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The role of dopaminergic dysfunction as an etiological factor in HIV-associated cognitive deficits and how it can be tested in animal models-by Francisco Catsarini, Jaume Aran and Marineide Aquino

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AIDS Patients Face Downside of Living Longer-By JANE GROSS Published: January 6, 2008 http://www.nytimes.com/2008/01/06/health/06HIV.html?pagewanted=all&_r=0 CHICAGO — John Holloway received a diagnosis of AIDS nearly two decades ago, when the disease was a speedy death sentence and treatment a distant dream. Yet at 59 he is alive, thanks to a cocktail of drugs that changed the course of an epidemic. But with longevity has come a host of unexpected medical conditions, which challenge the prevailing view of AIDS as a manageable, chronic disease. Mr. Holloway, who lives in a housing complex designed for the frail elderly, suffers from complex health problems usually associated with advanced age: chronic obstructive pulmonary disease, diabetes, kidney failure, a bleeding ulcer, severe depression, rectal cancer and the lingering effects of a broken hip. Those illnesses, more severe than his 84-year-old father’s, are not what Mr. Holloway expected when lifesaving antiretroviral drugs became the standard of care in the mid-1990s. The drugs gave Mr. Holloway back his future. But at what cost? That is the question, heretical to some, that is now being voiced by scientists, doctors and patients encountering a constellation of ailments showing up prematurely or in disproportionate numbers among the first wave of AIDS survivors to reach late middle age. There have been only small, inconclusive studies on the causes of aging-related health problems among AIDS patients. Without definitive research, which has just begun, that second wave of suffering could be a coincidence, although it is hard to find anyone who thinks so. Instead, experts are coming to believe that the immune system and organs of long-term survivors took an irreversible beating before the advent of lifesaving drugs and that those very drugs then produced additional complications because of their toxicity — a one-two punch. “The sum total of illnesses can become overwhelming,” said Charles A. Emlet, an associate professor at the University of Washington at Tacoma and a leading H.I.V. and aging researcher, who sees new collaborations between specialists that will improve care. “AIDS is a very serious disease, but longtime survivors have come to grips with it,” Dr. Emlet continued, explaining that while some patients experienced unpleasant side effects from the antiretrovirals, a vast majority found a cocktail they could tolerate. “Then all of a sudden they are bombarded with a whole new round of insults, which complicate their medical regime and have the potential of being life threatening. That undermines their sense of stability and makes it much more difficult to adjust.” The graying of the AIDS epidemic has increased interest in the connection between AIDS and cardiovascular disease, certain cancers, diabetes, osteoporosis and depression. The number of people 50 and older living with H.I.V., the virus that causes AIDS, has increased 77 percent from 2001 to 2005, according to the federal Centers for Disease Control, and they now represent more than a quarter of all cases in the United States. The most comprehensive research has come from the AIDS Community Research Initiative of America, which has studied 1,000 long-term survivors in New York City, and the Multi-Site AIDS Cohort Study, financed by the National Institutes of Health, which has followed 2,000 subjects nationwide for the past 25 years. The Acria study, published in 2006, examined psychological, not medical, issues and found unusual rates of depression and isolation among older people with AIDS. The Multi-Site AIDS Cohort Study, or MACS, will directly examine the intersection of AIDS and aging over the next five years. Dr. John Phair, a principal investigator for the study, which has health data from both infected and uninfected men, said “prolonged survival” coupled with the “naturally occurring health issues” of old age raised pressing research questions: “Which health issues are a direct result of aging, which are a direct result of H.I.V. and what role do H.I.V. meds play?” The MACS investigators, and other researchers, defend the slow pace of research as a function of numbers. The first generation of AIDS patients, in the mid-1980s, had no effective treatments for a decade, and died in overwhelming numbers, leaving few survivors to study. Those survivors, like Mr. Holloway, gaunt from chemotherapy and radiation and mostly housebound, lurch from crisis to crisis. Mr. Holloway says his adjustment strategy is simple: “Deal with it.” Still he notes, ruefully, that his father has no medical complaints other than arthritis, failing eyesight and slight hearing loss. “I look at how gracefully he’s aged, and I wish I understood what was happening to my body,” Mr. Holloway said during a recent home visit from his case manager at the Howard Brown Health Center here, a gay, lesbian and transgender organization. The case manager, Lisa Katona, could soothe but not inform him. “Nobody’s sure what causes what,” Ms. Katona told Mr. Holloway. “You folks are the first to go through this and we’re learning as we go.” Mr. Holloway is uncomplaining even in the face of pneumonia and a 40-pound weight loss, both associated with his cancer treatment. Has the cost been too high? He says it has not, “considering the alternatives.” Halfway across the country, Jeff, 56-year-old New Yorker who was found to have AIDS in 1987, said he asks himself that question often. Jeff, who asked that he not be fully identified, has had one hip replacement because of a condition called avascular necrosis, the death of cells from inadequate blood supply, and needs another to avoid a wheelchair. Many experts think that avascular necrosis is caused by the steroids many early AIDS sufferers took for pneumonia. “The virus is under control, and I should be in a state of ecstasy,” he said, “but I can’t even tie my own shoe laces and get up and down the subway stairs. ” His bones are spongy from osteoporosis, a disorder that afflicts many postmenopausal women but rarely middle-aged men, except