HIV in the Brain

[Mishma]

In 2004 I went on disability for HIV dementia. Lumbar punctures revealed a discordance between my CNS and my plasma; 12,000 in the CNS and UD in plasma. It has profoundly affected my ability to make cogent and logical arguments, recall chord progressions in songs I've played all my life, the lyrics to those same songs, remembering names, dates, long and short term memory problems in general, mentation, and significant  life events. Despite a recent switch from a protease inhibitor to a integrase inhibitor the problems still persist with several notable exceptions: My tinnitus and hyperacusis (hypersensitivty to sound) has resolved.

Since I contracted HIV early in the game (83-85?) and my nadir CD4 count in 1990 was 40 I had two of the significant risk factors for developing the dementia. It is disconcerting to me to read that despite early intervention and successful HAART, HIV related neurological disorders still persist.



HIV Infection of Astrocytes         
Written by Eliseo A. Eugenin      
Friday, 08 July 2011 06:23

HIV infection of astrocytes a novel brain viral reservoir that uses gap junction channels to amplify toxicity and facilitate viral rebound.


http://www.hiv-reservoir.net/index.php/the-news/142-hiv-infection-of-astrocytes-.html

An article written by Eliseo A. Eugenin. Ph.D, Assistant Professor of Pathology Center for AIDS Research (CFAR) Investigator, Dept. of Pathology. F727, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461, USA

HIV-1 enters the brain approximately 2 weeks after primary infection and despite successful antiretroviral therapy (ART), central nervous system (CNS) infection and HIV associated neurologic disorders (HAND) still persist in 50 % of infected individuals. This CNS compromise has been associated with amplification of damage rather that the virus itself, especially in the current ART era that effectively reduces viral load to undetectable or low levels (Gannon et al., 2011). The amplification mechanisms that result in neurological disorders in HIV-1 infected individuals are not completely understood.

It was known for many years that HIV can infect few astrocytes and viral replication in these cells is extremely restricted (Conant et al., 1994; Tornatore et al., 1994; Brack-Werner, 1999; Ohagen et al., 1999; Schweighardt and Atwood, 2001). Thus, the scientific community did not continue to examine the importance of this cell type in the pathogenesis of AIDS and its role as a viral reservoir. In the last few years we began re-examining the role of these cells in the context of AIDS and NeuroAIDS. We demonstrated in agreement with previous reports, that HIV infects only few astrocytes in vitro and in vivo, and that viral replication is extremely low to undetectable (Eugenin and Berman, 2007; Eugenin et al., 2011).

However and even thought only 5 % of the cells are infected, this cell type is the more abundant cell type in the brain, thus, the total number of infected cells correspond to a large number. Experiments to determine whether the virus alters cell death indicated that these infected cells in vivo and in vitro are protected from apoptosis, resulting in a perfect reservoir for the virus.

In addition, we detected that despite low to undetectable viral replication and numbers of infected cells, bystander killing of uninfected CNS cells surrounding these HIV infected astrocytes resulted in astrocyte, neuronal and endothelial apoptosis. This damage results in CNS dysfunction and BBB disruption even in the absence of viral replication. This is representative of the current ART era where viral replication and presence of highly infected cells is minimal.

We showed that gap junction channels, the only type of channel that connects directly the cytoplasm of two or more apposed cells (Saez et al., 2003), enable coordination of intercellular signals that are amplified from few HIV infected cells into uninfected cells. These channels normally coordinate different function such as metabolism, electrical signals, migration and intercellular signaling.

In pathological conditions, gap junction channels in astrocytes are usually down regulated, but HIV infection by an unknown mechanism, hijacks this communication system to spread toxicity and inflammation. Thus, HIV infection maintains the viability of these few infected cells, inducing bystander killing of uninfected surrounding cells and enhancing inflammation, resulting in CNS damage by a gap junction dependent mechanism.
 
 
We propose that astrocytes are an important viral reservoir within the brain, and also that gap junction channels are key mediators of amplification of damage from these few infected cells to uninfected cells even in non replicating viral conditions.


We propose that astrocytes are an important viral reservoir within the brain, and also that gap junction channels are key mediators of amplification of damage from these few infected cells to uninfected cells even in non replicating viral conditions. Our data suggest that elimination of the toxic effect of these viral reservoirs requires the elimination of both, the HIV immortalized astrocytes and the toxic signals generated by the HIV infected cells and amplified by gap junctions. Thus, both systems contribute to the pathogenesis of HAND and AIDS.

