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Metabolic Disorders in the Pathogenesis of Nervous System Damage in HIV Infected Drug Users

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Meeting Summary

Introduction

This workshop was planned, organized and conducted by Walter Royal, M.D., visiting neurologist from Johns Hopkins University School of Medicine, Baltimore, Jag H. Khalsa, Ph.D., Center on AIDS and Other Medical Consequences of Drug Abuse (CAMCODA), and Henry Francis, Director, CAMCODA, both within the National Institute on Drug Abuse (NIDA), a part of the National Institutes of Health (NIH). A group of nationally and internationally recognized neuroscientists/neurologists presented/discussed (i) current data on metabolic complications in the CNS of HIV-infected or AIDS patients using drugs of abuse; (ii) in-vitro tests and in-vivo models for the study of interactions-effects on P450 and other metabolic pathways; (iii) pharmacokinetic/pharmacodynamic aspects of drug action; (iv) the problems of design and conducting such studies in clinical populations; and (v) developing new drugs for the treatment of AIDS and drug addiction. Finally, they made recommendations for future research.

Since many investigators presented new and unpublished data, it was agreed that the abstracts could be placed on the NIDA's web site and only a brief executive summary should be published in a professional journal.

Abstracts

HIV and Drug Abuse in the Endinburgh 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.)

References

  1. Swan N. CDC report highlights link between drug abuse and spread of HIV. /NIDA_Notes/NNVol12N2/CDCReports.html, 1997.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. Gray F, Scaravilli F, Everall I, et al. Neuropathology of early HIV-1 infection. Brain Pathol 6:1-15, 1996.
  8. 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.
  9. Brack-Werner R, Bell JE. Replication of HIV-1 in human astrocytes. NeuroAIDS Science online (due date on the Web, end September 1999).
  10. Schrager LK, D'Souza MP. Cellular and anatomical reservoirs of HIV-1 in patients receiving potent antiretroviral combination therapy. JAMA 280:67-71, 1998.

Neurological Aspects of Substance Abuse

John C.M. Brust, M.D.

Abused substances in the United States are broadly categorized as opiates (eg., heroin), psychostimulants (eg., methamphetamine, cocaine), sedatives (eg., barbiturates, benzodiazepines), hallucinogens (eg., LSD), inhalants (eg., glues, gasoline), cannabis (marijuana), phencyclidine ("angel dust"), anticholinergics, ethanol, and tobacco. Intended effects and symptoms of overdose and withdrawal vary markedly among different agents. For example, ethanol or sedative withdrawal can cause fatal delirium tremens, whereas opiate withdrawal causes an unpleasant but not dangerous flu-like syndrome, and psychostimulant withdrawal causes depression but little in the way of measurable signs.

Neurological complications of substance abuse also vary with the agent. (1) Trauma in the case of ethanol or sedatives is usually the result of intoxication, whereas with other drugs is more likely the consequence of the drug's illegality. (2) Infection, a major risk for any parenteral drug abuser, includes HIV, endocarditis, hepatitis, tetanus, botulism, and a plethora of exotic organisms. (3) Seizures can be a feature of intoxication (eg., cocaine), of withdrawal (eg., ethanol) or of brain lesions consequent to drug use (eg., cerebral toxoplasmosis). (4) Parenteral drug use predisposes to ischemic and hemorrhagic stroke. Some drugs, eg., ethanol, cocaine, and tobacco, are risk factors for stroke by less wellunderstood mechanisms. (5) Persistently altered mentation is common among alcoholics, probably the result of both nutritional deficiency and direct toxicity. More controversial are the contributions of illicit drugs such as cocaine, marijuana, phencyclidine, and LSD to lasting cognitive impairment, for such studies tend to lack pre-drug use baselines. (6) Ethanol is an established teratogen, and animal studies demonstrate that other drugs (eg, cocaine) are harmful to fetuses, but in humans the effects are difficult to separate from inadequate prenatal care, ethanol, and tobacco. (7) Heroin users are at risk for acute transverse myelopathy, and nitrous oxide sniffers develop myeloneuropathy resembling that caused by cobalamin deficiency. (8) Alcoholic polyneuropathy is probably nutritional in origin. Heroin users have developed Guillain-Barre neuropathy and brachial plexopathy. Severe polyneuropathy affects sniffers of glues containing n-hexane. (9) Acute rhabdomyolysis is associated with use of opiates, psychostimulants, phencyclidine, and ethanol. (10) Miscellaneous neurological complications include quinine amblyopia, spongiform encephalopathy, and methylphenyltetrahydropyridine (MPTP)-induced parkinsonism in opiate users; dyskinesias in psychostimulant users, hypogonadism in marijuana users, and cerebellar ataxia in sniffers of products containing toluene.

