HIV And Drug Abuse in the Edinburgh Cohort: Research Challenges and Opportunities
Jeanne E. Bell, et al.,
Western General Hospital
HIV continues to escalate in drug users despite the availability of effective drug therapy. There is increasing concern that HIV and drug use may be synergistic in their neurotoxic effects, affecting particular neuronal subsets, including the dopaminergic and serotonergic systems and the blood brain barrier.1 Investigation of a cohort of HIV-infected drug users in Edinburgh, United Kingdom, who seroconverted in 1983-84 is informative in this regard. This cohort has displayed a particularly high prevalence of cognitive impairment and of HIV encephalitis (HIVE) and has provided the opportunity to study the natural history of HIV infection in the central nervous system (CNS).2,3 Direct HIV-1 isolates extracted from the brain proved to be non-syncytium-inducing and CCR5 dependent, and analysis of p17gag diversity between lymphoid and brain tissues in individual cases confirmed early sequestration within the CNS compartment of some viral strains.4 More comprehensive nucleotide sequencing in p17gag, pol and V1/2, V3, V4, and V5 hypervariable regions of env, in extracts from different brain regions compared with lymph nodes, showed different degrees of variability, both within and between subjects.5 Discordant phylogenetic groups between p17gag and V3 suggest that recombination events and multiple viral entry contribute to the diversity of HIV populations in vivo. Increasing diversity of HIV variants within the brain correlated with increasing severity of HIVE.5 However, we have not identified any distinctive feature that might be construed as a "signature of the Edinburgh virus."
Histopathological assessment of this cohort shows that drug use alone activates microglia (CD68 and MHCII upregulation), which may render the brain more susceptible to repeated viral entry and spread of productive infection.6 Evidence for both acute and chronic blood-brain barrier breakdown is found in white matter and basal ganglia of drug users, particularly HIV-infected drug users, and this is likely to facilitate entry of infected cells.7 In pre-AIDS cases, between 4 and 120 months post-seroconversion, the brain and meninges are infiltrated with CD8 lymphocytes, but there is no evidence of productive HIV infection.6 Since brain isolates have proved to be different from those in lymphoid tissue (and blood), it is clear that selective neuroadaptive pressures operate before HIVE supervenes. Drug abuse may be synergistic in this process, and different drugs are likely to operate in different neural systems (e.g., cocaine and amphetamines are likely to affect the dopamine system, and cocaine may contribute to blood-brain barrier breakdown).8 Other factors likely to influence the evolution of HIV in the CNS include the duration of HIV infection and degree of immune breakdown, the age and gender of the patient, the presence of comorbidity pathogens or of parallel covert infection in other cells such as astrocytes,9 and sequestration of virus within the CNS (a so-called sanctuary site) with shelter from effective antiviral therapy.10 Collections of clinically well-characterized HIV-infected tissues, such as the Edinburgh Brain Bank, are a vital resource to support ongoing studies of viral pathogenesis in the CNS and interactions with drug abuse. (This work is supported by the UK Medical Research Council.)
- Swan N. CDC report highlights link between drug abuse and spread of HIV. /NIDA_Notes/NNVol12N2/CDCReports.html, 1997.
- Bell JE, Donaldson YK, Lowrie S, et al. Influence of risk group and zidovudine therapy on the development of HIV encephalitis and cognitive decline in AIDS patients. AIDS 10:493-9, 1996.
- Bell JE, Brettle RP, Chiswick A, Simmonds P. HIV encephalitis proviral load and dementia in drug users and homosexuals with AIDS: Effect of neocortical involvement. Brain 121:2043-52, 1998.
- Hughes E, Bell JE, Simmonds P. Investigation of the dynamics of the spread of HIV-1 to brain and other tissues by evolutionary analysis of sequences from the p17gag and env genes. J Virol 71:1272-80, 1997.
- Morris A, Marsden M, Halcrow K, et al. Mosaic structure of the human immunodeficiency virus type 1 genome infecting lymphoid cells and the brain: Evidence for frequent in vivo recombination events in the evolution of regional populations. J Virol, in press.
- Tomlinson GS, Simmonds P, Busuttil A, Chiswick A, Bell JE. Microglial upregulation in drug users in presymptomatic HIV infection: Correlation with proviral burden in different brain regions. Neuropathol Appl Neurobiol, in press.
- Gray F, Scaravilli F, Everall I, et al. Neuropathology of early HIV-1 infection. Brain Pathol 6:1-15, 1996.
- Nath A, Booze RM, Hauser K, et al. Critical questions for neuroscientists in interactions of drugs of abuse and HIV infection. Neuro AIDS Science online 1999, submitted.
- Brack-Werner R, Bell JE. Replication of HIV-1 in human astrocytes. NeuroAIDS Science online (due date on the Web, end September 1999).
- Schrager LK, D'Souza MP. Cellular and anatomical reservoirs of HIV-1 in patients receiving potent antiretroviral combination therapy. JAMA 280:67-71, 1998.