We have been officially living with the reality of HIV/AIDS for almost 30
years now. You may think you know how it was transferred to humans but I expect the majority do not. The tale most of us have heard and internalized over the years involves a careless lab assistant and a monkey gone horribly wrong. This, my friends, is nothing more than a creative myth. There are two strains known in man: HIV-1 responsible for the majority of cases and originating from the common chimpanzee and the less virulent HIV-2 which originated from a type of a monkey known as the sooty mangabey. Current genetic and epidemiological evidence indicates that the simian immunodeficiency virus (SIV) first crossed from its host to humans around the turn of the last century, give or take 20 years. This process is likely to have occurred naturally/passively like that currently seen with bird flu. Once it had successfully infected humans, it morphed into the human immunodeficiency virus, commonly known as HIV, and began to spread throughout the Congo/Cameroon region of West-Central Africa (1, 2). Indeed, by 1960, HIV-1 appears already to have become genetically diverse in humans in Kinshasa, the Democratic Republic of the Congo (formerly Léopoldville, Belgian Congo) (3). One implication of this finding is that the retrovirus could not have originated from a lab mistake in recent times. The first known case suspected (in retrospect) of being HIV occurred in England in the late 1950s. A young English printer who had
spent a few years travelling with the Navy reported to the hospital with several unusual symptoms including purple skin lesions, fatigue, and rapid weight loss. Upon his death it was discovered that he had suffered from two unusual infections. One of these, Pneumocystis pneumonia, was extremely rare at the time but is commonly contracted by people who have developed the advanced form of HIV, known as acquired immunodeficiency syndrome or AIDS. Although tissue samples were saved from the printer, tests for HIV have been inconclusive. Interestingly, Sir Robert Platt, then president of the Royal College of Physicians, “wrote in the printer’s hospital chart that he wondered ‘if we are in for a new wave of virus disease now that the bacterial illnesses are so nearly conquered’ (4).” The oldest confirmed cases of HIV-1 dates back to samples taken in what was then Léopoldville, Belgian Congo in 1959 and 1960. The 1959 case was found in a sample taken from a man (5), the 1960 case from a sample from a woman (3). It is unknown whether or not these individuals ever developed full-blown AIDS. Another early case comes from a Norwegian sailor who first presented symptoms in 1969, eight years after spending time in West African ports where he contracted gonorrhea, indicating he was sexually active at the time. In 1976, he along with his wife and youngest daughter all died. Later it was confirmed that AIDS had wiped out his family (6,7). In 1969, a 15 year-old
African-American boy died of a secondary AIDS-related infection at the St. Louis City Hospital. Blood and tissue samples were taken from the boy, known to medical science as Robert R., were later confirmed to be HIV-1 positive. Although unconfirmed, he was suspected of being a prostitute. Robert R.’s admittance to the hospital in 1968 represents the earliest known case of the retrovirus to be confirmed in the USA.
Researchers believe HIV arrived
from the Congo to the USA by way
of Haiti where it appeared in 1966.
The retrovirus was then brought to the USA by a single unknown carrier sometime in the next three years. However, this carrier was not Robert R., as there is no documentation of him having left the country during his short life. Today, HIV has claimed nearly 30 million lives since it was first officially documented, making it one of the worst pandemics in human history. As of 2007, as many as 36.1 million more infected individuals are believed to be currently living with the disease. Although the deaths per annum associated with AIDS dropped by approximately
30% from 2005 to 2007, the new infection rate appears to be keeping up with deaths so the total number of infected individuals has remained reasonably stable over the last 3 years or more. More than 75% of women with AIDS live in Africa, with total infected African individuals accounting for at least 64% of the global infected population. South and South East Asia accounts for another 15% of the total infected global population.
The highest number of infected individuals found in one country can be found in South Africa, with Nigeria and India taking second and third respectively. Interestingly, the development of more effective antiretroviral drug combinations known collectively as highly active antiretroviral therapy, or HAART, has lead to a decrease in attention given to AIDS in the media. As a result, many in areas where HAART is readily available have developed the mistaken impression that AIDS is no longer a significant threat or is even gone. However, nothing could be further from the truth. In areas such as this, like the USA, the use of HAART has lead to significantly increased life expectancy and therefore a substantial increase in the size of the infected population.
