NATIONAL INSTITUTE ON ALCOHOL
ABUSE AND ALCHOLISM
REPORT TO THE EXTRAMURAL ADVISORY
BOARD
BRIEFING INFORMATION
STRENGTHENING ALCOHOL AND HIV/AIDS
BIOMEDICAL RESEARCH
CONTENTS
I. AIDS Epidemic: Overview and Introduction
B. Context for Research: Major Themes of the NIH Plan
1. Table 1: Prevalence of Alcohol Consumption HIV+
II. NIAAA Alcohol and HIV/AIDS Biomedical Research
A. Introduction and Background
B. Past Biomedical and Research Priorities
D. Research Opportunities: A New Research Approach:
From Bedside to Bench (and back again)
III. Strategic Plan Area: Natural History and Epidemiology
B. Research Priorities of the NIH FY 2007 Plan
C. Special Emphasis Area: Natural History and HAART
D. Special Emphasis Area: Biomedical Aspects of Alcohol,
HIV/AIDS, and Liver Disease
E. Special Emphasis Area: Alcohol and HIV-related Anemia
F. Special Emphasis Area: Modeling Alcohol-related Outcomes
IV. Strategic Plan Area: Etiology and Pathogenesis
B. Research Priorities of the NIH FY 2007 Plan
C. Special Emphasis Area: Alcohol, HIV/AIDS-Induced
Immune Modulation
D. Special Emphasis Area: Mucosal Immunity
E. Special Emphasis Area: Alcohol and Host Defense:
A New Role for Mitochondria in Coordinating The
Anti-Viral Immune Response
F. Special Emphasis Area: Alcohol, HIV/AIDS and the
Central Nervous System (CNS)
G. Special Emphasis Area: Alcohol, HIV/AIDS-Induced Effects
on the Microvasculature Endothelium
H. Special Emphasis Area: Alcohol Effects on Pulmonary Function
in the HIV-Infected Patient
V. Strategic Plan Area: Prevention Science: Vaccines
VI. Appendix
A. References by Special Emphasis Area
1. Braithwaite RS, Conigliaro J, Roberts MS, Shechter S, Schaefer A, McGinnis K, Rodriguez MC, Rabeneck L, Bryant K, Justice AC. Estimating the impact of alcohol consumption on survival for HIV+ individuals. AIDS Care April, 2007, Vol 4 Page 459-66.
2. Bagby G.J., Zhang P.,Purcell J.E. Didlier P.J., and Nelson S. Chronic Binge Ethanol Consumption Accelerates Progression of Simian Immunodeficiency Virus Disease. Alcoholism Clinical and Experimental Research, Vol30, No 10, October 2006.
3. Pfefferbaum A., Rosenbloom M.J., Adalsteinsson E., and Sullivan E.V., Diffusion tensor imaging with quantitative fibre tracking in HIV infection and alcoholism comorbidity: synergistic white matter damage. Brain (2006) Page 1 -17.
4. Justice A. (Guest Editor) Alcohol in HIV Infection: Insights from the Veterans Aging Cohort Study and the Veterans Affairs National Health Information System, August 2006, Vol 44, No. 8, Supplement 2.
This meeting is the first review of the biomedical aspects of the NIAAA portfolio and will serve to guide future directions in developing NIAAA research goals in the Alcohol and HIV areas. This area of research represents within and across-Institute collaboration involving both behavioral and biomedical research. Such collaboration reflects the broader need to develop effective transdisciplinary teams. As AIDS becomes a chronic “relapsing” disease with effective treatment, long term comorbidities such as alcohol use disorders and their impact on medication adherence and medical complications need to be understood over the course of the disease. It is critical that this plan be responsive to the new discoveries in both the alcohol and HIV/AIDS research communities. The recent XVI conference in Toronto Canada identified five “tracks” of research comprising over 13,000 abstracts and hundreds of presentations. The overall theme of the conference, “Time to Deliver,” highlighted critical developing modes of prevention (vaccines and microbicides) as well as distribution of treatment regimens into resource-poor areas where the highest incidence and prevalence of HIV infection are found.