References

  1. Brust JCM, Neurological Aspects of Substance Abuse. Boston, Butterworth- Heinemann, 1993.
  2. Brust JCM (ed). Neurologic complications of drug and alcohol abuse. Neurologic Clinics, Vol. 11, August 1993.
  3. Brust JCM, Drug dependence, In: Joynt R, Griggs R (eds). Clinical Neurology, Vol. 2, Chapter 21, Philadelphia, JP Lippincott Co., 1999, pp. 1-130.
  4. Brust JCM, Stroke and substance abuse. In: Barnett HJM, Mohr JP, Yatsu F, Stein BM (eds). Stroke: Pathophysiology, Diagnosis, and Management, Third Edition, New York, Churchill Livingstone, 1999, pp. 979-1000.
  5. Chiriboga CA, Brust JCM, Bateman D, Hauser WA. Dose-response effect of fetal cocaine exposure on newborn neurologic function. Pediatrics 103: 79-85, 1999.

Metabolic Abnormalities in HIV Infection

Adrian S. Dobs, M.D., M.H.S., The Johns Hopkins University School of Medicine

Hypogonadism in HIV Disease:

Pathologic evaluation of specimens from HIV-infected patients shows evidence of infiltration in both the testes and the hypothalamic-pituitary area. Testicular infection is slightly more common with cylomegalovirus, Mycobacterium avium-intracellulare, Toxoplasma gondii, or tuberculosis. In addition, HIV DNA has been found in 5 percent to 20 percent of spermatogonia and spermatocytes in the testes. Clinically, complaints possibly related to hypogonadism are nonspecific and include decreased libido, erectile dysfunction, gynecomastia, and muscle wasting. In addition, medications such as ketoconazole, heroin, alcohol, and methadone may also have direct effects on the gonads. Low serum T was originally reported at 38 percent of HIV-infected males. The prevalence of this abnormality increased with increasing level of illness so that 50 percent of active acquired immunodeficiency syndrome (AIDS) patients had levels below the normal range. These data have been corroborated by others, including Croxson et al., who reported that the defect was mainly testicular, and Lefrere et al., who found no correlation between serum T levels and gonadotropins (Lefrere, 1988). In addition to a direct HIV effect, disturbances of the hypothalamic-pituitary-gonadal axis may be a consequence of overall illness. The mechanism may be secondary to the release of cytokines by the activated phagocytic cells of the immune system.

Wasting in HIV:

Weight loss, and, more specifically, wasting, is a major problem in the care of patients with AIDS, contributing to the morbidity and mortality of the disease. The weight loss associated with HIV infection may consist of two components: acute weight loss, resulting primarily from acute secondary opportunistic infections, and chronic weight loss. Wasting has prognostic importance because death generally occurs when patients reach 66 percent of ideal body weight, similar to the degree of weight loss at which death occurs due to simple starvation. Although fat stores are preferentially depleted during starvation, loss of body cell mass (muscle and viscera) with relatively less fat loss is more common in HIV infection. Although total caloric intake at baseline did not predict subsequent wasting in the multicenter AIDS Cohort Study, recent data from metabolic studies suggest that anorexia and reduced caloric intake during episodes of opportunistic infection contribute to wasting. However, results from supplemental feeding studies in HIV-infected patients with wasting have been disappointing. Hormonal disturbances have been well-documented in HIV-infected men and may contribute to wasting. The consequences of low serum T may result in loss of lean body mass, decreased bone density, psychological changes, and sexual dysfunction. Following a large cohort of gay men, we found that declines in serum free testosterone occurred with small degrees of weight loss, before true wasting (>10 percent baseline weight) was achieved.

Treatment of HIV-Infected Men With Testosterone

The effect of testosterone treatment in this population is unknown. The decision to treat must be individualized and dependent on serum level, patient motivation, and clinical status. Rabkin et al. administered supra-physiological doses of testosterone to HIV-infected men and found improved quality of life (Rabkin, 1995). The efficacy and safety of testosterone therapy in HIV infection has been equivocal. Several studies, but not all, have shown increases in weight, lean body mass, and muscle strength with replacement. The use of other androgenic-anabolic steroids, such as nandrolone and oxandrolone, seem promising. Their long-term effects are not clear.

