Human immunodeficiency virus (HIV) inflicts disproportionate suffering on drug abusers. They have an extremely high prevalence of infection because the virus transmits easily via shared drug-injection equipment and through drug-influenced risky sexual behavior. They progress to disability and death more rapidly because diagnosis and treatment are often delayed and their lifestyle and circumstances limit their ability to adhere to demanding antiretroviral medication regimens.
And that's not all, according to two recent studies by NIDA-funded investigators. One found that crack cocaine users who are infected with HIV experience an accelerated decline in immune function that is independent of their adherence to therapy. In the other, cocaine and methamphetamine increased both the ease with which the HIV virus entered immune cells in laboratory cultures and its replication rate once inside the cells.
Accelerating the Development of AIDS
Dr. Marianna Baum and colleagues at Florida International University followed 222 HIV-positive drug abusers in Miami for 30 months. Each month, the participants reported on their drug and medication use, and they gave blood samples every 6 months to be assayed for levels of the virus and of the immune cell, CD4, that the virus primarily attacks. At each visit, the participants were designated as crack cocaine users or nonusers, depending on whether they reported taking the drug at any time during the previous 6 months. When the data were analyzed, they showed an association between crack cocaine use and more plentiful virus in users' blood that was independent of their degree of antiretroviral adherence. There were no significant differences in viral load associated with use of powdered cocaine, marijuana, or alcohol.
To investigate disease development, the researchers focused on the 130 participants who, at the start of the study, had more than 200 CD4 cells per microliter (μL) of blood. Among that group, use of crack cocaine more than doubled the likelihood of a participant's CD4 cell count dropping below that level—and thus meeting the criterion for an AIDS diagnosis—during the study. Dr. Baum and colleagues did not observe any changes in disease progression related to the use of powdered cocaine, marijuana, or alcohol.
To determine whether crack cocaine had an effect on HIV progression independent of its influence on adherence to HIV treatment, the researchers separately analyzed the data for the 53 participants with more than 200 CD4 cells/μL at baseline who were not taking antiretroviral drugs. Of the crack cocaine users in this group, 51 percent dropped below 200 CD4 cells/μL during the 30-month followup, compared with 13 percent of the nonusers of the drug. Dr. Baum says, "The results indicate that, in addition to reducing treatment adherence, crack cocaine increases the risk of progression to AIDS by accelerating the decline of the CD4 cell count."
In keeping with previous studies, the team also found that use of crack cocaine, but not the other drugs, reduced the success of antiviral medications. At the start of the study, among participants receiving antiretroviral therapy, 39 percent of nonusers of crack cocaine, as compared with 27 percent of users, had fewer than 400 copies of the virus per milliliter of blood, which is considered a sign that the antiviral regimen is working well. Moreover, the percentage of nonusers meeting this criterion was the same at the 12-month followup assessment, while the percentage of crack cocaine users who had fewer than 400 copies per milliliter had fallen from 27 to 15 percent.
Though the researchers are not sure why crack cocaine was the only drug among those studied to affect HIV progression independent of treatment adherence, Dr. Baum speculates that "it may be associated with the frequency of use. Crack cocaine is relatively inexpensive—around $3 to $5 per dose—and it can be bought easily on the street. The other drugs studied are more expensive than crack cocaine," and thus are used less frequently in the population studied, she says. Dr. Baum notes that frequent use of crack cocaine places socioeconomic pressures on the user, reducing the proportion of income used for medical care and food. Crack cocaine also decreases appetite and is associated with nutritional deficits that impair the immune system.
Dr. Baum notes that the new findings highlight the quest for better-targeted interventions to help HIV-infected patients quit illicit drug use: "We need to get these patients into drug treatment, not only because drug use affects adherence to HIV medications, but because we now know that drug abuse impacts disease progression itself."
Helping HIV Enter Cells
If crack cocaine drives HIV progression, how does it do so? Dr. Madhavan Nair of Florida International University suggests that the answer is, in part, that cocaine abets the virus' insidious strategy for attacking the immune system.
Dr. Nair and colleagues have been studying HIV's interaction with the first cells it encounters in the immune system. These cells, called dendritic cells, patrol the blood and tissues for potential pathogens. When a dendritic cell encounters viruses or bacteria, it binds them to receptors on its surface, draws them inside itself, and then alerts other immune cells to the presence of the pathogen.
Previous investigations have shown that HIV takes advantage of this system. It attaches to the dendritic surface receptors, rides the dendritic cells until they contact other cells, and then attacks those other cells. By weakening and destroying the additional cells—and CD4 cells, in particular—the virus cripples the body's ability to ward off subsequent viral and bacterial invaders.
Dr. Nair and colleagues examined dendritic cells and their components in blood from HIV-infected and uninfected individuals, including people who did and who did not use cocaine. The team found that cocaine increases production of one of the receptors, called DC-SIGN, that dendritic cells use to capture invading organisms. As a result, when the invading organism is HIV, dendritic cells pick up and deliver more of the virus, enhancing its spread to the CD4 and other cells with which they come in contact. Moreover, Dr. Nair found that cocaine increases the rate of replication of HIV within dendritic cells, increasing still further the virus' spread to other immune-system cells and contributing to the demise of dendritic cells.
How Methamphetamine Increases HIV Replication: When dendritic cells in laboratory culture were exposed to methamphetamine, activity increased in the gene for a receptor, CCR5, that the virus exploits to enter cells. Knocking out production of the D1 receptor prevented methamphetamine from producing this effect.Dr. Nair's team recently demonstrated that methamphetamine, like cocaine, stimulates production of receptors that draw HIV into dendritic cells. Using cell cultures, they documented that dendritic cells exposed to methamphetamine generated more than twice as many CXCR4 and CCR5 receptors within 24 hours, compared with unexposed cells. The percentage of methamphetamine-exposed cells infected with HIV was sevenfold that of control cells, and the viral replication rate inside them was 57 percent higher.
The initial mechanism of stimulant-induced dendritic cell receptor production appears to be the same as that underlying these drugs' psychoactive effects: hyperactivation of the dopamine neurotransmitter system. When the researchers treated drug-exposed, HIV-infected cell cultures with a chemical that prevents dopamine from influencing dendritic cells, the increase in dendritic cell receptors was suppressed.
Implications for Treatment
Dr. Nair says that learning the details of how dendritic cells interact with HIV and pass it on to other immune cells can provide a basis for effective new HIV treatment approaches. "Even with antiretroviral therapy, you cannot eliminate the HIV virus from the body," says Dr. Nair. "But if we could affect some of these specific receptors, we might be able to block the virus from entering the cells."
Dr. Jag Khalsa, chief of NIDA's Medical Consequences Branch, says, "Now that we understand this mechanism, we can try to develop drugs that target the receptors—blocking them so that methamphetamine or cocaine has no effect. NIDA is now funding research in this area."
Sources
Baum, M.K., et al. Crack-cocaine use accelerates HIV disease progression in a cohort of HIV-positive drug users. Journal of Acquired Immune Deficiency Syndromes 50(1):93-99, 2009. [Full Text]
Nair, M.P.N., et al. Methamphetamine enhances HIV-1 infectivity in monocyte derived dendritic cells. Journal of Neuroimmune Pharmacology 4(1):129-139, 2009. [Abstract]