The five tracks, all of which are relevant to alcohol and AIDS research, focus on A) etiology and pathogenesis, which encompass all aspects of HIV-1 biology and host response. Areas include genetics, viral fitness (structure and function), the progression of HIV disease, and both adaptive and innate immune responses that increase host susceptibility (measured in both human and animal models). Preclinical research on vaccines and microbicides acted as the focus for many discussions. The second track (B) targets clinical research, treatment and care. This track underscores the complexities of studying HIV/AIDS in human populations and the controversies related to diagnosis and treatment of HIV infection. A wide range of issues regarding antiretroviral therapies, access, and treatment failure were discussed. These issues included substance use comorbidities, the development of new therapies, pharmacokinetics, drug-drug interactions, adherence, short and long term adverse events, and roles of specific viral clade types in developing drug resistance. Approaches to care among women and children, marginalized groups such as substance abusers, and provision of care in resource limited settings were also addressed. In addition to these first two tracks there were discussions of the role of (C) epidemiology in guiding prevention activities; (D) social, behavioral and economic issues, and (E) the impact of policy on care provision and discrimination. Many of the research issues, particularly those outlined in the first two track areas of the XVI International AIDS Conference are relevant to the current NIAAA EAB review meeting.
Overall 300+ abstracts from the conference include references to alcohol as a cofactor. These abstract topics range from liver failure to cost of illegal alcohol production. This number is quite impressive since the meeting in general did not focus on the issue of substance abuse (particularly alcohol use) as a cofactor. For example, one abstract describes the finding that among providers of HIV care in resource-poor settings, approximately one third reported problem alcohol use themselves (as measured by the AUDIT). The author pointed to the devastating nature of the task of caring for AIDS patients with inadequate medical resources as the explanation for the levels of drinking and the susceptibility of these workers themselves to becoming infected.
Many individuals have contributed to the vitality of the NIAAA alcohol research portfolio. Research in this area is a difficult endeavor because of the dual expertise required in both the alcohol and HIV areas for development of successful applications. The current EAB meeting brings individuals on the Extramural Advisory Board of NIAAA together with AIDS experts who have an appreciation for alcohol research and with individuals who have developed some of the major AIDS research. Other individuals from within NIAAA have given generously of their time to help guide this document by describing current and future potential areas of research. I thank each of them for their thoughtful participation in this project and wish to acknowledge their help in making this document a useful tool for promoting alcohol and AIDS research in the future.
We believe that, through this planning opportunity made possible by senior staff of NIAAA, we will be able to identify critical directions for research that represent the best opportunities for improving patient outcomes in this time of increasing fiscal constraint. It must be noted that our current effort is set against the backdrop of a need for increasingly effective prevention research to develop vaccines and microbicides. The goals of our combined efforts in both the biological and behavioral areas are to help control the ongoing pandemic, to prevent new infections, and to provide effective care for those infected with HIV, many of whom have coexisting alcohol use disorders.
Kendall Bryant, Ph.D., AIDS Coordinator, NIAAA
I would also like to acknowledge Leslie Isaki, Ph.D., whose hard work in the area of alcohol immunology early in the epidemic helped NIAAA develop many important grant applications and attract new researchers in the basic biological alcohol and AIDS field of research.
The National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health (US Department of Health and Human Services), is the primary source of funds for alcohol and HIV/AIDS research and supports a continuing and expanding program of domestic and international research. NIAAA seeks to fulfill multiple goals identified in the National Institutes of Health Plan for HIV-Related Research through a broad range of research and collaborative activities focused on HIV/AIDS prevention and treatment among alcohol using, abusing, and dependent populations.
The past decade of NIAAA research funding has demonstrated the complexity of alcohol and HIV/AIDS relationships within both biomedical and behavioral research and the need to continue the effort to understand these relationships. Currently NIAAA receives approximately 27 million dollars annually for support of this research through the Office of AIDS Research, NIH. Annual plans are developed and submitted to the Office of AIDS Research for current, expanded, and new initiatives in the AIDS research area. The overall legislative mandate under the National Institutes of Health Revitalization Act (Public Law 103-43) provides for the development of HIV/AIDS plans in conjunction with outside experts for research in both the basic and applied areas of biomedical and social sciences.
