NATAP: Drug Users & HIV: Neurological Disease, Immune Function

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Retinoids and Drugs of Abuse: Implications for Neurological Disease Risk in

HIV-1 Infection

Clinical Infectious Diseases December 2003;37:S427-S432

W. Royal III,1 D. Vlahov,2,4 C. Lyles,4 and C. D. Gajewski3

1Morehouse School of Medicine, Atlanta, Georgia; 2New York Academy of

Medicine and 3Weil Medical College of Cornell University, New York, New

York; and 4s Hopkins Bloomberg School of Public Health, Baltimore,

land

ABSTRACT

Among injection drug users, human immunodeficiency virus (HIV) type 1

infection may be associated with an increased risk of nervous system disease.

For

HIV-infected drug users with vitamin A deficiency, the overall risk of

HIV-related morbidity and mortality may also be higher.

In previous studies, levels of retinol, retinol-binding protein, and

transthyretin in

samples from such individuals were examined and found to be lower than such

levels in seronegative control subjects. Also, in studies using an activated

mononuclear cell line, all-trans retinoic acid and 9-cis retinoic acid

suppressed production of the tumor necrosis factor (TNF)-a and interferon

(IFN)-g.

However, simultaneous exposure of the cells to morphine at a concentration

similar to that to which drug users are exposed resulted in increased production

of these cytokines. Therefore, morphine may alter the immunomodulatory

effects of retinoids, thereby potentially affecting the clinical outcome of

studies

involving retinoid administration to HIV-infected drug users and increasing

the risk for the development of HIV-related complications, including

neurological disease.

BACKGROUND

Neurological disease occurs in a large percentage of persons with HIV-1

infection and can affect all levels of the nervous system. In general,

abnormalities that are directly related to infection with HIV occur late in the

course of

infection after the onset of significant immunosuppression. These

abnormalities, which can involve any area of the nervous system, include

peripheral

neuropathy, myelopathy, and HIV dementia. In patients with dementia,

pathological

studies have revealed the presence of characteristic abnormalities, such as

disruption of the blood-brain barrier, diffuse white matter pallor, microglial

nodules, and multinuclear giant cells with astrocyte proliferation and neuronal

loss. The cause of the actual damage to nervous system tissue appears to be

related to the effects of neurotoxic compounds released by activated

macrophage/microglial cells, astrocytes, and endothelial cells and to toxicity

associated

with HIV proteins, such as gp120, tat, and nef. Among the inflammatory

mediators and products that have been associated with HIV-related neurotoxicity

are

the proinflammatory cytokines IFN-g, TNF-a, IL-1b, and IL-6, quinolinic acid,

nitric oxide, platelet-derived growth factor, and prostaglandins. In addition,

there is also increased production and release of proinflammatory chemokines,

including macrophage inflammatory protein (MIP)-1a, MIP-1b, RANTES (regulated

on activation, normal T cellexpressed and secreted), and monocyte

chemoattractant protein (MCP)-1, which can further promote the infiltration of

mononuclear

phagocytes into nervous system tissue.

Micronutrient deficiencies occur commonly in persons with HIV-1 infection.

During the course of infection, retinol (vitamin A alcohol) deficiency can occur

early on in the setting of significant immunosuppression and AIDS. In

seronegative persons, retinol deficiency can be associated with decreased CD4+

lymphocyte numbers and CD4+/CD8+ lymphocyte ratios, and in some persons, these

measurements can be increased following administration of retinol. In drug

users,

low serum vitamin A (retinol) levels have been associated with an increased

risk of progression to AIDS and a higher HIV-related mortality. Therefore, in

such persons, retinal deficiency can have detrimental effects on the clinical

course of HIV-1 infection.

Drug use as a risk factor of HIV infection has been apparent since the early

days of the epidemic. Currently, drug use remains a leading cause of infection

and accounts for a disproportionately high percentage of AIDS cases overall.

However, the role of abused substances on the clinical course of HIV infection

has been unclear. With respect to opioids, in vitro studies demonstrate that

receptor agonists can suppress lymphocyte and monocyte immune function and

can increase HIV replication in infected monocytes and macrophages. In vivo,

neuropathological studies involving patients with AIDS have revealed evidence of

HIV encephalitis more frequently in brains from opioid users than in brains

from gay males, suggesting that drug users may be at greater risk for developing

HIV dementia. This is in contrast to epidemiological studies that showed no

increase in progression of HIV-related nervous system disease among drug users

compared with HIV-infected gay men. These persons, however, were at earlier

stages of HIV infection, which resulted in a low frequency of infection among

both risk groups.

In this report are presented studies in which we measured parameters of

retinoid metabolism (retinol, retinol-binding protein, and transthyretin) in a

cohort of HIV-infected drug users and examined possible effects of morphine on

production of proinflammatory cytokines by retinoid-exposed U937 cells, a human

mononuclear cell line.

