Causes

Overview

The precise pathogenic mechanisms involved in the development of HIV-associated neurocognitive disorders (HAND) are not yet fully understood. 


Virus-related factors

HIV enters the brain early in infection, possibly via infection of leukocytes that subsequently cross the blood-brain barrier.2,3

  • Although neurons are not directly infected by HIV, data suggest that they may be damaged or functionally impaired by the effects of viral proteins, such as gp120 and tat, and/or inflammatory mediators generated during sustained immune activation.2,3
  • HIV-associated encephalopathy is characterised by gliosis, microglial nodules, perivascular macrophage accumulation and the presence of multinucleated giant cells,3 suggesting an inflammatory aetiology and the involvement of astrocytes in immune activation and chemotaxis.
    • HIV-associated cognitive impairment correlates with the increased presence in the CNS of activated, but not necessarily HIV-infected, macrophages/microglia.4
    • Studies have shown the presence of low levels of HIV RNA in the CNS despite access to highly active antiretroviral therapy (HAART), and microglial/macrophage activation in the brain despite plasma HIV RNA suppression.3
    • There is some evidence that peripheral reservoirs of HIV, such as bone marrow, are important in the aetiology of HAND.3
       
  • The synaptic-dendritic neuronal damage seen in HAND may potentially be reversible, which would be consistent with the fluctuating symptoms and less aggressive degree of inflammation described in the post-HAART era.3
    • However in one study, previous advanced immunosuppression was associated with current neurocognitive impairment, suggesting that a non-reversible component of neuronal injury may occur in some patients.5,6 
       

Other factors

In addition to factors directly related to the virus and corresponding immune response, there are other factors that may be present in HIV-infected people and that could theoretically contribute to neurocognitive impairment. 


  • Medical conditions and comorbid factors:
    • vitamin B12 deficiency7
    • vascular disease,4 prior cardiovascular disease and cardiovascular risk factors8,9
    • diabetes and insulin resistance9
    • the metabolic syndrome9
    • thyroid dysfunction7
    • hepatitis C virus infection2,9–11
    • neurosyphilis7
    • depression7,12
    • sleep disorders13
    • substance abuse7,11
       
  • Increased survival of HIV-infected individuals:
    • effects of aging2,14
    • decreasing cardiac function is associated with accelerated brain aging15

References

  1. Department of Health and Human Services. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Accessed 3 March 2011.
  2. McArthur J, Steiner J, Sacktor N, Nath A. Human immunodeficiency virus-associated neurocognitive disorders: Mind the gap. Ann Neurol. 2010;67:699–714.
  3. Valcour V, Sithinamsuwan P, Letendre S, et al. Pathogenesis of HIV in the central nervous system. Curr HIV/AIDS Rep. 2011;8:54–61.
  4. Ghafouri M, Amini S, Khalili K, Sawaya BE. HIV-1 associated dementia: symptoms and causes. Retrovirology. 2006;3:28.
  5. Robertson KR, Smurzynski M, Parsons TD, et al. The prevalence and incidence of neurocognitive impairment in the HAART era. AIDS. 2007;21:1915–1921.
  6. McArthur JC, Brew BJ. HIV-associated neurocognitive disorders: is there a hidden epidemic? AIDS. 2010;24:1367–70.
  7. Taiwo B, Hicks C, Eron J. Unmet therapeutic needs in the new era of combination antiretroviral therapy for HIV-1. J Antimicrob Chemother. 2010;65:1100–1107.
  8. Wright EJ, Grund B, Robertson K, et al. INSIGHT SMART Study Group. Cardiovascular risk factors associated with lower baseline cognitive performance in HIV-positive persons. Neurology. 2010;75:864–873.
  9. Clark US, Cohen RA. Brain dysfunction in the era of combination antiretroviral therapy: implications for the treatment of the aging population of HIV-infected individuals. Curr Opin Invest Drugs. 2010;11:884–900.
  10. Vigil O, Posada C, Woods SP, et al. Impairments in fine-motor coordination and speed of information processing predict declines in everyday functioning in hepatitis C infection. J Clin Exp Neuropsychol. 2008;30:805–815
  11. Gonzalez R, Cherner M. Co-factors in HIV neurobehavioural disturbances: substance abuse, hepatitis C and aging. Int Rev Psychiatry. 2008;20:49–60.
  12. Bragança M, Palha A. Depression and Neurocognitive Performance in Portuguese Patients Infected with HIV. AIDS Behav. 2011. [Epub ahead of print]
  13. Nokes KM, Kendrew J. Correlates of sleep quality in persons with HIV disease. J Assoc Nurs AIDS Care. 2001;12:17–22.
  14. Chang L, Lee PL, Yiannoutsos CT, et al. A multicenter in vivo proton-MRS study of HIV-associated dementia and its relationship to age. Neuroimage. 2004;23:1336–1347.
  15. Jefferson AL, Himali JJ, Beiser AS, et al. Cardiac index is associated with brain aging. The Framingham Heart Study. Circulation. 2010;122:690–697.