This meeting focuses on briefly reviewing some of the major basic biological and related biomedical treatment research issues and priorities in the area of HIV/AIDS and alcohol. The primary goal of this review and subsequent discussion is to provide a framework for continuing and expanding existing lines of research, as well as suggesting new alcohol-related initiatives for the prevention and treatment of HIV/AIDS. Because of the scope of ongoing research in the NIAAA portfolio, we decided that this meeting would not directly address behavioral or social issues, particularly in the area of behavioral prevention. The areas of behavioral prevention and prevention sciences (combining both behavioral and biological research) will be addressed in part within the high priority topic of vaccines and in subsequent meetings. Specific basic biological and biomedical topics will be treated in greater depth based on current findings and program priorities in the FY2005 and FY2006 portfolios. The current meeting is focused on achieving some of the broader strategic goals outlined below. (Portions of text are highlighted for emphasis.)
(1) Evaluate the impact of research on biological mechanisms and biomedical patient-focused research in identifying the role of alcohol in tissue and organ injury and identifying mechanisms of action underlying accelerated morbidity and mortality in co-occurring alcohol use disorders and HIV/AIDS.
(2) Assess progress in identifying the impact of alcohol use on susceptibility to infection and early progression (set points and trajectories) of HIV/AIDS-related morbidity and mortality, and the implications of bench and clinical research in this area for prevention and treatment of HIV/AIDS in domestic and applicable international contexts.
(3) Discuss methods for and progress in targeting new research to the areas of clinical health most relevant to future improvements in early diagnosis and treatment of HIV+ individuals with alcohol use disorders.
(4) Identify and integrate significant emerging research areas (e.g. Biomarkers, Rapid Testing, Viral Genetics, and Vaccine Development) that appear especially important to the alcohol and AIDS mission of NIAAA.
(5) Identify ways to improve patient-focused health research through improved measurement of alcohol use and analysis of relevant data, identification of current and new biomedical indices related to alcohol and AIDS illnesses, and development of models for measuring provider care and patient-relevant quality of life outcomes.
(6) Discuss the use of this research to inform and target new opportunities for biomedical and biological research, including advancing understanding of the epidemic through simulation studies and informed statistical modeling.
(7) Evaluate ongoing activities and suggest future program activities to increase the use of NIAAA research resources and findings for preventing and reducing illness and injuries, including expansion of applied biological and biomedical research in domestic and international populations at-risk due to alcohol use.
(8) Integrate biological and clinical/behavioral approaches and teams of researchers to address complex biobehavioral problems such as “Prevention for Positives”, which may include issues in medications adherence, toxicity, failure, and computer assisted clinical decision-making paradigms, and interventions to reduce transmission.
(9) Understand the more efficient use of existing datasets and available HIV/AIDS cohorts to conduct research, including clinical trials for vaccines and therapeutics and epidemiological studies of comorbid disorders.
Presented in this document are some of the selected areas of biological and biomedical research within a broader NIH framework for effective action. These brief sections comprise reviews of both past and ongoing research highlighting promising findings, and discussion of areas of research critical to HIV and AIDS prevention and treatment.
Opportunities for continuing, expanding, and developing new initiatives are discussed. Of particular importance are findings providing further evidence that alcohol use and misuse increases the morbidity and mortality of HIV+ alcohol users who may or may not be receiving treatment. While the impact of alcohol or HIV/AIDS on morbidity and mortality may be independently explained by additive effects, it is the interactive (synergistic) effects that are of greatest interest to basic research, and that are indicators of underlying shared or interactive mechanisms of action. For this reason general methodological issues need to be addressed in the measurement of alcohol and HIV/AIDS conjoint characteristics at the individual and population levels. As research continues to illustrate, it is the pattern of alcohol use relative to HIV disease course, including early infection, treatment initiation, and failure, which determines the complex multiple effects on individual survival and quality of life.