Other Metabolic Effects Seen in HIV Infection

With the broader use of antiretrovirals, several metabolic disturbances have been observed. The most noteworthy is a lipodystrophy or redistribution of body fat away from the peripheral ann addition to the cosmetic issues, the full health effects of this are not known, but there seems to be associated hypertriglyceridemia and glucose intolerance. Cooper et al. have postulated that the protease inhibitors act by interfering with an enzyme vital to lipid metabolism. The hyperinsulinism may be present at baseline before the use of protease inhibitors (Hadigan, 1999).

References

  1. Bhasin S, Sorer TW, Asbel-seth N, Kilbourne A, Hays R, Sinha-hikm I, Shen R, Arver S, Beall G. Effects of testosterone replacement with a nongenital transdermal system, androderm, in human immunodeficiency virus-infected men with low testosterone levels. Int J Clin Endocrinol Metab 1998.
  2. Chlebowski R, Grosvenor M, Lillington L, Sayre J, Beall G. Dietary intake and counseling, weight maintenance, and the course of HIV infection. J Am Diet Assoc 95:433-5, 1995.
  3. Coodley G, Loveless M. HIV-associated wasting. J Acquir Immune Defic Syndr 4:826, 1991.
  4. Coodley GO, Loveless MO, Nelson HD, Coodley MK. Endocrine dysfunction in the HIV wasting syndrome. J Acquir Immune Defic Syndr 7:46-51, 1994. Croxson TS, William EC, Miller LK, Levit CD, Senie R, Zumoff B. Changes in the hypothalamic-pituitary-gonadal axis in human immunodeficiency virus-infected homosexual men. J Clin Endocrinol Metab 68:317-21, 1989.
  5. Dobs AS, Dempsey MA, Ladenson PW, Polk BF. Endocrine disorders in men infected with human immunodeficiency virus. Am J Med 84:611-6, 1998.
  6. Grinspoon S, Corcoran C, Askari H, Schoenfeld D, Wof L, Burrows B, Walsh M, Hayden D, Parlman K, Anderson E, Basgoz N, Klibanski A. Effects of androgen administration in men with the AIDS wasting syndrome. Ann Intern Med 129:18-26, 1998.
  7. Grunfeld C, Feingold KR. Metabolic disturbances and wasting in the acquired immunodeficiency syndrome. N Engl J Med 327:329-37, 1992.
  8. Grunfeld C. What causes wasting in AIDS? New Engl J Med 333:123-4, 1995.
  9. Hadigan C, Miller K, Corcoran C, Anderson E, Basgoz N, Grinspoon S. Fasting hyperinsulinemia and changes in regional body composition in HIV-infected woman. J Clin Endocrinol Metab 84:1932-7, 1999.
  10. Kotler DP, Tierney AR, Wang J, Pierson RN Jr. Magnitude of body-cell-mass depletion and the timing of death from wasting in AIDS. Am J Clin Nutr 50:444-7, 1989.
  11. Kotler DP, Wang J, Pierson RN. Body composition studies in patients with the acquired immunodeficiency syndrome. Am J Clin Nutr 42:1255-65, 1985.
  12. Rabkin JG, Rabkin R. Testosterone replacement therapy for HIV-infected men. The AIDS Reader 136-44, July/August 1995.

AIDS and Opiates in a Monkey Model

Robert M. Donahoe, Ph.D., Emory University School of Medicine

Injection drug abuse (IDA) is a prominent cofactor in AIDS, and opiates are among the primary drugs involved. Opiates, themselves, modulate and compromise immunity and have been shown to modulate infections with HIV-1 in vitro. However, human clinical and epidemiological data have been equivocal in defining the relationship of opiate abuse and AIDS. Variable data are extant to support the notion that opiates exacerbate, retard, or cause no change in progression of AIDS. The main problem seems to relate to the complexity of the AIDS/IDA milieu so that epidemiological investigations are hampered in their ability to separate relevant variables. For example, we have found that opiates and cocaine, two drugs often shared in circumstances of IDA, can have counter-opposing effects on immune processes. This finding illustrates how the individual role of these two drugs in a complex IDA milieu would be difficult to discern.