DISCUSSION

Vitamin A deficiency has been associated with a number of immune effects,

such as altered mononuclear cell proliferation and responsiveness associated

with

either suppressed or enhanced specific cytokine production. Clinically,

severe deficiency may be complicated by the occurrence of infectious disorders,

as

demonstrated by an increased frequency of infectious diarrheal and pulmonary

disease in children with vitamin A deficiency and ocular disease. We have

reported that levels of retinol are also low in CSF from HIV-seropositive

patients

with evidence of severe immunosuppression, which may potentially increase the

risk for the development of neurological disease in infected persons.

Among the potential causes of decreased blood retinol levels are decreased

dietary intake and poor intestinal absorption. Indeed, the members of the cohort

studied have been found to pursue diets containing less than the recommended

content of vitamin A. However, the subjects examined in this study also

underwent dietary counseling, and it is, therefore, likely that their dietary

vitamin A content exceeded that generally expected of community-based drug

users.

Among HIV-infected persons, there may be increased vitamin A utilization. This

can occur in association with increased hepatic synthesis of acute-phase

proteins and because of increased consumption of retinol by immune cells as the

immune system mounts specific and nonspecific responses. This increased

metabolic

demand may not be met with routine vitamin supplementation. RBP and TTR are

synthesized by the liver and by the choroid plexus in the CNS. Decreased blood

levels of these proteins may occur in the context of impaired liver function.

However, even under normal circumstances, RBP that is not bound to retinol is

readily excreted by glomerular filtration, with excretion increased in persons

with

sepsis and decreased in the setting of acute and chronic renal failure. In

HIV infection, fever, infection, and other hypermetabolic states result in

increased urinary blood flow, which results in increased excretion of RBP and

urinary loss of plasma retinol.

Therefore, it is possible that a cycle develops in which HIV infection

triggers events that result in depressed plasma vitamin A levels, which, in

turn,

lead to worsening of HIV disease. The effects of changes in retinol, RBP, and

TTR levels in blood on the corresponding measurements in CSF are unclear at this

time.

With respect to opioids, in vitro studies demonstrate that receptor agonists

can suppress lymphocyte and monocyte immune function and can increase HIV

replication in infected monocytes and macrophages. In addition, as stated

previously, HIV encephalitis, which is a complication of late-stage HIV disease,

may

be identified more frequently in brains from HIV opioid users with AIDS than

in brains from their gay male counterparts, suggesting that opioids might

increase the rate of HIV disease progression.

Epidemiological data from numerous studies, however, have not entirely

supported this hypothesis, showing no increase in progression of HIV disease

among

drug users. For example, in comparisons of HIV seroconverters in the ALIVE

study with seroconverters in an Italian drug user cohort, there was no effect of

race, heroin use only versus polydrug use, or risk group (comparisons were made

with gay men and persons who acquired HIV infection through heterosexual

exposure). Notably, Galai et al. demonstrated that during the first 2 years

following seroconversion, gay men had more significant declines in CD4+ cell

counts

than do drug users. In addition, other investigations involving the ALIVE

cohort have demonstrated no overall effect of drug use on the median duration of

HIV infection before the onset of AIDS or on progression of HIV infection as

measured by disease markers such as CD4, neopterin, 2-microglobulin, and total

serum IgA levels. Reported drug use patterns, including episodes of withdrawal

or overdose, similarly do not appear to alter the course of HIV infection.

This finding contrasts with information from animal studies, in which a chronic

stable dose of opioid appears to protect from progressive retroviral disease,

and intermittent opioid dosing, representing acute episodes of opioid

withdrawal, was associated with the development of disease progression in the

animals.

Neurological complications of HIV infection appear to be linked to mechanisms

that involve up-regulation of proinflammatory immune responses. Retinoid

compounds can suppress proinflammatory cytokine and chemokine production,

effects

that may be beneficial to persons with CNS inflammation secondary to HIV

infection. In vitro studies of the effects of retinoids on immune function have

generally involved incubation of the cell cultures with the retinoid prior to

activation. In our studies, morphine, all-trans retinoic acid, 9-cis retinoic

acid, and

PHA were added simultaneously to the cultures, which might simulate responses

obtained with initiation of vitamin A treatment in HIV-infected persons.

These studies need to be followed up with investigations of effects of these

agents at varying time points, concentrations, and durations of exposure, as

well

as their effects on differentiated cells and with studies done in vivo.

Certainly, experimental effects observed in isolated in vitro systems cannot be

expected to precisely model the numerous factors that affect results obtained

from

epidemiological studies. Nevertheless, such information could prove to be

useful in elucidating specific effects of drugs of abuse on retinoid-induced

immunomodulation and the potential utility of retinoid compounds in the

treatment

of neurological disease related to HIV infection.

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