Of those infected with HIV in North America, approximately a third of them use cannabis to help
alleviate symptoms of the infection or side effects from the treatments. Cannabis preparations are most frequently used for appetite stimulation/nausea suppression and multiple types of pain suppression. Considering the immunosuppressive effects of acute administration of cannabinoids, many have wondered if this practice is “safe.” Is cannabis therapy only palliative (symptom relief without curative properties) for those infected with HIV, or might it actually help fight the infection at some levels? Does cannabis therapy pose any risks to those fighting HIV? What role, if any, does the endocannabinoid system play in the progression of HIV to AIDS? Although far from definitive, the rest of this article will explore what is currently known about the answers to these questions and what this information might mean to the average HIV positive individual.
Cannabinoids in the Treatment of AIDS Wasting
One of the few broadly recognized legal medical uses of cannabinoids
is in the treatment of wasting due to AIDS, cancer chemotherapy, and severe anorexia. The primary active constituent of cannabis, THC, has the interesting honor of appearing on the DEA’s scheduling twice. THC is scheduled once in the list of most dangerous drugs with no known accepted medical use (Schedule I) as “Tetrahydrocannabinols: THC, Delta-8 THC, Delta-9 THC and others” and again as less dangerous with only moderate abuse potential and accepted medical use (Schedule III) as “Dronabinol: Marinol, synthetic THC” (13, 14, 15). A chemical cannot magically change pharmacodynamic or pharmacokinetic properties just because it originates from a man-made process and not biosynthesis. On a purely molecular level, our bodies cannot distinguish between the two sources. I don’t know about you, but to me, the current insistence that THC has two legitimate schedules seems like a pretty delusional stance to take. Regardless of this insanity, doctors in the USA are federally allowed to prescribe Marinol to those suffering from AIDS wasting syndrome. Where therapeutic cannabis laws have been enacted, these patients may also utilize preparations of cannabis to help reduce nausea and stimulate the poor appetite associated with AIDS wasting. In 2005, Woolridge, et al. collected data from 520 HIV patients attending a large clinic and collected statistics on rates of cannabis use, reported reasons for use, and whether or not the patient felt cannabis improved symptoms. Use of cannabis to control symptoms was reported by 27% (143) of those who completed the questionnaire. Of these 143 cannabis-using patients, 97% experienced appetite stimulation and 93% reduced nausea (12). This finding is not surprising considering that anandamide, one of the primary endocannabinoids, helps to maintain healthy serotonin and dopamine levels, feeding behaviours, and cognitive functioning during periods of diet reductions like those seen in wasting syndromes. Anandamide is also involved in the initiation of feeding behaviours by means of CB1 cannabinoid receptor activation in the hypothalamus. It is this involvement of the endocannabinoid system in the regulation of feeding behaviours that explains why cannabis and THC stimulate appetite and combat wasting. Several studies have investigated how effectively both Marinol and standardized cannabis improve signs of wasting in HIV positive individuals. How well cannabinoid-based treatments hold up depends on how one defines success. The recommended dose of Marinol for appetite stimulation is 2.5mg twice daily. Studies prior to 2000 used this dose. In 1995, 2.5mg Marinol twice daily was compared to placebo to treat symptoms of wasting in 139 HIV patients. Patients were randomly assigned to either the drug (88) or the placebo (51) group. When compared to the placebo group, the group receiving the Marinol reported substantial improvements over pre-study baseline in appetite, mood, and decreased nausea. Mean weight was stable in the Marinol group as compared to a small drop in weight for the placebo group. Over the course of the study, only 10% of the placebo group gained 2kg or more whereas this was achieved by 22% of those in the Marinol group. These findings lead the authors to conclude that THC was “safe and effective” at alleviating symptoms of AIDS wasting. A long term (12 month) trial of 2.5mg Marinol in late-stage AIDS patients, which concluded THC was safe and effective in the long run, was published by the same group two years later. Again
Marinol was associated with stable body weight and significantly improved appetite. Interestingly, the degree to which appetite improved over baseline was dependant on how long the patient had been on Marinol therapy such that scores during the first four months improved by 50-75% but went up to the 200% range thereafter. These studies help demonstrated something about the 2.5mg dose of Marinol. It is an effective appetite stimulating dose but does not appear to consistently initiate weight gain, a fact that other researchers have used to claim that THC is ineffective when compared to other anti-wasting drugs. A 1997 study compared the suggested dose of Marinol to that of megestrol acetate, the two doses together and a sub-therapeutic dose of megestrol acetate and the suggested dose of Marinol together. Both groups using full doses of megestrol acetate gained an average of 6kg over the 12 week period. The group receiving Marinol alone lost an average of 2kg while the sub-therapeutic dose of megestrol acetate plus Marinol only lost 0.3kg. The difference between the four groups was found to be highly statistically significant. The lack of weight gain observed in the Marinol group lead the researches to conclude that THC was not an effective treatment compared to other available anti-wasting drugs.
