Accelerated ageing of the brain found in some HIV-positive people

CATIE News

Want to receive publications straight to your inbox?

CATIE

Since 1996, the widespread availability of potent combination anti-HIV therapy in high-income countries has resulted in dramatic changes in the HIV epidemic—deaths due to AIDS-related infections and cancers are no longer common.

Combination anti-HIV therapy works by greatly reducing HIV levels in the blood. This allows the immune system to begin making repairs. Since most high-income countries have subsidized access to health and social welfare systems, researchers increasingly expect that HIV-positive people who have minimal co-existing health conditions and who can adhere to therapy are likely to achieve near-normal life spans.

Despite this optimistic expectation for the future of HIV-positive people in high-income countries, there are some areas of concern, including these:

  • No combination or intensity of currently available anti-HIV therapy can cure HIV infection.
  • Although the immune system does improve because of therapy, it is never completely restored and HIV-positive people remain at heightened risk for the development of cancer.
  • No one knows what prolonged HIV infection does to the body.
  • The long-term side effects of combination anti-HIV therapy are unknown.

Inflammation

Although anti-HIV therapy can greatly reduce virus levels in the blood, small amounts of HIV continued to be produced within the body’s lymph nodes and tissues. This low-level production of HIV causes the immune system to be in an activated state.

The activation of the immune response is a normal response to infection. Once an infection has been brought under control, the immune system dampens down activation. However, because HIV infection persists, the immune system appears to be continuously activated. Such prolonged activation may in turn affect a broad range of the body’s organs and tissues. This is because the immune system has cells that rove around the body and can take up residence in organs and tissues. There, activated immune cells can affect the surrounding tissues of organs, disturbing the health and functioning of these organs.

Enter the brain

One organ that may be negatively affected by prolonged HIV infection is the brain. Since the earliest days of the HIV pandemic, researchers recognized that, in some cases, HIV infection could eventually result in behavioural and cognitive changes—including difficulty thinking clearly, problems with memory, confusion, delirium, and, in extreme cases, dementia. Now that potent combination anti-HIV therapy is widely available, AIDS-related dementia is rare in high-income countries. But emerging research suggests that subtle impairment of the brain’s thinking abilities occurs even in HIV-positive people who are adherent to therapy and who do not engage in substance use. These findings have spurred further research into HIV’s impact on the brain.

Brain scientists

The University of California at San Diego is recognized as a centre of excellence in research on HIV and its effects on the brain. Neuroscientists at that university recently completed a project to explore the issue of ageing of the brain in HIV-positive people. Their preliminary findings suggest that the brains of some HIV-positive people appear to be prematurely aged to a considerable degree.

Magnetic scans

A critical aspect of the recent San Diego study is that researchers used a technique called fMRI (functional magnetic resonance imaging). MRIs are widely used in hospitals to provide painless and detailed images of the body. MRIs work by exposing the body to a powerful magnetic field and taking images of the effect of this magnetic field on cells and tissues.

In the case of fMRI, people are asked to perform activities—such as viewing images or answering questions—while the scan is in progress. These activities help scientists see what parts of the brain are in use during the scan and capture their activities. fMRI also can detect the difference between blood that is low in oxygen and blood that is rich in oxygen and how this difference affects brain cells. Neuroscientists have found fMRI useful when studying complex processes in the brain, such as reading, language skills and behaviour.

Study details

In San Diego, researchers recruited two groups of people for their study, as follows:

  • 26 HIV-positive volunteers
  • 25 HIV-negative volunteers

The average profile of the HIV-positive people was as follows:

  • 23% female, 77% male
  • age – 39 years
  • CD4+ count – 486 cells
  • 60% were taking anti-HIV therapy

None of the participants had any of the following conditions:

  • other neurologic illness
  • stroke
  • major psychiatric disorders
  • substance use in the previous three months (confirmed with urine testing)

All participants received fMRI and they viewed images during portions of the scan.

Results

The research team found that HIV-positive people had significantly reduced blood flowing in their brains, regardless of their age and whether or not they used anti-HIV therapy. After comparing fMRI scans from the two groups in the study, the researchers said that the effect of HIV infection on the brain was “equivalent to a 21-year increase in brain age.”

What’s more, researchers also found reduced levels of oxygen in the blood circulating in the brains of HIV-positive people, again regardless of age and whether or not they were using anti-HIV therapy. The research team found that the level of oxygen present in the blood in the brains of HIV-positive participants—regardless of their age—was similar to that seen in people who were 15 years older.

Ebb and flow

Blood supplies nutrients that brain cells need in order to function. It also brings oxygen to brain cells and carries away waste products such as carbon dioxide. Reduced blood flow to the brain may result in decreased oxygen and nutrients available to brain cells. In turn, this could reduce the ability of brain cells to work at their best. Over prolonged periods this reduced flow of oxygen and nutrients may, in theory, age the brain.

Caution needed

Here are some points to bear in mind when considering this research on ageing and the brain:

  1. The type of research design used by the San Diego team is called a cross-sectional study. Such studies are analogous to a snapshot in time. They can only give researchers a picture of what is happening to a group of people at a particular moment in time.
  2. The study team acknowledges this issue and calls for a longitudinal study—one that would track changes over long periods of time in the brains of volunteers. This kind of study would reveal more about the nature of the condition that researchers have uncovered. Also, a longitudinal study would confirm the findings from the present study. Such confirmation is required.
  3. Another limitation of the present study is the modest number of HIV-positive volunteers. Because of this, researchers cannot be certain that the accelerated ageing that they have uncovered is a common feature of HIV infection.
  4. One of the issues that affect neurologic research is substance use, including the abuse of alcohol, exposure to cocaine, crystal meth, heroin and other illicit substances. These drugs can damage the brain and affect intellectual functioning. Roughly equal proportions of people in both study groups (40%) had a history of substance use. A future study needs to investigate any possible connection between substance use, HIV infection and ageing.