some with AIDS. No research has explained the unusual incidence. In addition, Jeff has Parkinson’s disease, which is causing tremors and memory lapses. He is in an AIDS support group at SAGE, a social service agency for older gay men and lesbians. His fellow group members also say they find the illnesses associated with age more taxing than the H.I.V. infection. One 69-year-old member of the group, for example, has had several heart attacks and triple bypass surgery, and his doctor predicts that heart disease is more likely to kill him than AIDS. Cardiovascular disease and diabetes are associated with a condition called lipodystrophy, which redistributes fat, leaving the face and lower extremities wasted, the belly distended and the back humped. In addition, lipodystrophy raises cholesterol levels and causes glucose intolerance, which is especially dangerous to black people, who are already predisposed to heart disease and diabetes. At Rivington House, a residence for AIDS patients on the Lower East Side of Manhattan, Dr. Sheree Starrett, the medical director, said that neither heart disease nor diabetes was “terribly hard to treat, except that every time you add more meds there is more chance of something else going wrong.” Statins, for instance, which are the drug of choice for high cholesterol, are bad for people with abnormal liver function, also a greater risk among blacks. Many AIDS patients have end-stage liver disease, either from intravenous drug use or alcohol abuse. Among Dr. Starrett’s AIDS patients is 58-year-old Dominga Montanez, whose first husband died of AIDS and whose second husband is also infected. “My liver is acting up, my diabetes is out of control and I fractured my spine” because of osteoporosis, Ms. Montanez said. “To me, the new things are worse than the AIDS.” There are no data that compare the incidence, age of onset and cause of geriatric diseases in the general population with the long-term survivors of H.I.V. infection. But physicians and researchers say that they do not see people in their mid-50s, absent AIDS, with hip replacements associated with vascular necrosis, heart disease or diabetes related to lipodystrophy, or osteoporosis without the usual risk factors. “All we can do right now is make inferences from thing to thing to thing,” said Dr. Tom Barrett, medical director of Howard Brown. “They might have gotten some of these diseases anyway. But the rates and the timing, and the association with certain drugs, makes everyone feel this is a different problem.” One theory about why research on AIDS and aging has barely begun is “the rapid increase in numbers,” Dr. Emlet said. The federal disease centers’ most recent surveillance data, from 33 states that meet certain reporting criteria, showed that the number of people 50 and older with AIDS or H.I.V. infection was 115,871 in 2005, nearly double the 64,445 in 2001. Another is the routine exclusion of older people from drug trials by big pharmaceutical companies. The studies are designed to measure safety and efficacy but generally not long-term side effects. Those explanations do not satisfy Larry Kramer, founder of several AIDS advocacy groups. Mr. Kramer, 73 and a long-term survivor, said he had always suspected “it was only a matter of time before stuff like this happened” given the potency of the antiretroviral drugs. “How long will the human body be able to tolerate that constant bombardment?” he asked. “Well, we are now seeing that many bodies can’t. Once again, just as we thought we were out of the woods, sort of, we have good reason again to be really scared.” The lack of research also limits a patient’s care. Dr. Barrett says the incidence of osteoporosis warrants routine screening. Medicare, Medicaid and private insurers, however, will not cover bone density tests for middle-aged men. Marty Weinstein, 55 and infected since 1982, has had a pacemaker installed, has been found to have osteoporosis, and has been treated for anal cancer and medicated for severe depression — all in the last year. He also has cognitive deficits. A former professor of psychology in Chicago, he presses his doctors about cause and effect. Sometimes they offer a hypothesis, he said, but never a certain explanation. “I know the first concern was keeping us alive,” Mr. Weinstein said. “But now that so many people are going to live longer lives, how are we going to get them through this emotionally and physically?”
AIDS Patients Face Downside of Living Longer-By JANE GROSS
Published: January 6, 2008
http://www.nytimes.com/2008/01/06/health/06HIV.html?agewanted=all&_r=0
CHICAGO — John Holloway received a diagnosis of AIDS nearly two decades ago, when the disease was a speedy death sentence and treatment a distant dream.
Yet at 59 he is alive, thanks to a cocktail of drugs that changed the course of an epidemic. But with longevity has come a host of unexpected medical conditions, which challenge the prevailing view of AIDS as a manageable, chronic disease.
Mr. Holloway, who lives in a housing complex designed for the frail elderly, suffers from complex health problems usually associated with advanced age: chronic obstructive pulmonary disease, diabetes, kidney failure, a bleeding ulcer, severe depression, rectal cancer and the lingering effects of a broken hip.
Those illnesses, more severe than his 84-year-old father’s, are not what Mr. Holloway expected when lifesaving antiretroviral drugs became the standard of care in the mid-1990s.
The drugs gave Mr. Holloway back his future.
But at what cost?
That is the question, heretical to some, that is now being voiced by scientists, doctors and patients encountering a constellation of ailments showing up prematurely or in disproportionate numbers among the first wave of AIDS survivors to reach late middle age.
There have been only small, inconclusive studies on the causes of aging-related health problems among AIDS patients.
Without definitive research, which has just begun, that second wave of suffering could be a coincidence, although it is hard to find anyone who thinks so.
Instead, experts are coming to believe that the immune system and organs of long-term survivors took an irreversible beating before the advent of lifesaving drugs and that those very drugs then produced additional complications because of their toxicity — a one-two punch.

