HIV
infection is a worldwide epidemic
More
than 36 million people are infected with HIV around the world
(WHO, 1999). Over 70 percent of these people are located in sub-Saharan
Africa. In this year alone, an estimated 5.3 million people --
including 600,000 children younger than 15 -- were infected with
HIV. An estimated 22 million have died from HIV over the past
2 decades since the disease was recognized, with over 3 million
expected to die from the disease this year.
Although the rate of HIV infection has stabilized in many industrialized nations, the greatest increase rates of infection are now being seen in Eastern Europe and central Asia. A 60 percent increase in the total number of people infected with HIV was reported in this region, for an addition of approximately a quarter of a million of infected people. The majority of new infections in this region are directly related to intravenous drug use.
Facts:
Sources: World Health Organization, Centers for Disease Control & Prevention |
Heterosexual activity and intravenous drug use are the prevalent risk factor exposures for acquiring HIV and developing AIDS in the United States
- Approximately 140,000 estimated new cases of AIDS acquired from heterosexual activity were diagnosed in women in 1999
- Approximately 100,000 estimated new cases of AIDS acquired from intravenous drug use were diagnosed in women in 1999
- Approximately 20,000 estimated new cases of AIDS acquired from heterosexual activity were diagnosed in men in 1999
- Approximately 40,000 estimated new cases of AIDS acquired from intravenous drug use were diagnosed in men in 1999
- Young girls between the ages 13-19 are twice as likely to be diagnosed with HIV as boys in the same age group
Source: Centers for Disease Control and Prevention
The interaction of substance abuse and HIV-1 infection merge in similar high-risk populations
- Younger age-groups
- Heterosexual activity without protection
- Multiple sex partners
- Teen use of methamphetamine
and methamphetamine related drugs (Ecstasy) are on the rise in
the US
- 1 out of 10 teen-agers surveyed has tried methamphetamine
- 1 out of 10 teen-agers surveyed has tried Ecstasy
- Over 100,000 estimated emergency room visits were related to methamphetamine in 2000
- Over 9 million Ecstasy tablets were confiscated in 2000, as compared to 400,000 in 1997
- Twice as many illegal methamphetamine manufacturing labs were found in the state of Ohio in 2000 as compared to 1997
Sources: World
Health Organization, Centers
for Disease Control and Prevention, Newsweek
magazine
Neurological impairments and cognitive dysfunction represent a persistent, debilitating and escalating problem associated with all age-groups for many HIV-1 infected people
- HIV neurocognitive disorders are classified into two sequential levels of severity: 1) minor cognitive/motor disorder; and 2) dementia (HIV associated dementia or HAD).
- The cognitive impairments have been generally characterized by poor attentional functions, memory deficits, and reduced alertness.
- No single variable has been determined as a necessary condition for the development of cognitive impairments and dementia.
Methamphetamine
(METH) as an important cofactor for the progression of HAD
The overall use of psychostimulants, such as METH, is increasing in populations that are at high risk not only for HIV-1 infection, but also for transmission.
- Psychostimulants, in particular, are linked to increased risk of HIV-1 infection.
- Intravenous cocaine use significantly increased the risk of HIV-1 infection, with a seroprevalence of 35%, in daily cocaine users.
- Among gay and bisexual men, METH use was significantly associated with the risk of sexual transmission of HIV-1 infection.
- The seroprevalence of HIV-1 was significantly higher for bisexual men METH users, compared to non-METH users.
- Male METH users are more likely to inject the drug, to use it for sexual enhancement, have multiple sexual partners without protection, and become HIV-1 infected. Moreover, most of these individuals reported "binging" on top of chronic, repeated dosing.
An important aspect in considering reasons that lead to the development of HAD is the influence of cofactors that can enhance the neurodegenerative effects of HIV-1.
- Several similarities exist between METH neurotoxicity and HAD, including neuropsychological/behavioral symptoms, neuroanatomic predilection for the basal ganglia, psychopharmacologic alterations, and potential mechanisms of degeneration.
- Taken together, the scientific body of data supports the concept that both METH and HIV induce a subcortical mediated neurologic clinical disease, that is the result of altered striatal neurochemistry and morphology, with confirmed (or highly suspected) altered dopamine metabolism.