Understanding how basic biological and biomedical research may be strengthened requires an understanding of current NIAAA activities in these areas. Two broad areas of focus characterize NIH/NIAAA biomedical research: 1) Etiology and Pathogenesis; and 2) Epidemiology and Natural History. Within the area of Etiology and Pathogenesis are a variety of issues concerning both host-virus relationship and the clinical manifestations of HIV disease. These topics broadly cover NIAAA interests in immune function and neurological impairment.
AIDS Epidemic Overview and Introduction
Kendall J. Bryant, Ph.D.
AIDS Coordinator, NIAAA-NIH
Division of Epidemiology and Prevention Research
NIAAA Alcohol and HIV/AIDS Biomedical Research
Kendall J. Bryant, Ph.D.
AIDS Coordinator, NIAAA-NIH
Division of Epidemiology and Prevention Research
Deidra Roach, M.D.
Program Officer
Division of Treatment and Recovery Research
Strategic Plan Area: Natural History and Epidemiology
Samir Zakhari, Ph.D.
Director
Division of Metabolism and Health Effects
Diane Lucas, PhD
Program Officer
Division of Metabolism and Health Effects
Deidra Roach, M.D.
Program Officer
Division of Treatment and Recovery Research
Kendall J. Bryant, Ph.D.
AIDS Coordinator, NIAAA-NIH
Division of Epidemiology and Prevention Research
Strategic Plan Area: Etiology and Pathogenesis
Diane Lucas, PhD
Program Officer
Division of Metabolism and Health Effects
Roger Sorensen, Ph.D.
Program Officer
Division of Neurological and Behavioral Research
Ellen Witt, Ph.D.
Program Officer
Division of Neurological and Behavioral Research
Strategic Plan Area: Prevention Science: Vaccines
Kendall J. Bryant, Ph.D.
AIDS Coordinator, NIAAA-NIH
Division of Epidemiology and Prevention Research
Maria Miquez, M.D.
Research Faculty
University of Miami
Editing and Organization
Deidra Roach, M.D.
Kendall J. Bryant, Ph.D.
Susan Maier, Ph.D.
Additional Comments and Scientific Review
Kenneth Warren, Ph.D.
Howard Moss, M.D.
Abraham Bautista, Ph.D.
I. AIDS EPIDEMIC: Overview and Introduction
HIV and sexually transmitted diseases (STDs) are among the most common infectious diseases. There are an estimated 40,000 to 60,000 new cases of HIV infection per year in the United States. The rate of growth in new cases is particularly high among young women (who now account for 47% of new cases) and among young adults ages 13-29 (who now comprise 39% of new cases). New HIV infections also appear to be resurging among young gay and bisexual men nationwide, and may be focused within party-going and substance-using cohorts. (CDC MMWR 2004) The U.S. Centers for Disease Control and Prevention (CDC MMWR 2004) reports that an estimated 850,000–950,000 persons in the United States are living with human immunodeficiency virus (HIV), including 180,000–280,000 who do not know they are infected. To examine trends in diagnosis for 2000–2003, the CDC analyzed HIV and acquired immunodeficiency syndrome (AIDS) together as HIV/AIDS (i.e., HIV infection with or without AIDS), counted by the year of earliest reported diagnosis of HIV infection. From 2000 to 2003, in 32 states that used confidential, name-based reporting of HIV and AIDS cases for >4 years, the overall annual rate of diagnosis of HIV/AIDS remained stable. However, rates among non- Hispanic black females were 19 times higher than rates among non-Hispanic white females, underscoring the need for continued emphasis on programs targeting females in racial/ethnic minority populations, their partners, and their families to reduce the number of cases of HIV/AIDS.