 

A major consequence of HIV infection is the development of cognitive deficits due to the effects of infection on the CNS. These deficits, usually referred to as HAND (HIV Associated Neurocognitive Disorders), are commonly classified in three categories, according to their severity: asymptomatic, mild and dementia. Although highly active anti retroviral therapy (HAART) has significantly improved patient quality of life as well as life expectancy, HIV-associated cognitive deficits, which are present in up to 40% of HIV infected patients  (Cysique, Maruff, & Brew, 2004),  remain a challenging issue. The study of these cognitive deficits is important not only for themselves, but also because they may have a negative impact on the patient’s adherence to treatment (McArthur, 2004).

 

cicloo do vírus

Regarding HAND, several etiological factors have been identified, particularly, neurotoxic factors produced by infected macrophages, expression of pro-inflammatory cytokines (Merrill, 1992) and the production of the HIV-1 Nef protein by infected astrocytes (Chompre et al., 2012), and others.

 

 

In this paper, we discuss the role of dopaminergic dysfunction as an etiological factor of neurocognitive impairment in HIV patients, as suggested by Wang et al. (2004). We also propose requirements for an animal model by which this contribution of dopaminergic dysfunction to HAND could be tested. An improved understanding of this contribution may aid development of treatment strategies for reversing or, at least, alleviating HAND. Meulendyke et al. (2012) suggest that Minocycline (an microglial/astroglial inhibitor) may contribute to protect “against nigroestriatal dopaminergic dysfunction”.