- Excitotoxicity appears to be a common mechanism for the neurodegenerative effects of METH and HIV-1 neurodegeneration.
Understanding
the relationship between HIV-1 infectivity and METH use and disease
progression is important in terms of current epidemiological
patterns and the pathophysiology of HIV-1 related disease.
What are the "Global Research Questions?"
- Do psychostimulants predispose people for increased susceptibility or transmission of HIV?
- Do psychostimulants predispose HIV-infected people to advanced onset of AIDS?
- Do psychostimulants predispose HIV-infected people to advanced onset of neurodegeneration?
Why is this research difficult to do with humans? Human case cohort studies with HIV-1 and drug abuse are complicated by:
- Failure to address the time of HIV infection onset
- Variability in HIV isolate
- Variability in drug abuse history
- Poor patient study compliance
- Co-infection with other diseases
- Concurrent use of antiviral medications
- Difficulty in studying the mechanisms by which this interaction occurs
FIV
As A Model Of NeuroAIDS And Drug Abuse
Several experimental animal models have been used to study retroviral induced neurologic disease, including feline, non-human primate, murine and caprine species
- Retroviruses are a special type of virus discovered in the early 1900's. They can be classified into 2 broad categories: simple and complex. Retroviruses infect a wide variety of animal species as well as humans, with effects on the entire spectrum of cell replication and survival, from cell growth (cancer) to cell death (AIDS).
- Lentiviruses are a genus in the retrovirus family. Lentiviruses
have in common the ability to cause life-long infection, infect
cells of the immune and nervous system, and be transmitted from
one animal or person to another through bodily fluids.
- Lentiviruses are species-specific-they only infect a certain species. That is, HIV only infects people, and FIV only infects cats.
- Lentiviruses are very similar across species with close to a 90% homology between HIV and FIV in genetic structure
- Animals with natural lentivirus infections include the cat, monkey, sheep, goat, and horse.
- Feline immunodeficiency virus (FIV) is a neurotropic lentivirus that produces a protracted state of immunodeficiency and encephalopathy in the felidae species.
- The origin of FIV can be traced back to infectivity of African lions over 1 million years ago. This lentivirus became host adapted in this species, with over 95% of sampled free-ranging lions positive for FIV antibody. These lions remain relatively disease free in the wild. Natural infection of other felidae eventually circumvented to globe, where FIV can now be found on practically all continents.
The feline model of neuroAIDS and drug abuse offers an excellent opportunity to evaluate the synergistic effects of METH and HIV-1 interaction for the following reasons:
- FIV and HIV-1 are both lentiviruses with structural and biochemical similarities
- The FIV model is a natural one dependent upon active viral replication and host immune interaction
- The clinical syndrome and temporal disease progression are similar
- FIV results in reproducible, and reliable outcome measures of neurologic and behavioral disturbances
- Specific pathogen free cats are available, thus removing any influence of other infectious agents
- The feline nervous and immune systems are well characterized
- The cat and human have almost identical METH pharmacokinetic profiles
- Chronic METH dosing schedules can be performed in the cat
- METH induces similar striatal neurotoxicity in the cat and human
- Excitotoxicity appears to be a common mechanism of neurodegeneration for both species
What
this study will accomplish
- Determine if and how the chronic use of a psychostimulant may alter the immune function and amount of virus in the body and brain.
- Determine if and how the chronic use of a psychostimulant may advance the neurodegeneartive and neurobehavioral effects of HIV
- Determine if common mechanisms of neurodegeneration are found between HIV and psychostimulant use
How this research may help people
- This information will not only help to define the actual changes that occur, but will allow more detailed information about the reasons these changes occur, and hopefully, allow more scientific approaches to be used in reversing these negative effects in people
- More global research issues on the effect of drugs and/or body processes on immune function, the response of the immune system to viruses, and specifically, the response to HIV, may be studied.
- In particular, the information learned from psychostimulant research may be the precursor for further studies on the effects of how stress influences the immune response to HIV, since psychostimulants magnify many of the known stress responses of the body.
How
was this study funded?
The National Institute on Drug Abuse approved the five-year project, awarding $355,750 for the first year. The total support for the term of the project is $1.68 million.
