The Immune System, HIV and Shrinking Brains

In the previous report, researchers in London, UK, found very little changes in the brains of medically stable HIV-positive men compared with those of HIV-negative men of similar age and educational background. However, the London team used a sensitive and high-resolution MRI scanner that found that parts of the brains of some HIV-positive men were smaller than those of HIV-negative men. The London team did not, as part of their study, further investigate possible reasons for this difference. However, an American team of researchers has conducted a study to begin the process of possibly explaining similar differences found in some HIV-positive American men.

Preliminary findings from the American study in the journal Cerebral Cortex suggested that there is a link between the proportion of HIV-infected cells circulating in the blood and decreased size of certain parts of the brain. If their findings are confirmed by future studies, this may have implications for when in the course of HIV infection therapy should begin. Also, research may be needed to develop drugs that can protect brain cells from the toxic effect of HIV's proteins and inflammatory signals released by HIV-infected cells. Before delving into the details about the American study, we review some background information and remind readers that due to limitations in the design of this study, its findings should be treated as preliminary.

Brain Cells and HIV

HIV does not infect brain cells (neurons). However, it does infect monocytes, cells of the immune system, which, in their mature form are called macrophages. Monocytes/macrophages (m/m) can be found throughout the body; indeed these cells travel all over the body, including the brain. Some cells that are closely related to macrophages, called microglia, are permanent residents of the brain, where they are supposed to protect this organ.

Unlike T-cells, m/m do not quickly die when infected with HIV. The virus takes over m/m and turns them into mini-factories that produce HIV and viral proteins and chemical signals of inflammation -- all of which have a harmful effect on brain cells. For instance, a healthy T-cell or m/m communicates with brain cells, each different type of cell releasing chemical signals and proteins that keep the other cells in good working order. But once HIV infects an m/m, instead of releasing chemical signals that stimulate the well being of neurons, the infected m/m releases compounds that injure brain cells.

In the previously mentioned American study, researchers focused only on macrophages. In part, this focus arose because of previous studies linking HIV-infected macrophages to neurocognitive impairment.

Study Details

Researchers enrolled 19 HIV-positive participants, all of whom were taking ART and most of whom had a viral load in the blood of less than 50 copies/ml. Participants were free from the following:

• major mental health issues
• head injury
• a history of substance use

Participants underwent limited neurocognitive testing and technicians conducted MRI scans of the brain. Also, specialized laboratory testing that focuses on detecting HIV-infected monocytes in blood samples was done. The study team zeroed in on these cells because previous studies have found a connection between relatively high levels of infected monocytes in the blood and an increased risk for neurocognitive impairment and dementia.

Specifically the team assessed the amount of HIV DNA in monocytes. Technicians were able to identify monocytes in blood samples because these cells displayed the protein CD14 on their surface. Their assay for this had a lower limit of detection -- 10 copies per million cells. This assay is available for research use only.

The average profile of participants in the study was as follows:

• 18 men, 1 woman
• age -- 55 years
• CD4+ count -- 500 cells
• lowest ever (nadir) CD4+ count -- 170 cells
• 18 out of 19 participants had a viral load less than 50 copies/ml; the remaining person had a value of 158 copies/ml
• length of HIV infection -- 16 years

Results

The study team was able to divide participants into two groups, as follows:

• 10 participants without detectable HIV-infected cells in the blood
• 9 participants with detectable HIV DNA in the blood, an average of 132 copies per million cells

Technicians also took high-resolution MRI scans of the brains of participants. Among people with detectable HIV-infected cells in the blood, scientists found a modest degree of brain shrinkage or atrophy. Among people without detectable HIV-infected cells in the blood, there was generally no noticeable brain atrophy. This difference between the two groups was statistically significant.

Statistical analysis found no relationship between decreased brain size and any of the following factors:

• age
• educational level
• current CD4+ count
• lowest-ever CD4+ count

Participants with decreased brain size seemed to perform worse on some neurocognitive tests. But, bear in mind that only a limited number of such tests were done in this study.