More light has been shed on this controversy since 2000. Haney in 2002 reported that both Marinol and smoked cannabis standardized for THC content effectively increase food intake in a small study population of nine patients. Marinol appeared to produce a greater weight gain, however, smoked cannabis was rated higher for improved appetite and mood.
Interestingly, Haney got these results using Marinol doses that were four to twelve times the recommended dose for appetite stimulation (10mg, 20mg, 30mg), indicating that perhaps the recommended dose is conservatively small compared to what might be required for more severe conditions such as AIDS wasting (The standardized cannabis doses used in this study were standard government issue joints of 1.8%, 2.8% and 3.9% THC.) (21). Three years later, Haney and colleagues, published more detailed findings concerning the use of smoked cannabis vs. Marinol in the treatment of AIDS wasting. Using the same doses as Haney’s earlier study, the effects of Marinol and smoked cannabis were compared in 15 HIV patients with signs of wasting and 15 without. For a few patients, the 30mg dose of Marinol was too intense, however, all other doses of both Marinol and cannabis were
well tolerated. Significant increases in caloric intake were associated with both cannabis and Marinol when compared to placebo for the group with signs of wasting but not those without (22). Clearly the appropriately anti-AIDS wasting dose of Marinol is as much as 8 times that currently recommended for full effect. Furthermore, it may only be effective at an increasing weight in those who are already expressing evidence of wasting.
This effect is comparable to that observed when cannabis with a low percent THC is smoked for the same purpose.
Cannabinoids and HIV-Related Pain
The 2005 study by Woolridge and colleagues into the reasons why HIV patients used cannabis found that 94% of the cannabis using respondents reported that cannabis reduced muscle pain, 90% reported reductions in HIV-related neuralgia, and 85% reductions in parenthesis (burning, itching, tingling or prickling sensations in the skin with no apparent cause). A few studies have begun to confirm what patients have known for years
and to elucidate how cannabinoids are able to produce this relief. In early 2007 Abrams, et al., reported that smoked cannabis standardized to 3.56% THC was significantly more effective than placebo (THC- free cannabis) at reducing daily HIV-related pain and did so with a significantly greater degree of reduction. This effect was most powerful for the first dose. Smoked cannabis also reduced evidence of HIV-related hypersensitivity to mildly painful mechanical stimuli but did not affect response to typically painful high temperatures. The authors concluded that “smoked cannabis was well tolerated and effectively relieved chronic neuropathic pain from HIV-associated sensory neuropathy. The findings are comparable to oral drugs used for chronic neuropathic pain (23).” Ellis, et al., published a confirmation of this finding two years later using even more stringent inclusion criteria and experimental design (24). Use of cannabinoids to treat HIV induced neuropathic hypersensitivity is also supported by evidence from animal models investigation of how HIV is capable of inducing such neuropathic changes. In one such study, the synthetic cannabinoid WIN 55,212-2 (WIN) was able to inhibit HIV-induced hypersensitivity to mechanical stimuli in rats by inhibiting the activity of a particularly toxic HIV protein known as gp120 (25).
Cannabinoids, HIV and the Immune System of the CNS
HIV is able to infect the central nervous system (CNS), enabling it to alter the functioning of the immune cells in the brain. Key changes to the CNS immune system brought about by HIV have been associated with the development of dementia. Cannabinoids are known to modulate the immune system in both the periphery and the CNS and many have attempted to investigate how HIV and cannabinoids interact. One study
used monkeys with CNS infections of SIV to examine how this class of retrovirus altered the endocannabinoid system. They found that in particular, SIV caused upregulation of CB2 receptors in three CNS
immune cell types. The authors concluded that once CNS infection had occurred its progression might be facilitated by the inhibition of the antiviral properties of these immune cells via CB2 mediated immunosuppression (26). Furthermore, at least one early study on lymphocytes containing both CB1 and CB2 receptors found that treating the culture with HIV combined with either THC, WIN, or CP-55,940, all of which bind to both receptors, resulted in increased evidence of infection compared to HIV treatment alone (27). This finding, however, has not been replicated in live animals and the concerns posed by the monkey study by and large have not been substantiated either. In fact, most of the evidence appears to point in the opposite direction. One of the types of CNS immune cells found to upregulate CB2 receptors in response to SIV is microglia. WIN has been found to potently inhibit the replication of HIV in microglial and CD4(+) lymphocyte cell cultures (28), and at least in the microglia, this occurs via a CB2 receptor-dependent mechanism (29). Morphine behaves rather differently in this test. Suppression and stimulation of expression of the virus were produced by morphine in a time-dependent fashion. Nor did morphine behave consistently between lymphocyte and microglial cultures. This finding suggests that when it comes to HIV-related pain management, cannabinoids might be a less harmful choice than morphine. One of the things microglial cells are known for is significantly contributing to the development of dementia in conditions like multiple sclerosis, AIDS and Alzheimer’s disease. Once activated, these CNS immune cells wreak havoc on the brain. Activation of CB2 receptors on microglia has been found to
inhibit their activation through inhibition of one of their main activation pathways. CB2 activation also suppressed the release of nitric oxide (NO) and tumour necrotic factor alpha (TNF-alpha) from microglia (30). Both NO and TNF- alpha are known to be involved in activated microglial-related CNS cell damage. The release of NO from macrophages may also play a roll
in HIV-induced CNS cell damage (31) and at least one study has found that CP-55,940 can
suppress the release of NO by macrophages through CB1 and CB2 mediated mechanisms. Another way in which cannabinoids have been found to potentially inhibit the dementia-inducing nature of HIV is through restoring the blood-brain barrier (BBB) after HIV assault. Although HIV does not directly infect the endothelial cells in the BBB it can produce
several changes in them which alter their ability to effectively bar entry into the brain.