Animal models have also been used to investigate the role of opiates in AIDS. Our laboratory has reported data from a small pilot study that opiates delivered regularly to rhesus monkeys infected with SIV, the simian analogue of human AIDS viruses, show slower progression of AIDS. Another lab has shown an opposite finding, however. Differences in the virus stocks used in these two studies and in drug-dosing regimens may account for differences in outcomes. Currently, we have expanded studies in this regard, using a much larger cohort of monkeys and better controls to determine how AIDS progression is affected by opiates. Also, from studies on effects of opiates on immune responses in monkeys, where AIDS viruses are not involved, we have learned that opiates can have both stabilizing and de-stabilizing immune effects, depending on the circumstances of drug dosing. Accordingly, we have hypothesized that opiates have the potential to both exacerbate and retard progression of AIDS depending on the context in which the drug is delivered as well as the viral status of the host and other host factors. Our ongoing studies are designed to test this hypothesis.

References

  1. Donahoe, RM, Nicholson JKA, Madden JJ, Donahoe F, Shafer DA, Gordon D, Bokos P, Falek A, Coordinate and independent effects of heroin, cocaine, and alcohol abuse on T-cell E-rosette formation and antigenic marker expression. Clin Immunol Immunopathol 41:254-264, 1986.
  2. Chuang RY, Blackbourne DJ, Chuang LF, Liu Y, Kilam KF, Jr. Modulation of simian AIDS by opioids. Adv Biosci 86:573-583, 1993.
  3. Donahoe RM, Byrd L, McClure HM, Fultz P, Brantley M, Marsteller F., Ansari AA, Wenzel D, Aceto M. Consequences of opiate-dependency in a monkey model of AIDS. Adv Exp Med Biol 335:21-28, 1993.
  4. Donahoe RM, Vlahov D. Opiates as potential cofactors in progression of HIV-1 infections to AIDS. J Neuroimmunol 83:77-87, 1998.
  5. Sharpe CW. Pharmaconeuroimmunology, AIDS and other diseases. J Neuroimmunol 83:1-174, 1998.

HIV-1-Associated Dementia: A Metabolic Encephalopathy Fueled by Viral Replication in Mononuclear Phagocytes

Howard F. Gendelman, University of Nebraska Medical Center

HIV-1-associated dementia (HAD) is a dreaded complication of progressive viral infection. It is associated with HIV-1-induced immunosuppression and productive replication in brain tissue. HIV neuropathogenesis revolves around infection and immune activation of brain mononuclear phagocytes (MPs) (perivascular and brain macrophages and microglia). These cells in conjunction with astroglia secrete neurotoxins producing neuronal injury. The mechanisms for neuronal death are mediated principally through HIV-1-infected MPs (1-5). How this occurs, however, remains poorly understood. To determine the cause of neuronal demise in HAD, novel techniques in neurobiology, virology, cellular immunology, and neurochemistry were developed. Quantitative tests for neuronal function included those utilizing ELISA, lactate dehydrogenase (LDH), calcium imaging, electrophysiology, neuronal apoptosis, glutamate receptor regulation, and reverse phase-high performance liquid chromatography (RP-HPLC). These assays were developed in order to uncover potential immune regulatory mechanisms for HAD-related neuronal injury. Our studies demonstrated that viral and cellular secretory products from immune-activated HIV-1-infected macrophages produce profound neurotoxicity in hippocampal and cortical neurons through both apoptosis and necrotic mechanisms. The intracellular signaling pathways, the identity of the specific immune neurotoxic factors, and their mechanisms for MP activation will be discussed.

References

  1. Zheng J, Ghorpade A, Thylin MR, Cotter R, Niemann D, Epstein L, Swartz J, Shepard R, Liu X, Nukuna A, Gendelman HE. Lymphotropic virions affect chemokine receptor-mediated neural apoptosis: Implications for HIV-1-associated dementia. J Virol 73:0000-0000, 1999.
  2. Zheng J, Thylin M, Ghorpade A, Xiong H, Persidsky Y, Cotter R, Niemann D, Che M, Zeng Y, Gelbard HA, Shepard RB, Swartz J, Gendelman HE. Intracellular CXCR4 signaling, neuronal apoptosis, and neuropathogenic mechanisms for HIV-1 associated dementia. J Neuroimmol 98:185-200, 1999.
  3. Petito CK, Kerza-Kwiateeki AP, Gendelman HE, McCarthy M, Nath A, Podack ER, Shapshak P, Wiley CA. Review: Neuronal injury in HIV infection. J Neuro Virol 5:327-341, 1999.
  4. Xiong H, Zen YC, Zheng J, Thylin M, Gendelman HE. Blockade of long-term potentiation by HIV-1 infected macrophage secretory products: A mechanism for cognitive dysfunction in HIV-1-associated dementia. J Neuro Virol, in press.
  5. Persidsky Y, Ghorpade A, Rasmussen J, Limoges J, Liu X, Stins M, Fiala M, Way D, Kim K, Witte M, Weinand M, Carhart L, Gendelman HE. Microglial chemokines regulate monocyte migration through the blood-brain barrier in HIV-1 encephalitis. Am J Pathol, in press.