This proposal is to study the synergy of methamphetamine neurotoxicity and FIV-induced basal ganglia neurodegeneration. HIV and meth abuse very often co-exist in humans, and such patients are very difficult to treat.
Researchers believe that meth
decreases T-cells, while FIV reduces astrocyte's ability to scavenge
glutamate, thus acting synergistically to drive glutamate-mediated
excitotoxicity. The feline model will provide valid and important
information about the synergistic effects of meth abuse and HIV-1
infection.
One of the reviewers stated about this
project:
"Given the increasing population of HIV-positive drug users and the growth in meth abuse, these studies have the potential to provide valuable information regarding the interaction of drugs of abuse and HIV neurotoxicity," and "understanding the relationship between HIV-1 infectivity and meth use and disease progression is important in terms of current epidemiologic patterns and the pathophysiology of HIV-1 related disease."
The NIDA Institutional Review Group "found this application to be an extremely well integrated proposal encompassing multiple levels of analysis to fully characterize clinically relevant variables in an animal model."
The IRG "agreed that FIV ... is ... a relevant model, which is used in this proposal ... to maximum effect to address questions which cannot easily be examined in humans infected with HIV."
Michael Podell is a Doctor of
Veterinary Medicine at Ohio State University. He "and
his collaborators and consultants are extremely well suited to
carry out the proposed work," according to the IRG.
They were the first to characterize FIV neuropathology.
Cats
exhibit similar pharmacokinetics of meth as humans (i.e. very
slow elimination of meth) (Baggot
JD, Davis LE. A comparative study of the pharmacokinetics of
amphetamine. Res Vet Sci, 1973, 14:207-15; and their own work).
The cat model allows long-term
study of FIV-meth neuropathologic interaction.
FIV is a natural model
of HIV/AIDS. The progression of the FIV disease signs and symptoms
in cats resembles HIV/AIDS. In particular, FIV is a well-documented
model of neuro-AIDS, with characteristic progressive neurodegeneration
and behavioral deficits.
The IRG wrote: "The FIV
model has demonstrated homology with HIV ... on numerous levels
and most importantly reflects progressive immunodeficiency and
neurologic impairment."
FIV is a serious problem in the cat population, and therapies that result from these experiments will be applicable to this natural cat disease.
As with HIV, FIV results in a
rapid decline in T-helper (CD4) lymphocytes, and a gradual, irregular
decline in T-suppressor (CD8) lymphocytes.
Every animal model of
HIV has certain drawbacks, since lentiviruses are species-specific.
Various models complement each other to provide a picture of
the human disease. The FIV model is appropriate to measure neuropathology
predictive of that of HIV.
The number of animals and dosage
regimens used in this project were evaluated by peer review and
deemed to be appropriate.
This proposal,
combining drug and immune challenges, is expected to lead to
progress in understanding neurodegenerative mechanisms that can
be applied to other neurologic diseases, such as stroke, Parkinson's,
and Alzheimer's diseases.
Organizations that support this research
National Institute on Drug Abuse
Americans for Medical Progress
Additional information
Animals in biomedical research
- Americans for Medical Progress
- American Physiological Society
- National Association for Biomedical Research
- National Center for Research Resources, National Institutes of Health
- Society for Neuroscience
Drug Abuse:
- National Institute on Drug Abuse
- Partnership for a Drug Free America
- Substance Abuse and Mental Health Services Administration
AIDS
- Center for Disease Control and Prevention
- National Library of Medicine AIDS Search
- Pediatric AIDS Foundation
- American Foundation for AIDS Research
Ohio State University news releases explaining this research can found here:
"NIH Approves Study of FIV and Methamphetamine Use: May Lead to Better AIDS Treatments" 10/6/00
"Study of FIV and Methamphetamine Use Could Lead to Treatments Against AIDS," 7/7/00
How is this
study monitored?
This study -- like all Ohio State
University research using animals -- will be monitored consistently
by both the Institutional
Laboratory Animal Care and Use Committee and the Office
of University Laboratory Animal Resources, as well as by
regular reviews by the National Institutes of Health and the
National Institute on Drug Abuse.
