Thursday, December 5, 2013

Implications of Chronic Alcoholism for HIV Infection

Alcohol dependence is the most common form of drug abuse in the US, with around 7% of the population meeting criteria for alcoholism (Grant 1994). We all know that the effects of alcohol are wide-ranging, impacting both behavior and physiology; it impairs judgement, motor skill, etc. It has been known to weaken the immune system, and research in the past few years has linked the effects of alcohol to HIV infection. Common sense tells us that alcohol promotes risky behaviors, including those that increase the possibility of HIV infection (sex, drugs, etc.). Recent interest in binge drinking and HIV has produced data showing alcohol in a binge pattern changed the proportion of immune cells after SIV infection in rhesus macaques, a common animal model for HIV, and may even increase the disease course (Molina et al 2006, Poonia et al 2006). But researchers at the Scripps Research Institute have also showed that chronic alcoholism may generate microenvironments in the body that are more vulnerable to HIV infection.

To accomplish this study, the researchers developed a protocol in which rhesus macaques self-administered alcohol orally, twice a day for 30 days before infection and during infection. To do this, they mixed alcohol and an orange flavored drink in different ratios, and conditioned the animals to drink the solution (replacing water with the alcohol solution for a short duration). The final concentration given to the animals was 6% alcohol, similar to the alcohol content of most beers, and animals drank enough alcohol per day to cause blood alcohol levels that in humans are greater than the legal driving limit and would decrease motor skill. When the animals were conditioned, they were infected with SIVmac251, a strain of SIV that induces high peak and steady viral loads and is also known to infect the CNS (Burdo et al 2005). SIVs, simian immunodeficiency viruses, are retroviruses that infect non-human primates and produces symptoms and changes in physiology that mirror those induced by HIV infection (it is generally believed that HIV originated from SIV crossing the species barrier to humans).

After SIV infection, plasma viral loads, as well as viral loads in tissues (brain, liver, spleen) in alcohol-consuming animals did not differ than controls, who were fed just the orange solution without alcohol. However, alcohol consumption did significantly increase the viral load in the CSF. Furthermore, when looking at inflammatory cytokines and lymphocyte subsets, the authors found that alcohol decreased IFN-alpha, CD4 T cells, and NK cells in the brain, suggesting that alcohol may dampen the immune response to the virus in the brain. As SIVmac251 is known to infect the CNS, this data suggests that chronic alcohol may increase the susceptibility of the CNS to HIV infection and further complications, such as HIV encephalitis. However, as actual brain tissue did not show increased viral load, a definitive link between alcohol and CNS HIV infection/complications needs to researched.

The authors also looked at general lymphocyte populations in the blood and other organs, such as the liver, spleen, and lymph nodes. They found that although in the blood CD8 T cells and NK cells did not differ when animals where given alcohol, CD4 T cells in the blood were significantly  reduced 7 days post infection (dpi) as a result of alcohol consumption, CD4 T cells being the primary target of HIV/SIV infection. In tissues, the authors saw varying results: the SIV+EtOH group (alcohol-consuming) showed increased population of CD4 T cells in the cervical lymph nodes (LN) but a lower population of these cells in the liver and brain. The authors then subdivided CD4 T cells into CD62L+CD45RA- central memory (CM) and CD62L+-CD45RA- effector memory (EM), which are generally thought to produced more CD4 T cells and provide support for CD8 cytotoxic T cells during the secondary response, respectively. They found that the SIV+EtOH group had fewer CD4 CM T cells in the blood, spleen, liver and LNs, and fewer CD4 EM in the blood. Even more specifically, they found CD4+ CCR5+CD95+ T cells, which are targets of HIV/SIV viral infection and also show memory, increased in the spleen and LN of alcohol-consuming macaques. They also found decreased population of NK cells in the spleen, cervical LN, and brain.