Cannabinoid agonists have been found to block or even reverse many of these changes both in culture and animal models. Cannabinoids also inhibited the ability of the macrophage/microglial precursor cells (monocytes) to move across the BBB (32). The ability to restore the BBB after HIV assault by cannabinoid agonists is likely to suppress HIV infection of the CNS and thus the eventual development of dementia. Although the concerns posed by Benito, et al. 2005, with their work on SIV-induced changes in monkey brains (26) may not be presented by HIV itself, there is always the concern of secondary infection to consider. Cabral and Marciano-Cabral, 2004, were stimulated by the observation that CNS infections by opportunistic amoebae were more common in AIDS patients to investigate how THC affected infection rates of the amoebae in mice. There was a dose-dependent increase in infection-related mortality rate for mice treated with THC compared to those that were not. The increase in infection-related deaths appeared to be the result of the immunosuppressive effects on macrophages and microglia produced by THC.
THC inhibited the ability of these cells to fight off the infection in the brain, indicating that it might also make HIV patients more susceptible to opportunistic secondary infections of the CNS (33). However, this implication has yet to be confirmed.
Can We Exploit HIV/Endocannabinoid Interactions?
The answer to this question is most certainly yes. Early research on HIV/endocannabinoid interactions did not look promising (27, 34, 35)
and it was concluded (36), possibly correctly, that these interactions featured prominently in disease progression and ultimate downfall of the immune system. Some more recent work such as Benito, et al.
2005, with monkeys, have added to this concerning knowledge base,
finding overexpression of not just CB2 receptors in specific cells but also fatty acid amide hydrolase (FAAH ) production as well (26). FAAH is responsible for the enzymatic breakdown of anandamide after it has been released. In some cases, these interactions may indicate that CB1 agonist drugs like cannabis may not always be the best choice or may even potentially exacerbate some particular process in the progression of HIV to AIDS. Instead, many cases would suggest manipulating the endocannabinoid system itself may be a more suitable approach.
Research into HIV/endocannabinoid interactions have found many possible targets for therapeutic manipulation of the endocannabinoid system to either aid in the body’s natural attempts to fight the drug or counteract the ways in which HIV alters the endocannabinoid system to facilitate its own spread and development. One of the issues, however, with interpret-
ing how to use these interactions to our advantage successfully is that often the particular action observed is very cell-type dependent. In 2002, Esposito and colleagues found that a line of rat neuroimmune cells, when treated with HIV proteins, would release high levels of NO resulting in a toxic effect on the cells. This HIV-induced overexpression of NO resulted in a down-regulation of CB1 receptors and in anandamide transporter activity in the cells. On the other hand, it was found that CB1 receptor activation significantly inhibited the NO release, development of cell toxicity, and CB1 receptor/anandamide transporter downregulation resulting from HIV protein assault. Here both direct CB1 activation through exogenous drugs like THC or WIN could be beneficial as well as therapies targeting means of up-regulating the endocannabinoid system through FAAH inhibition and stimulation of endocannabinoid production.