 

Cocain Use, Neurpsychological Test Performance and Minor Cognitive-Motor Disorder in HIV-1 Seropositive Individuals

Karl Goodkin, M.D., Ph.D., et al. University of Miami School of Medicine

We investigated the association between the presence of HIV-1 associated minor cognitive-motor disorder (MCMD) (AAN, 1991), impairment on the Figural Visual Scanning Task (FVST), which measures information processing speed (Wilkie et al, 1990), and performance on the Mini-Mental Status Examination (MMSE) (Folstein et al., 1975) with self-reported and interviewer-defined cocaine use and use disorder (First et al., 1995) measures. Subjects were homosexual men having sustained the loss of a significant other in the prior six months who were at the baseline assessment of a randomized clinical trial of a bereavement support group intervention (Goodkin et al., 1999). Subjects with MCMD also had confirmation of decreased functional status by the Sickness Impact Profile (Bergner et al., 1981).

Among 123 HIV-1+ subjects, 44 had MCMD and 79 did not meet MCMD criteria. HIV associated dementia was an exclusion criterion. Controlling for age, educational level, and psychological distress, there was an association between lifetime history of cocaine use and the presence of MCMD with higher risk for MCMD being associated with higher cocaine use. Cocaine dependence also showed a trend toward an increased risk for MCMD. For the Figural Visual Scanning Task (FVST) outcome, the N was 205, including HIV-1- subjects. Lifetime cocaine use similarly showed a significant association with increased likelihood of impairment. In a separate analysis, a trend toward this association being modified by HIV-1 serostatus was observed. In contrast to the results with MCMD, cocaine abuse disorder showed a statistically significant increase in risk for impaired performance on the FVST. Cocaine dependence also showed a trend in this direction, as above with MCMD. These analyses showed that both the effect of abuse disorder and the trend with dependence were modified by HIV-1 serostatus.

For the MMSE score, no statistically significant effects were observed, though trends were uncovered in the same direction for cocaine use over the prior six months and for a history of abuse or dependence. We conclude that we have obtained preliminary evidence to support the hypotheses that increased level of cocaine use and the presence of use disorders are associated with deleterious effects documented with the three cognitive outcome measures tested. In order to have more definitive evidence of these associations, it would be necessary to conduct a larger study allowing for entry of more impaired individuals to increase the statistical power and to control for antiretroviral medication usage, ethnicity, closed head trauma history, history of non-substance use psychopathology, pain, fatigue (and constitutional symptoms more generally), motivation, sensory impairment, and level/use disorder of other psychoactive substances.

References

  1. American Academy of Neurology. Nomenclature and research case definitions for neurological manifestations of human immunodeficiency virus Type-1 (HIV-1) infection. Neurology 1991;41:778-785.
  2. Bergner M, Bobbitt RA, Carter WB, Gilson BS. The Sickness Impact Profile development and final revision of a health status measure. Med Care 1981; 19:787-805.
  3. First MB, Spitzer RL, Gibbon M, Williams JBW: Structured Clinical Interview for DSM-IV Axis I Disorders. Biometric Research Dept., NY State Psychiatric Institute: NY, 1995.
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  5. Goodkin K, Blaney NT, Feaster DJ, Baldewicz T, Burkhalter JE, Leeds B: A randomized controlled trial of a bereavement support group intervention in human immunodeficiency virus type 1-seropositive and seronegative homosexual men. Arch Gen Psychiatry 1999; 55(1):52-59.
  6. Wilkie FL, Eisdorfer C, Morgan R et al: Cognition in early human immunodeficiency virus infection. Arch Neurol 1990;47:433-440.