The authors followed monocytes and macrophages (another population of immune cells susceptible to HIV infection; CD14+CD16low and CD14+CD16+, respectively) as well and found them to be decreased at 7 dpi in the alcohol-consuming population. In addition, looking more specifically, in the blood these monocytes and macrophages had increased expression of CCR5 (a coreceptor frequently used by HIV/SIV), CD44v6 (an adhesion molecule correlated to brain-inflammatory HIV/SIV), and CCR2 (a chemokine receptor linked to monocyte infiltration and cognitive decline). Correspondingly, they found that tissue macrophages had increased CCR5 and CD44v6 expression in the liver and brain, respectively. This reaffirms the author's suspicion that alcoholism can induce vulnerability to HIV/SIV infection in certain microenvironments within the body.

By simulating HIV infection in macaques that consume alcohol chronically in similar quantities as seen in human consumption, Marcondes et al have found results that support the notion that alcoholism can increase susceptibility to HIV infection. Mainly they found that inflammatory cytokines and lymphocyte subsets were altered, especially in brain, where they were decreased. This could perhaps mean more CNS involvement during HIV infection in chronic alcohol abusers. They found CD4 T cells (central and effector memory) were decreased in SIV+EtOH animals, suggesting that perhaps HIV killing of these cells were more efficient when alcohol was present. They also found that CCR5, one of the HIV coreceptors, was upregulated in monocytes and macrophages, suggesting that alcohol perhaps made these cells more vulnerable to HIV/SIV infection. However, the results presented in this paper need to be taken with a grain of salt. Although they found altered lymphocyte populations, overall viral load in the blood and in the tissues were no different in the alcohol consuming condition; in addition, results were mixed for other tissues such as the spleen, liver, LN, etc. It is also important to differentiate the alterations in lymphocyte populations with their role in HIV infection. A decrease in lymphocyte population may not necessarily suggest more vulnerability but rather more killing. An increase in inflammatory cytokines/lymphocytes in peripheral blood may mean a better immune response to HIV infection, but in the brain it may have negative consequences (e.g. encephalitis, leading to cognitive decline). Overall, while this study has shown somewhat mixed results for different tissues, these authors have been able to show that alcohol does have negative effects on the immune response during SIV/HIV infection, although the extent to which alcohol effects viremia and conversion to AIDS (in general HIV progression), and HIV encephalitis, needs to be studied further. Nevertheless, we can add vulnerability to HIV to the long list of reason to avoid alcohol abuse; this is very pertinent to those young persons undergoing secondary education who, by most parameters, qualify for chronic alcoholism. wink.

Main Article:

Marcondes, M. C. G., Watry, D., Zandonatti, M., Flynn, C., Taffe, M. A. and Fox, H. (2008), Chronic Alcohol Consumption Generates a Vulnerable Immune Environment During Early SIV Infection in Rhesus Macaques. Alcoholism: Clinical and Experimental Research, 32: 1583–1592.

Other References:

Burdo THMarcondes MCLanigan CMPenedo MCFox HS (2005Susceptibility of Chinese rhesus monkeys to SIV infectionAIDS, 1917041706.

Grant, B. F. (1994), Alcohol consumption, alcohol abuse and alcohol dependence. The United States as an example. Addiction, 89: 1357–1365.

Molina, P. E., McNurlan, M., Rathmacher, J., Lang, C. H., Zambell, K. L., Purcell, J., Bohm, R. P., Zhang, P., Bagby, G. J. and Nelson, S. (2006), Chronic Alcohol Accentuates Nutritional, Metabolic, and Immune Alterations During Asymptomatic Simian Immunodeficiency Virus Infection. Alcoholism: Clinical and Experimental Research, 30: 2065–2078.

Poonia BNelson SBagby GJVeazey RS (2006). Intestinal lymphocyte subsets and turnover are affected by chronic alcohol consumption: implications for SIV/HIV infectionJ Acquir Immune Defic Syndr 41:537547.

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