 

Dopamine is a neurotransmitter that belongs to the catecholamine family. Dopamine is produced from the amino acid, tyrosine, which undergoes two changes to yield dopamine. Firstly, a hydroxylation by tyrosine hydroxylase occurs to yield dihydroxyphenylalanine, (DOPA) and afterwards DOPA is converted by decarboxylation by the enzyme dihydroxyphenylalanine decarboxylase (DDC) to yield dopamine. Most dopamine is acquired through food intake (80%) while the rest, a small proportion, comes from the synthesis of phenylalanine in the liver.

Dopamine synthesis occurs in the cytoplasm of the neuron and then dopamine is transported within the secretory vesicles of the neuron for storage and subsequent discharge. This whole process is highly dependent on ATP. Once stored at nerve terminals, dopamine is ready to be released into the synaptic cleft. Upon release into the synaptic cleft, dopamine exerts its function and afterwards, most of it is recaptured by the Dopamine Transporter (DAT), which is located in the presynaptic membrane.

Dopamine in high concentrations in the synaptic cleft may trigger inflammatory and apoptotic processes that cause tissue damage. However the enzyme, monoamine oxidase-B (MAO-B) may degrade dopamine that is not recaptured.

Dopamine receptors are members of the family of G protein coupled receptors. They are divided into two classes: D1 receptors, represented by D1 and D5 receptors that increase cAMP upon binding of dopamine, and D2 receptors represented by D2, D3 and D4, that, on the other hand, inhibit the production of cAMP.

 

d-transmsisn

 

The distribution of receptors in the central nervous system is quite heterogeneous. D1 is present in the nucleus striatum and in the neocortex. D2 is present in N. striatum, the substantia nigra and pituitary. D3 is found in the olfactory tubercle, Nucleus accumbens and hypothalamus, while D4 is present in the frontal cortex, the midbrain and medulla oblongata and the D5 receptor is found in the hippocampus and hypothalamus.

 

_basal_ganglia
Basal ganglia

 

There are 3 main pathways controlled by dopamine: 1.- The pathway of the nigro striatal system, comprising 80% of the dopamine in the brain, projects rostrally from cell bodies in the substantia nigra pars compacta to the richly innervating endings in the caudate nucleus and putamen, two nuclei that, taken together, are called the striatum. 2.- The pathway originating in the ventral tegmental area, which has widely divergent projections innervating many areas of the forebrain, most notably the cerebral cortex, nucleus accumbens and other limbic structures. 3. The tubero infundibular pathway, in which dopamine release occurs directly in the portal system connecting the median eminence to the anterior pituitary and tonically inhibits the release of prolactin by the pituitary lactotrophs. Finally, there is also a very discreet pathway for dopamine release, located on the floor of the fourth ventricle, called area postrema.

dopamine1

 

It is well established that HIV primarily affects the basal ganglia, which are  a main efferent for dopamine release (Silvers et al., 2007). Since dopamine is known to play a major role in the regulation of cognitive processes (Nieoullon, 2002), it seems a valid assumption (Levine et al., 2012) that the disruption of its normal rate of production due to lesions of the basal ganglia brought about by the HIV infection of the CNS is a contributing factor to the development of HAND (Kumar et al., 2011; Webb et al. 2010).

According to Chang (2008), “reduced dopaminergic function may contribute to cognitive dysfunction in HIV patients with or without additional cocaine abuse”. When there is, indeed, substance abuse, the severity of HAND may increase (Purohit et al. 2011). Moreover, Gaskill (2009; 2012) states that dopamine is able to modulate macrophage functions because macrophage express dopamine receptors. This becomes particularly relevant given that drug abuse leads to increased dopamine levels, exacerbating the effects of macrophage on the CNS. In addition, recent studies (Midde, Gomez & Zhu, 2012) indicate that the HIV -1 Tat protein affects the dopaminergic tone of infected subjects by inhibiting the DAT and VMAT 2 proteins. Previously, Ferris et al. (2009) had already discovered that the dopamine transporter (DAT) becomes significantly less efficient in the presence of the HIV Tat protein. Zhu et al. (2011) explain this as a consequence a protein-protein interaction between Tat and DAT. Also, according to Ferris et al. (2009) this lower efficiency of DAT could be just the start of Tat-induced loss of nerve terminal function, which would be greatly augmented by the interaction of Tat protein with cocaine. Levine et al. (2013) through  differential expression analysis studies identified genes highly correlated with neurocognitive impairment, among them genes implicated in dopaminergic tone.