 

The HPA Axis in HIV-1 Infection

Mahendra Kumar, Ph.D., University of Miami School of Medicine

Several lines of evidence suggest that neuroendocrine abnormalities in general and HPA activity in particular occur in both HIV-1 infection and individuals indulging in drug abuse. For instance, our studies showing attenuated norepinephrine as well as ACTH and cortisol responses to a cold pressor challenge in asymptomatic HIV-1+ individuals support such a concept (Kumar et al., 1991, 1993). Furthermore, these studies are congruent with the occurrence of autonomic neurophathies observed in HIV-1 infection (Freeman et al., 1990). Recently, we observed that the attenuated response to the cold pressor challenge was not a consequence of any possible reduction in pain perception in HIV-1 infection; furthermore, our data on investigations on mirror-star tracing and speech challenges also support that the neuroendocrine responses are compromised in HIV-1 infection. These findings could be related to studies showing that HIV-1 auxiliary protein, vpr, may interact with glucocorticoid receptors (Kino et al., 1999) and that a sequence of pre-gag region in HIV-1 genome has close homology with the sequence in the POMC-promoter region (Licinio et al., 1995), which is responsible for activating the POMC gene. Since HPA axis activity impacts cytokines such as IL-6, these findings are very important in understanding the pathogenesis in the central nervous system of HIV-1-infected individuals. This line of research has become all the more significant since recent studies show that highly potent antiretroviral therapies (HAART) may also induce metabolic disorders (Carr et al., 1998; Yanovski et al., 1999). This presentation will review the latest findings in this area and would also present research hypotheses needed to be tested for understanding the mechanisms involved in the development of neuroendocrine abnormalities in HIV-1-infected IDUs. (Supported by grants R01 MH 48637 and R01 DA12792)

References

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  7. Yanovski JA, Miller KD, Kino T, Friedman TC, Chrousos GP, Tsigos C, Falloon J. J Clin Endocrn Metabol 84:1925-31, 1999.

 

Synaptic Dysfunction and Degeneration in AIDS

M.P. Mattson, et al., University of Kentucky

Synaptic terminals are subjected to high levels of oxidative and metabolic stress and calcium influx and are therefore sites where neurodegenerative cascades likely begin in many different disorders, including HIV dementia. We find that apoptotic biochemical cascades (caspase activation, loss of membrane phospholipid asymmetry, mitochondrial membrane depolarization, and release of factors that induce nuclear apoptosis) are activated locally in synaptic compartments in experimental models of neurodegenerative disorders such as Alzheimer's disease and stroke (Exp Neurol 153:35-48; Brain Res 807:167-76). The HIV protein Tat can also induce mitochondrial dysfunction and degeneration of synaptic terminals. Tat endangers neurons, rendering them vulnerable to excitotoxicity and apoptosis by a mechanism involving excessive calcium influx (Exp Neurol 154:276-88). We have identified a novel neuronal death-related protein called Par-4, which acts at an early step in the cell death process before mitochondrial dysfunction and caspase activation (Nature Med 4:957-62). Par-4 levels are increased in degenerating neurons in experimental models of Alzheimer's and Parkinson's diseases. Par-4 is induced at the translational level in synaptic terminals, wherein it contributes to local degenerative cascades following apoptotic triggers such as glutamate and trophic factor withdrawal. Par-4 levels are increased in hippocampal neurons in patients with HIV encephalitis, and Par-4 appears to be a key mediator of Tat-induced neuronal apoptosis (Am J Pathol 155:39-46). Collectively, the data suggest that HIV-derived proteins may promote synaptic dysfunction and degeneration, which may result in deficits in cognitive and motor functions in AIDS patients.

References

  1. Mattson, M. P., J. N. Keller and J. G. Begley (1998) Evidence for synaptic apoptosis. Exp. Neurol. 153: 35-48.
  2. Mattson, M. P., J. Partin and J. G. Begley (1998) Amyloid b-peptide induces apoptosis-related events in synapses and dendrites. Brain Res. 807: 167-176.
  3. Kruman, I., A. Nath and M. P. Mattson (1999) HIV-1 protein Tat induces apoptosis of hippocampal neurons by a mechanism involving caspase activation, calcium overload and oxidative stress. Exp. Neurol. 154: 276-288.
  4. Guo, Q., W. Fu, J. Xie, H. Luo, S. F. Sells, J. W. Geddes, V. Bondada, V. Rangnekar, and M. P. Mattson (1998) Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer's disease. Nature Med. 4: 957-962.
  5. Kruman, I., A. Nath, W. F. Maragos, S. L. Chan, M. Jones, V. M. Rangnekar, R. J. Jakel and M. P. Mattson (1999) Evidence that Par-4 participates in the pathogenesis of HIV encephalitis. Am. J. Pathol. 155:39-46.