In 2004 Maccarrone, et al., found significant changes to endocannabinoid system functioning in the neocortex of rats following assault by a particularly toxic HIV protein. The protein, gp120, was found to induce increased FAAH production and anandamide transporter activity while suppressing levels of anandamide itself. However, the enzyme responsible for anandamide production was unaffected. The activity of an enzyme capable of creating endogenous FAAH inhibitors from anandamide was also drastically reduced following HIV gp120 assault. As a result of this up-regulation of FAAH and subsequent down-regulation of anandamide in the rat neocortex, a delayed apoptotic response to HIV gp120 protein assault was observed in neo-cortex cells. Apoptosis is programmed cell death, or a process that once switched on results in the cell terminating its own life
processes. FAAH inhibitors were found to effectively attenuate gp120-induced apoptosis, although anandamide transporter inhibitors did not.
Co-administration of FAAH inhibitors and products which stimulate anandamide production may be especially useful in reducing these effects during the gp120 assault. It would also be useful to
elucidate the pathways involved in anandamide inhibition of gp120-induced apoptosis in the neocortex as more direct targeting of these pathways may be possible. Sancho, et al. 2005, found that a lesser-known endocannabinoid known as N-arachidonoyldopamine (NADA) was capable of significantly inhibiting HIV infection of two human immune cell and one brain cell lines. Other endocannabinoids such as anandamide and 2-AG (2 arachidonoylglycerol) did not produce this effect, nor was the effect found to be dependent on known receptors for NADA. This antiviral effect of NADA was found to be additive with at least one other antiviral medication. NADA was able to inhibit the replication of HIV by targeting the ability of NF-kappaB to be activated by TNF-alpha or HIV (39). NF-kappaB is a transcription factor recruited by HIV in the replication of more HIV and inhibiting its activation inhibits the ability of HIV to make more copies of itself. Stimulation of NADA production, inhibition of intercellular removal and breakdown of NADA and/or systemic NADA administration may yet prove to be useful parts of an effective HIV antiviral regiment.
Evidence Against the use of Cannabinoid Base Therapies in HIV Patients
Overall, there is minimal concrete evidence so far as to suggest cannabinoids pose a significant risk to those infected with HIV; however, some warnings still should be considered. As stated before, animal studies suggest THC may increase the risk of infection of the brain by opportunistic amoebae in HIV patients (33). Another study has suggested that THC may significantly increase the mortality rate of HIV patients previously infected with other viral infections like herpes simplex virus (40). A hybrid study using human immune cells implanted into immunosuppressed mice found that THC reduced CD4 expression in these cells. CD4 levels are used as an indicator of HIV progression in HIV and AIDS patients. In general, CD4 levels and degree of HIV infection appear to be inversely related such that as HIV infection goes up CD4 levels drop. So the finding that THC can induce suppression of CD4 expression in these cells is alarming. Although co-administration of HIV and THC did not reduce CD4 levels beyond that observed with THC alone, HIV infection rates were significantly increased (50 times greater) compared to administration of HIV alone. After five
days of treatment with THC, the cells were also found to have up-regulated the expression of two of the receptors essential to HIV infection of new cells. This effect had diminished to non-significant levels by 10 days of THC treatment but the damage had already been done. The number of infected cells had been substantially elevated by the period of increased viral receptivity. These findings lead the authors to suggest that there exists a window early on in THC-based therapies for HIV when THC is actually enhancing HIV replication and thereby facilitating the progression from HIV to AIDS (41). Taken together these studies do not paint a positive picture of THC in the treatment of symptoms of HIV.
One thing to be considered, however, is that all three are animal studies using mice and there may be something special about the mouse response to THC under these conditions producing the negative results.
There is at least one factor that might warrant real consideration when trying to decide if THC-based treatment for HIV and AIDS-related symptoms is the right choice. One study has found that Marinol and Cannabis use can interact negatively with some retrovirus inhibitors. In this study, measures of health and disease progression were taken and then follow up scores were taken again a year later. Use of Marinol or cannabis by patients taking azidothymidine or an azidothymidine/dideoxycytidine combination was found to be associated with declining health at year’s end. At the beginning of the study, the use of cannabis or Marinol by patients taking dideoxyinosine was associated with reduced CD4 levels. However, those on dideoxyinosine are the most likely to have low CD4 counts to begin with, so it is hard to know what to make of this finding. Dideoxyinosine has been associated with the development of pancreatitis. However, by year’s end, all signs of pancreatic health had substantially improved in the subset of cannabis/Marinol using patients on dideoxyinosine (42). Clearly, cannabinoids affect health differently in HIV patients depending on which antiviral therapies they are also taking, something which should be taken into account when either starting cannabinoid-based therapies for the first time or when starting or changing antiviral therapies.