Gupta et al. (2011) considered the possibility that DA receptors, especially DRD3, which is expressed in macrophages, mediate the increase of macrophages infected in the presence of methamphetamine and increased dopamine, and concluded that a polymorphism of the DRD3 gene (rs6280TC) modulates its binding affinity. Therefore, inheriting a variant of this polymorphism may increase macrophage susceptibility to HIV infection.

Webb (2009) points out that dopamine is a common link amongst the major factors related to neurocognitive impairments in HIV patients, such as attention deficits, language difficulties and motor dysfunction, although, as Perry (2010) hypothesizes, early dopaminergic synaptic dysfunction would occur before any loss of dopaminergic neurons and therefore could be reversible.

Gelman (2012) found in a post-mortem study that patients with neurocognitive disorders failed to downregulate D2 receptors in the prefrontal cortex. This finding could be relevant to attempts to alter synaptic plasticity pharmacodynamically in HIV infected individuals.

Moran et al. (2013) have tested alterations in the dopaminergic system due to the effects of HIV infection in the CNS in rats.

Since the pathological mechanisms underlying HAND are not completely understood, Jaeger & Nath (2012) advocate the necessity of developing animal models to study these disorders further and to test new therapeutic approaches.

Gorantla et al. (2011) have established five requirements that animal models should, ideally, meet in order to accurately reflect HAND: First, the animals should have virus-susceptible target cells, such as macrophages, that express receptors for viral infection and they also should have cell systems adequate to host the whole viral life-cycle. Secondly, the animals must be infected through known viral portals, such as blood. Third, infection should last long enough to replicate the chronic nature of the disease. Fourth, the Blood Brain Barrier of the model should permit leukocyte transmigration due to the viral infection and, finally, virus target cells and viral reservoirs have to be maintained. Also, it must be considered that HIV is a lentivirus and as such it presents unique molecular and biological properties, including an extended incubation period. Moreover, lentiviruses are species specific, which implies that effects observed in laboratory animals may not occur in the same form in human subjects.

Rodents are used for some HIV infection models, although HIV cannot infect rodent cells. To create suitable models, mice or rats are either modfied transgenically to express viral genes or are modified by transplantion of HIV infected cells into immunodeficient tissues of the animal. The advantage of using rodents, besides their size, is that there are established methodologies for the manipulation of their genomes (see also Jaeger & Nath, 2012). These models have limitations regarding the expression of end-organ disease and, among others, their relatively short life span, which is not adequate to observe the effects of the disease on the CNS. However in recent years a new mouse model has been made with an engrafted human immune system that is more adequate for studying relationships between peripheral infection and neuropathobiology. Also, this engrafted human immune system model is highly specific because in it, brain disease develops only following HIV infection and suppression of the immune system. Moreover, as grafts survive as long as the animal itself, the model allows long term studies of CART. Jaeger & Nath (2012) have proposed an alternate model that would reunite the main characteristics of HAND in a single physiological system, with both a human immune system and human CNS cells, that has the advantage over previous models employing human brain macrophages and astrocytes susceptible of HIV infection. This proposed model also would allow the study of long term effects on the brain of CART therapy, which is suspected to cause neurotoxicity.

In summary, there is substantial evidence for deleterious effects of alterations in the dopaminergic system due to HIV infection on cognitive processes. In this paper, we have considered features that animals models should have to study these consequences of HIV adequately. These considerations emphasize the great potential utility of specific animal models for the study of the impairment of executive function due to HIV infection and the role of dopamine.

Sam Szafran, Escalier anamorphique charcoal on paper
Sam Szafran, Escalier anamorphique charcoal on paper

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