References
-Brack-Werner R (1999) Astrocytes: HIV cellular reservoirs and important participants in neuropathogenesis. Aids 13:1-22.
Conant K, Tornatore C, Atwood W, Meyers K, Traub R, Major EO (1994) In vivo and in vitro infection of the astrocyte by HIV-1. Adv Neuroimmunol 4:287-289.
-Eugenin EA, Berman JW (2007) Gap junctions mediate human immunodeficiency virus-bystander killing in astrocytes. J Neurosci 27:12844-12850.
-Eugenin EA, Clements JE, Zink MC, Berman JW (2011) Human immunodeficiency virus infection of human astrocytes disrupts blood-brain barrier integrity by a gap junction-dependent mechanism. The Journal of neuroscience : the official journal of the Society for Neuroscience 31:9456-9465.
-Gannon P, Khan MZ, Kolson DL (2011) Current understanding of HIV-associated neurocognitive disorders pathogenesis. Current opinion in neurology 24:275-283.
-Ohagen A, Ghosh S, He J, Huang K, Chen Y, Yuan M, Osathanondh R, Gartner S, Shi B, Shaw G, Gabuzda D (1999) Apoptosis induced by infection of primary brain cultures with diverse human immunodeficiency virus type 1 isolates: evidence for a role of the envelope. J Virol 73:897-906.
-Saez JC, Berthoud VM, Branes MC, Martinez AD, Beyer EC (2003) Plasma membrane channels formed by connexins: their regulation and functions. Physiol Rev 83:1359-1400.
-Schweighardt B, Atwood WJ (2001) HIV type 1 infection of human astrocytes is restricted by inefficient viral entry. AIDS Res Hum Retroviruses 17:1133-1142.
-Tornatore C, Chandra R, Berger JR, Major EO (1994) HIV-1 infection of subcortical astrocytes in the pediatric central nervous system. Neurology 44:481-487.

[songs06]

They used to tell, microglias (central nervous system's special defence cells - roots to macrophages) is the cause of HIV dementia, and they are reservoir of the HIV in the brain. But now these guys tell astocytes are also reservoir? This is bad news because astrocytes are most common glial cells in the brain, which are doing even blood brain barrier, and also doing most of the works in the brain. They are like worker cells. I might get gap junctions cause inflammation but how HIV enters astrocytes is what i don't get? They don't have receptors or co-receptors for HIV.

And is there anyone knows which ARD enters Blood Brain Barrier better than others? I really don't have any idea about this topic.

[friskyguy]

A Powerpoint presenation by Dr. Scott Letendre http://www.neurohiv.com/PUB/FILE/letendre.pdf
contains many details of the most recent science on this topic, including an updated CPE scale.......as of 2010....the latest one that I know of.
Refer to pages 17 and 18.

Part of the issue is that the meds with the highest CPE ranks are not ones that we typically use (AZT, indinavir, nevirapine), while some of our most commonly prescribed medications (tenofovir) are below average.
Medications that have above average CPE rank include abacavir, emtricitabine, efavirenz, maraviroc and raltegravir.

Higher CPE values are associated with lower HIV RNA levels in the CSF.....so the theory is that the higher your meds are ranked the more protection they are doing for your brain by keeping HIV replication and damage to a minimal

[Mishma]

http://www.ncbi.nlm.nih.gov/pubmed/17147503

This abstract would suggest HIV uses the CCR5 receptor for entry.


AIDS Res Hum Retroviruses. 2006 Nov;22(11):1152-61.
CCR5-, DC-SIGN-dependent endocytosis and delayed reverse transcription after human immunodeficiency virus type 1 infection in human astrocytes.
Deiva K, Khiati A, Hery C, Salim H, Leclerc P, Horellou P, Tardieu M.
Source
Laboratoire "Immunité antivirale systémique et cérébrale," INSERM U-802, Faculté de Médecine Paris-Sud et Université Paris-Sud eleven, 94276 Le Kremlin-Bicêtre Cedex, France.
Abstract
We sought to determine the pathway of HIV-1 entry into human astrocytes and the fate of HIV-1 by detecting viral DNA and GFP-tagged HIV-1 in HIV-1-infected primary astrocytes. Immunochemistry and FACS analysis were used to assess the expression of DC-SIGN in human purified cultures of astrocytes. HIV-1 LTR was detected by PCR in infected cultures of human embryonic astrocytes at their third passage. GFP-Vpr-labeled R5 tropic HIV-1 was used to infect astrocytes, and was followed by confocal microscopy. Forty percent of astrocytes expressed DC-SIGN at the membrane level. Viral DNA was detected 5 days after infection in human astrocytes, but not in the presence of anti-CCR5 and anti-DC-SIGN mAbs. T20, NH4Cl, and bafilomycin had no effect on viral DNA detection. We found that 67% of the fluorescent GFP-Vpr-labeled R5 tropic HIV-1 viruses were present in the endosomes of astrocytes at 24 h, but not in the presence of anti-CCR5 or DC-SIGN mAbs. Bafilomycin and NH(4)Cl each increased the amount of fluorescent HIV-1 detected outside endosomes. Titers of p24 remained low from day 1 to day 5 postinfection, in the presence or absence of NH4Cl. Astrocytes express DC-SIGN and HIV-1 penetrates into these cells through CCR5- and/or DCSIGN- mediated endocytosis, via a pH-dependent pathway, with a delayed reverse transcription after infection without productive infection.

Here is a link to a good graphic from our genetics group.

http://learn.genetics.utah.edu/content/addiction/reward/cells.html

[songs06]

well my combination looks like not CSF friendly. (i'm on tenofovir and lopinavir.) but it also looks like more blood brain barrier cross, more neurological and psychological side effects. (like efavirenz) Article says HIV enters CNS after 2 weeks. It seem to me like, more you wait you for starting the treatment, more risk of HIV dementia. Because even it is linked, having high CD4 count doesn't mean you have undetectable CSF or HIV is not replication in your brain. So i think starting early treatment is still looks better than waiting.

Also CCR5 and CXCR4 are famous co-receptors for HIV, but i knew they are on microgial cells but not on a glial cell like astrocytes. They always blamed microglial cells for HANDs. Very strange article indeed.