 

Dopaminergic and Non-Dopaminergic Interactions Between HIV Proteins and Drugs of Abuse

A. Nath, Booze RM, Hauser K, Maragos W, Cass W, Mactutus C Departments of Neurology, Microbiology and Immunology, Anatomy and Neurobiology, University of Kentucky, Lexington, KY

 

HIV infection selectively targets the basal ganglia resulting in loss of dopaminergic neurons, decreased dopamine levels in the cerebrospinal fluid and increasing susceptibility to Parkinsonism (Mirsattari et al 1998). HIV proteins gp120 and Tat when injected into the basal ganglia cause selective neuronal loss and gliosis (Jones et al 1998). Gp120 produced a much more gliotic reaction as compared to Tat, while Tat leads to loss of nigrostriatal fibers . Gp120 and Tat also cause synergistic neurotoxicity when adminstered together at subtoxic dosages and these proteins may also synergize with other neurotoxic compounds such as glutamate to cause neurotoxicity(Nath et al 2000) Common drugs of abuse such as methamphetamine and cocaine also cause dopaminergic dysfunction (Nath et al., in press). In vitro studies show that gp120 and Tat cause synergistic neurotoxicity with methamphetamine and cocaine, the latter of which can be blocked by estrogen. Such synergistic neurotoxicity, however, may not be limited to dopaminergic drugs, since Tat and morphine also cause synergistic neurotoxicity in striatal neurons that can be blocked by naloxone (Gurvell et al., submitted). The combination of well defined in vitro studies with the use of pharmacologically and physiologically relevant animal models of drug abuse will greatly advance this area of research in identifying the underlying mechanisms responsible for interactions with HIV and drugs of abuse as well as identifying appropriate pharmacological interventions.

References

  1. Bansal AK, Mactutus CF, Nath A, Anderson C, Booze RM. Intravenous cocaine abuse: a rodent model for potential interactions with HIV proteins Neuroimmune Circuit Proceedings. In press.
  2. Gurwell JA, Nath A, Martin KM, Chen Y, Hauser KF. Synergistic Neurotoxicity of Opioids and HIV-1 Tat Protein in Striatal Neurons (submitted).
  3. Jones, M., Olafson, K., Del Bigio, M. R., Peeling, J., Nath, A. 1998. Intraventricular injection of human immunodeficiency virus type 1 (HIV-1) Tat protein causes inflammation, gliosis, apoptosis, and ventricular enlargement. J Neuropathol Exp Neurol 57:563-570.
  4. Mirsattari, S. M., Power, C., Nath, A. 1998. Parkinsonism with HIV infection. Mov Disord 13:684-9.
  5. Nath, A., Haughey, N. J., Jones, M., Anderson, C., Bell, J. E., Geiger, J. D. 2000. Synergistic neurotoxicity by human immunodeficiency virus proteins Tat and gp120: protection by memantine. Ann Neurol 47:186-94.
  6. Nath A, Jones M, Maragos W, Booze RM, Mactutus C, Bell J, Mattson M. Neurotoxicity and Dysfunction of Dopaminergic Systems Associated with AIDS Dementia. J Psychopharmacology In Press.

 

Micronutrients and Neuropsychological Function in HIV/AIDS

Gail Shor-Posner, Ph.D., University of Miami School of Medicine

The potential consequences of nutritional alterations in HIV-1 disease are manifold, including acceleration of disease progression and a dramatic, increased risk for HIV-1-related mortality.1 Nutritional factors may also have an important role in preserving neuropsychological function. Damage to the central nervous system in HIV/AIDS is manifested by many neurological symptoms, similar to those associated with nutritional deficiencies that are widespread in HIV-1 infection, particularly in drug users.2 A major focus of our research investigations has been to evaluate nutritional status as a cofactor in cognitive and psychosocial function. These studies, conducted over the past decade, demonstrate that adequate pyridoxine (vitamin B6) status is important in averting psychological distress,3 and indicate that some of the neuropsychological impairment noted in HIV disease may be due to inadequate cobalamin (vitamin B12) status.4 Support for this proposal is provided from cobalamin therapy studies demonstrating a therapeutic response in HIV-1-seropositive subjects referred for neurological evaluation,5 and resolution of HIV-associated dementia symptoms in a patient with low vitamin B12 levels.6 Antioxidant deficiencies have been associated with markedly reduced survival in HIV-1 disease,1 and neuronal degeneration.7 Although the precise cause of HIV-1-associated neuropathogenesis remains unknown, HIV-1 replication, immune activation, and oxidative stress have been associated with neuronal damage. Selenium, a biological antioxidant, is required for the activity of glutathione, a major protective enzyme against oxidative stress in the brain. In addition to its ability to reduce oxidative stress, selenium may decrease neuropathogenesis through suppression of TNF-alpha and IL-8 induced HIV-1 replication, neuronal apoptosis, and blood-brain barrier damage.8-10 As drugs of abuse appear to potentiate oxidative stress, selenium administration could be of particular benefit in preserving neuropsychological function in HIV-1-seropositive men and women who abuse drugs.