AIDS is one of the leading causes of death among men and women between the ages of 25 and 44, many of whom became infected as young adults. Although deaths from AIDS are beginning to decline, the characteristics of these deaths are shifting in response to chronic disease management practices using highly active antiretrovirals (and their toxic interactions with alcohol and other drugs). In 2004 an estimated 14,000 deaths in the US were directly attributed to AIDS-related diseases, as compared to approximately 40,000 in 1996. However, individuals now live longer with effective treatment of AIDS, and mortality is attributed to other non-AIDS-related diseases such as liver failure and lung disease. Internationally the scope and impact of the AIDS epidemic is growing rapidly. Limited epidemiological information makes it difficult to accurately estimate incidence and prevalence rates in developing countries. However, the overall level of infection is currently estimated at approximately 45 million and will surpass 65 million by 2010. (World Health Organization, 2004) Increased incidence rates can be found in some of the countries with the highest per capita drinking rates and in specific heavy drinking populations at risk for HIV in these countries (e.g. Russia, India, China and South Africa). [AIDS Epidemic Update December, 2004]
Drinking alcohol increases both the risk for infection with HIV and the morbidity and mortality of patients who progress to AIDS, the clinical manifestation of HIV infection. Both animal and clinical research point to intervening biological and biomedical-related processes as explanations for accelerated progression of AIDS. These underlying processes are poorly understood. Identifying these mechanisms is important to predict the course of the illness for individuals who have misused alcohol in the past and may continue to drink while infected.
It is increasingly clear that both the direct and indirect effects of alcohol misuse contribute to HIV treatment failure and lost years of life. These outcomes are important at both the individual and population levels of analysis and must be considered in the development of effective interventions. While problem drinking in the general population impairs host immune-mediated responses and causes alcohol-related tissue and organ damage, these effects may also be attributed to the toxicity of AIDS medications among AIDS patients who drink. In particular, the research presented here and work that is in progress support the conclusion that perhaps no level of alcohol consumption is “safe” once individuals are infected with HIV. However, medical care providers are often unaware of the acute and chronic interactions of alcohol with HIV/AIDS progression and treatment, and do not take this into account when making clinical care decisions.
B. Context for Research: Major Themes of the NIH Plan
(Excerpted from NIH Plan for FY2007)
The FY 2007 NIH research agenda continues the following overarching themes: a strong foundation of basic science; research to prevent and reduce HIV transmission, including vaccines, microbicides, and behavioral interventions; research to develop better therapies for those who are already infected; international research, particularly to address the pandemic in developing countries; and biomedical and behavioral research targeting the disproportionate impact of AIDS on minority populations in the United States. In particular, this budget request places highest priority on the discovery, development, and preclinical testing of additional HIV vaccine candidates. The evaluation of an AIDS vaccine will require extensive testing in the United States and in international settings where there is a high incidence of HIV. High priority is placed on funding to move promising vaccine candidates into large-scale clinical trials to evaluate the potential for effectiveness.
The Plan establishes the NIH AIDS research agenda in the following Scientific Areas of Emphasis: Natural History and Epidemiology; Etiology and Pathogenesis; Therapeutics; Vaccines; and Behavioral and Social Science. The Plan also addresses the cross-cutting areas of: Microbicides; HIV Prevention Research; Racial and Ethnic Minorities; Women and Girls; International Research; Training, Infrastructure, and Capacity Building; and Information Dissemination. The key priorities for the two research areas most directly related to NIAAA biomedical research interests, Natural History and Epidemiology and Etiology and Pathogenesis, and directions for future research are summarized below.
Alcohol Consumption
Alcohol consumption likely plays a pivotal but incompletely defined role in HIV viral replication, disease progression, potentiation of comorbid conditions, and increased frequency of adverse medical events from treatment with antiretroviral regimens. These findings have clear implications for prevention and treatment research in those countries that have been regularly employing medications for the treatment of AIDS and those that are beginning to develop the capacity to distribute and use these drugs. As has been continually emphasized by major world health organizations both in the US and abroad, improved prevention strategies should be the primary focus for stopping the spread of HIV, and effective treatment is part of a comprehensive prevention plan to reduce rates of infection. Effective treatment for both alcohol and HIV/AIDS leads to reductions in viral load, viral mutation, and subsequent infectivity.
