attachment to the surface of a CD4+ cell, but I have never came across the idea that this protein can also be secreted to elicit further damage.
ReplyDeleteThis is also the first time I have heard of the gp120 being secreted, that is very interesting. With regards to your question about the target for drug treatment, I think the specific mechanism that causes this is needed to be able to answer that question. As you described there are many proposed mechanisms but none that are for sure or close to it yet. The reason I think the mechanism needs to be known instead of targeting more generally, is because if the wrong mechanism is targeted it could cause even more damage or an accelerated degradation of the BBB instead of helping. I think this is an interesting topic, also having studied HIV so much,it's effect on the brain was not covered in much detail- it seems to be an area of limited knowledge.
ReplyDeleteMaybe you could target through activation of Wnt signaling that strengthens tight junctions? It might depend on if microglia are infected before the virus is even diagnosed, but I think treatment of HIV would need multiple drugs. You also might block immune cells from crossing, but repairing the wall of tight junctions seems to me like a potential target. Attached is an article about Wnt and the BBB.
ReplyDeletehttp://jcb.rupress.org/content/183/3/371.full.pdf
I found from my research on HIV that AIDS patients have circulating gp120 in their serum. Researchers think that HIV infected cells shed gp120 due to massive virus yield. One study done by Toneatto et al., showed in HIV-1 gp120 transgenic mice levels of gp120 in the serum of these mice were comparable to the levels found in AIDS patient’s serum. They showed that the transgenic mice’s brains had significantly higher expression of two proteins (ICAM-1 and VCAM-1) expressed in endothelial cells in the blood brain barrier. These proteins are adhesion molecules used by endothelial cells to recruit leukocytes. The authors of this paper think that gp120 is responsible for some on the changes seen in the blood brain barrier by acting as a cytokine leading to the upregulation of adhesion molecules in the endothelial cells.
ReplyDeleteToneatto S, Finco O, Putten H, Abrignani S and Annunziata P. Evidence of blood-brain barrier alteration and activation in HIV-1 gp120 transgenic mice. AIDS 1999. 13:2343-2348.
Very interesting read! In response to your question about treatment targets, my immediate thought was "what aspect of the CNS is being targeted here?". I studied neurobiology for several years prior to deciding to be a statistics geek. I still have a love for neuro...one of the things that always fascinated me about neruo-degenerative diseases is how many different ways there are to affect the CNS. I found an article that contends HAD is more a result of synaptic loss rather than neuronal cell loss. They think the presence of specific HIV proteins leads to biological cascades which culminate in synaptic degradation. I wonder if (like so many mechanisms) this arises from multiple effects...or if HAD is really a family of diseases (much like ALS, "Lou Gherrig Syndrome") which has different causes resulting in the same observed symptoms.
ReplyDeleteBhagavathi Perumal, Madhusoothanan, and Saranya Dhanasekaran. "HIV associated dementia: Role for neurosteroids." Medical Hypotheses (2012).