Results in Perspective

The findings from the present study linking the number of HIV-infected monocytes in the blood to modest reductions in brain size make some sense. HIV-infected monocytes can travel to and accumulate within the brain. More HIV-infected monocytes within the brain may burden this organ with large numbers of HIV and viral proteins. Moreover, that the loss of brain tissue occurred in people with very little production of HIV in the blood (that is, a viral load generally less than 50 copies/ml) is somewhat concerning.

The disappearance of brain tissue was termed “cortical thinning” by the U.S. team. This problem has been found in other studies with HIV-positive people, however, those studies have not always controlled for substance use, mental health issues and other factors that could also affect the health of the brain.

What Are the Implications?

The greatest degree of cortical thinning in the present study occurred in a part of the brain called the bilateral anterior insula (or simply insula for short). This tissue is involved in many higher functions such as:

• control of vocal cords
• processing information about the sense of touch, pain and temperature
• processing information about the position of the body
• hand-eye coordination
• attention

Based on experiments both with mice and with HIV-negative people, the U.S. team suggests that damage to the insula may result in these problems:

• problems concentrating
• difficulty assessing risk in different situations
• impaired visual memory

The U.S. team noted that the insula is connected to several other regions of the brain, such as:

• cingulate cortex
• orbitofrontal cortex
• temporal pole
• superior temporal sulcus

In the present study, MRI scans revealed a degree of shrinkage in these regions of the brain in people who had HIV-infected monocytes detected in their blood. Damage to these additional parts of the brain could, the researchers stated, have the following impacts:

• decrease control and coordination of muscles
• affect judgment and control of impulsive behaviour
• reduce a person's ability to remember pictures, objects, faces and possibly some words

The present study focused mostly on the insula, but much more research is needed on the different parts of the brain affected by HIV infection and how this might affect a person's neurocognitive function and personality, as well as ways to slow or reverse this damage.

Caution Needed When Interpreting Data

The present study had several limitations, as follows:

• It was cross sectional in nature. This is analogous to taking a picture and trying to build a complete profile of a person. People change over time, and so monitoring over time with multiple MRI scans and neurocognitive testing over a period of years is needed. Cross-sectional studies are cheaper and perhaps simpler to run than longitudinal studies. However, cross-sectional studies can only provide limited information.
• The number of participants was relatively small.
• Only limited neurocognitive assessments were performed.

Due to these limitations, the U.S. team cannot prove that the loss of brain tissue was directly caused by a greater burden of HIV-infected monocytes in the brain. However, the present study does provide a foundation for a bigger, longer and more intensive study of how HIV infection could affect different parts of the brain.

If another study confirms the present study's findings, one implication arising from such research is that it might be helpful to begin anti-HIV therapy as early as possible after HIV infection. Such early initiation of therapy could help to reduce the burden of HIV-infected monocytes in the brain and to preserve this vital organ.

Later in this issue of TreatmentUpdate, we will report on a potential therapy for protecting the brain from the effects of HIV infection.