References

  1. Baum MK, Shor-Posner G, Lai S, et al., High risk of mortality in HIV infection is associated with selenium deficiency. JAIDS 15:370-4, 1997.
  2. Baum MK, Shor-Posner G, Zhang G et al., HIV-1 infection in women is associated with severe nutritional deficiencies. JAIDS 16:272-8, 1997.
  3. Shor-Posner G, Morgan R, Wilkie F, Eisdorfer C, Baum MK. Plasma cobalamin levels affect information processing speed in a longitudinal study of HIV-1 disease. Arch Neurol 52:195-8, 1995.
  4. Shor-Posner G, Feaster D, Blaney NT, et al. Impact of vitamin B6 status on psychological distress in a longitudinal study of HIV-1 infection. Int J Psychiat and Med 24:209-22, 1994.
  5. Kieburtz KD, Giang DW, Schiffer RB, Vakil N. Abnormal vitamin B12 metabolism in human immunodeficiency virus infection. Association with neurological dysfunction. Arch Neurol 48:312-4, 1991.
  6. Herzlich BC, Schiano TD. Reversal of apparent AIDS dementia complex following treatment with vitamin B12. J Intern Med 233:495-7, 1993.
  7. Ramaekers VT, Calomme M, Vanden Berghe D, Makropoulos W. Selenium deficiency triggering intractable seizures. Neuropediatrics 25:217-23, 1994.
  8. Sappey C, Legrand-Poels S, Best-Belpomme M, et al. Stimulation of glutathione peroxidase activity decreases HIV type 1 activation after oxidative stress. AIDS Res Hum Retrovir 10:1451-61, 1994.
  9. Hori K, Hatfield D, Maldarelli F, Lee BJ, Clouse KA. Selenium supplementation suppresses tumor necrosis factor a-induced human immunodeficiency virus type 1 replication in vitro. AIDS Res and Hum Retrovir 13:1325-31, 1997.
  10. Moutet M, d'Alessio P, Malette P, Devaux V, Chaudiere J. Glutathione peroxidase mimics prevent TNF alpha- and neutrophil-induced endothelial alterations. Free Radic Biol Med 25:270-81, 1998.

Future Research

The workshop participants recommended the following research on: "Metabolic Disorders in the Pathogenesis of Nervous System Damage in HIV-Infected Drug Abusers."

Research areas:

  1. Development of a brief Neuro-AIDS Clinical Rating Scale that combines assessments that can identify abnormalities which can occur specifically secondary to drug use (e.g. motor abnormalities that result from basal ganglia involvement) with tests that are useful for identifying abnormalities that also occur in other risk groups.
  2. Development of drug user cohorts that reflect regional differences in drug use patterns and behavior, realizing that these factors may potentially change over time.
  3. Support infrastructure for making animals available which are needed for performing in vivo and in vitro studies of SIV infection.
  4. Development of surrogate markers for nervous system involvement in drug users. This would include techniques such as MR spectroscopy.
  5. Identification of common and unique immunologic and pathologic mechanisms that are important in the pathogenesis of HIV related neurologic disease in drug users.
  6. Drug development.
  7. Elucidate neurotransmitter abnormalities.
  8. Examine neuroendocrine effects (HPA, autonomic disturbances).
  9. Examine the role of oxidative stress.
  10. Modulation of viral replication in brain by drugs of abuse.
  11. Examine neuroimmune mechanisms.
  12. Determine the effects of age, gender, ethnicity and genetics on the risk of developing neurologic complications and on the course of the nervous system disease.

The following specific projects were recommended:

  1. Effects of estrogen on risk of developing cognitive impairment and motor dysfunction.
  2. Examine evidence for illicit drug-induced mutagenesis in brain cells.
  3. Interactive effects of drug use and HIV infection on apoptotic pathways in the CNS.
  4. In vivo effects of drugs of abuse on the blood-brain barrier and CNS immune responses in humans and primates.
  5. Effects of neuroprotective compounds (e.g. cyclophilins) in animal models and humans.
  6. Studies of regional localization of virus in brains from drug users.