What’s next?

The research team does not encourage “the use of fMRI for routine diagnostic evaluation of HIV-positive individuals because of its expense and relatively limited availability.” However, the researchers acknowledge that future research with fMRI may be useful in helping neuroscientists gain insight into how HIV infection can damage the brain. They state that fMRI “could assist in the evaluation of neuroprotective therapeutic strategies for older HIV-positive patients.”

The present study has uncovered something important—the apparent accelerated ageing of the brains of some HIV-positive people. Researchers need to confirm this, determine the extent of the problem and figure out ways of helping to slow or rejuvenate ageing brains.

Look for this:

The upcoming issue of CATIE’s Positive Side magazine (Winter 2010) features a first-person article by activist Maggie Atkinson on the topic of neurocognitive problems in HIV. You can read about her experience and what she learned about protecting her brain. ‘A Mind of Her Own’ can be found at:

http://www.positiveside.ca/e/V11I2/Mind_e.htm

—Sean R. Hosein

REFERENCES:

  1. Snider WD, Simpson DM, Nielsen S, et al. Neurological complications of acquired immune deficiency syndrome: analysis of 50 patients. Annals of Neurology. 1983 Oct;14(4):403-18.
  2. Levy JA, Shimabukuro J, Hollander H, et al. Isolation of AIDS-associated retroviruses from cerebrospinal fluid and brain of patients with neurological symptoms. Lancet. 1985 Sep 14;2(8455):586-8.
  3. Carne CA, Tedder RS, Smith A, et al. Acute encephalopathy coincident with seroconversion for anti-HTLV-III. Lancet. 1985 Nov 30;2(8466):1206-8.
  4. Appay V, Sauce D. Immune activation and inflammation in HIV-1 infection: cause and consequences. Journal of Pathology. 2008 Jan;214(2):231-41.
  5. Grossman Z, Meier-Schellersheim M, Paul WE, et al. Pathogenesis of HIV infection: what the virus spares is as important as what it destroys. Nature Medicine. 2006 Mar;12(3):289-95.
  6. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Medicine. 2008 Oct 21;5(10):e203.
  7. Cadogan M, Dalgleish AG. HIV immunopathogenesis and strategies for intervention. Lancet Infectious Diseases. 2008 Nov;8(11):675-84.
  8. Herbeuval JP, Nilsson J, Boasso A, et al. HAART reduces death ligand but not death receptors in lymphoid tissue of HIV-infected patients and simian immunodeficiency virus-infected macaques. AIDS. 2009 Jan 2;23(1):35-40.
  9. Boasso A, Hardy AW, Anderson SA, et al. HIV-induced type I interferon and tryptophan catabolism drive T cell dysfunction despite phenotypic activation. PLoS One. 2008 Aug 13;3(8):e2961.
  10. French MA, King MS, Tschampa JM, et al. Serum immune activation markers are persistently increased in patients with HIV infection after 6 years of antiretroviral therapy despite suppression of viral replication and reconstitution of CD4+ T cells. Journal of Infectious Diseases. 2009 Oct 15;200(8):1212-5.
  11. Ostrowski SR, Katzenstein TL, Thim PT, et al. Low-level viremia and proviral DNA impede immune reconstitution in HIV-1-infected patients receiving highly active antiretroviral therapy. Journal of Infectious Diseases. 2005 Feb 1;191(3):348-57.
  12. Robinson-Papp J, Byrd D, Mindt MR, et al. Motor function and human immunodeficiency virus-associated cognitive impairment in a highly active antiretroviral therapy-era cohort. Archives of Neurology. 2008 Aug;65(8):1096-101.
  13. Robinson-Papp J, Elliott KJ, Simpson DM. HIV-related neurocognitive impairment in the HAART era. Current HIV/AIDS Reports. 2009 Aug;6(3):146-52.
  14. Becker JT, Kingsley L, Mullen J, et al. Vascular risk factors, HIV serostatus, and cognitive dysfunction in gay and bisexual men. Neurology. 2009 Oct 20;73(16):1292-9.
  15. Simioni S, Cavassini M, Annoni JM, et al. Cognitive dysfunction in HIV patients despite long-standing suppression of viremia. AIDS. 2010: in press.
  16. Holdsworth SJ, Bammer R. Magnetic resonance imaging techniques: fMRI, DWI, and PWI. Seminars in Neurology. 2008 Sep;28(4):395-406.
  17. Ances BM, Liang CL, Leontiev O, et al. Effects of aging on cerebral blood flow, oxygen metabolism, and blood oxygenation level dependent responses to visual stimulation. Human Brain Mapping. 2009 Apr;30(4):1120-32.
  18. Brown GG, Perthen JE, Liu TT, et al. A primer on functional magnetic resonance imaging. Neuropsychology Review. 2007 Jun;17(2):107-25.
  19. Crowe SM, Westhorpe CL, Mukhamedova N, et al. The macrophage: the intersection between HIV infection and atherosclerosis. Journal of Leukocyte Biology. 2010; in press.
  20. Ances BM, Vaida F, Yeh MJ, et al. HIV infection and aging independently affect brain function as measured by functional magnetic resonance imaging. Journal of Infectious Diseases. 2010; in press.