References

1. Pulliam L, Rempel H, Sun B, et al. A peripheral monocyte interferon phenotype in HIV infection correlates with a decrease in magnetic resonance spectroscopy metabolite concentrations. AIDS. 2011 Sep 10;25(14):1721-6.
2. Valcour VG, Shiramizu BT, Shikuma CM. HIV DNA in circulating monocytes as a mechanism to dementia and other HIV complications. Journal of Leukocyte Biology. 2010 Apr;87(4):621-6.
3. Shiramizu B, Williams AE, Shikuma C, et al. Amount of HIV DNA in peripheral blood mononuclear cells is proportional to the severity of HIV-1-associated neurocognitive disorders. Journal of Neuropsychiatry and Clinical Neurosciences. 2009 Winter;21(1):68-74.
4. Saitoh A, Hsia K, Fenton T, et al. Persistence of human immunodeficiency virus (HIV) type 1 DNA in peripheral blood despite prolonged suppression of plasma HIV-1 RNA in children. Journal of Infectious Diseases. 2002 May 15;185(10):1409-16.
5. Parisi SG, Andreis S, Mengoli C, et al. Baseline Cellular HIV DNA Load Predicts HIV DNA Decline and Residual HIV Plasma Levels During Effective Antiretroviral Therapy. Journal of Clinical Microbiology. 2011 Nov 30. [Epub ahead of print]
6. Piketty C, Weiss L, Assoumou L, et al. A high HIV DNA level in PBMCs at antiretroviral treatment interruption predicts a shorter time to treatment resumption, independently of the CD4 nadir. Journal of Medical Virology. 2010 Nov;82(11):1819-28.
7. Fink GR, Frackowiak RS, Pietrzyk U, et al. Multiple nonprimary motor areas in the human cortex. Journal of Neurophysiology. 1997 Apr;77(4):2164-74.
8. Eckert MA, Menon V, Walczak A, et al. At the heart of the ventral attention system: the right anterior insula. Human Brain Mapping. 2009 Aug;30(8):2530-41.
9. Jones CL, Ward J, Critchley HD. The neuropsychological impact of insular cortex lesions. Journal of Neurology, Neurosurgery, and Psychiatry. 2010 Jun;81(6):611-8.
10. Jones CL, Minati L, Harrison NA, et al. Under pressure: response urgency modulates striatal and insula activity during decision-making under risk. PLoS One. 2011;6(6):e20942.
11. Kuhnen CM, Knutson B. The neural basis of financial risk taking. Neuron. 2005 Sep 1;47(5):763-70.
12. Fineberg NA, Potenza MN, Chamberlain SR, et al. Probing compulsive and impulsive behaviors, from animal models to endophenotypes: a narrative review. Neuropsychopharmacology. 2010 Feb;35(3):591-604.
13. Berlin HA, Rolls ET, Kischka U. Impulsivity, time perception, emotion and reinforcement sensitivity in patients with orbitofrontal cortex lesions. Brain. 2004 May;127(Pt 5):1108-26.
14. Pourtois G, Vocat R, N'diaye K, et al. Errors recruit both cognitive and emotional monitoring systems: simultaneous intracranial recordings in the dorsal anterior cingulate gyrus and amygdala combined with fMRI. Neuropsychologia. 2010 Mar;48(4):1144-59.
15. Dhar M, Pourtois G. Early error detection is generic, but subsequent adaption to errors is not: evidence from ERPs. Neuropsychologia. 2011 Apr;49(5):1236-45.
16. Simões-Franklin C, Hester R, Shpaner M, et al. Executive function and error detection: The effect of motivation on cingulate and ventral striatum activity. Human Brain Mapping. 2010 Mar;31(3):458-69.
17. Brew BJ, Crowe SM, Landay A, et al. Neurodegeneration and ageing in the HAART era. Journal of Neuroimmune Pharmacology. 2009 Jun;4(2):163-74.
18. Chang L, Andres M, Sadino J, et al. Impact of apolipoprotein E ε4 and HIV on cognition and brain atrophy: antagonistic pleiotropy and premature brain aging. Neuroimage. 2011 Oct 15;58(4):1017-2.
19. Kallianpur KJ, Kirk GR, Sailasuta N, et al. Regional Cortical Thinning Associated with Detectable Levels of HIV DNA. Cerebral Cortex. 2012; in press.
20. Jernigan TL, Archibald SL, Fennema-Notestine C, et al. Clinical factors related to brain structure in HIV: the CHARTER study. Journal of Neurovirology. 2011 Jun;17(3):248-57.
21. Becker JT, Maruca V, Kingsley LA, et al. Factors affecting brain structure in men with HIV disease in the post-HAART era. Neuroradiology. 2011 Mar 22. [Epub ahead of print]
22. Becker JT, Sanders J, Madsen SK, et al. Subcortical brain atrophy persists even in HAART-regulated HIV disease. Brain Imaging and Behavior. 2011 Jun;5(2):77-85.
23. Cohen RA, Harezlak J, Gongvatana A, et al. Cerebral metabolite abnormalities in human immunodeficiency virus are associated with cortical and subcortical volumes. Journal of Neurovirology. 2010 Nov;16(6):435-44.
24. Tate DF, Sampat M, Harezlak J, et al. Regional areas and widths of the midsagittal corpus callosum among HIV-infected patients on stable antiretroviral therapies. Journal of Neurovirology. 2011 Aug;17(4):368-79.