Table one, compiled by Braithwaite et al., (2007) presents a summary of the 1) prevalence of recent alcohol consumption; and 2) prevalence of hazardous alcohol consumption for multiple domestic HIV+ samples. Recent Drinking ranged from 37% to 68%. . Prevalence of hazardous drinking ranges from 5% to 28%. International samples from resource-poor countries have reported substantially higher rates in excess of 80%. AUDIT scores have also indicated problem drinking in as high as 60% of HIV+ individuals. This range of drinking indicates that samples of HIV+ patients vary over a wide range. Presumably, those that are receiving AIDS medications have also been warned about continued drinking. These findings indicate that drinking may be problematic for some individuals before, during, and after infection and may shape the context for treatment with medications when they are available.
C: Table 1. Prevalence of alcohol consumption among United States HIV+ samples in the era of Highly Active Antiretroviral Therapy. (From Braithwaite et al, 2007). See Recent Publications, Appendix C.
Author
N
Year
Study
Prevalence of recent alcohol consumption
Prevalence of hazardous alcohol consumption
Braithwaite (ACER05)
2,762
2005
Veterans Aging Cohort Study (VACS)
46%
9%*
Tucker (03)
1,910
2003
HIV Cost and Services Utilization Study (HCSUS)
52%
14%*
Lucas (02)
695
2002
Hopkins
NR
5%
Kleeburger (01)
539
2001
Multicenter AIDS Cohort Study (MACS)
NR
6%
Samet (03)
349
2003
Boston
43%
19%
Stein (05)
262
2005
Brown
48%†
28%†
Cook (01)
212
2001
Pennsylvania
46%
19%
Golin (02)
140
2002
Adherence and Efficacy to Protease Inhibitor Therapy
(ADEPT)
37%
NR
Arnsten (01)
67
2001
Bronx HIV Epidemiologic Research on Outcomes Study (HEROS)
NR
22% ‡
Chesney (00)
65
2000
Adult AIDS Clinical Trials Group) (AACTG)
(AACTG)
68%
NR
NR = Not reported
* Only considers those hazardous drinkers who are also binge drinkers (>=5 drinks in at least one day during previous month); therefore these are likely underestimates.
† All individuals had a history of alcohol problems.
‡ “Alcohol use more than several days per week” was used as proxy for hazardous alcohol consumption
II NIAAA Alcohol and HIV/AIDS Biomedical Research
A. Introduction and Background
Research studies are beginning to elucidate the influence of alcohol use, abuse, and dependence on the systemic biological changes observed during the course of HIV infection and treatment. Data from these studies are of particular clinical significance because heavy and sustained alcohol consumption can change the physiology and biology of virtually every cell in the body, thereby modifying the function of components of the digestive tract, immune system, cardiovascular system, endocrine system, reproductive system, brain and central nervous system, and musculoskeletal system.
Figure 1: Multiple Impact of Alcohol on Tissue and Organ Systems
Alcohol Use and Immune Response
Both acute and chronic alcohol use can affect the immune system at the level of innate or acquired immune responses. The humoral and cellular components of the specific immune system can be equally damaged by alcohol use, emphasizing the impact of alcohol as a modulator of host defense. Impaired immunity in patients with chronic alcohol use has long been described in the medical literature. Studies investigating lymphocytes and lymphocyte subpopulations in chronic alcoholics have consistently shown decreased lymphocytic cell numbers in the circulating blood. These lymphocytes have also been reported to respond abnormally to in vitro stimulation by mitogens or antigens, suggesting an adverse effect on their capacity to react appropriately to infection.
In addition to the alcohol-induced decreased number of lymphoid cells, impaired proliferation response has been described, suggesting that ethanol-exposed lymphocytes have a reduced capacity to undergo proliferation and differentiation in response to an antigenic challenge. Research demonstrating the adverse effects of alcohol on immune system function is consistent with clinical evidence of an increased incidence of infections among alcoholics. Chronic alcoholics are more prone to infections with a variety of pathogens and have decreased ability to fight against infections. Clinical findings support a correlation between excessive alcohol consumption and infections with certain extracellular (e.g., Streptococcus pneumoniae) and intracellular (e.g., Mycobacterium tuberculosis) bacterial infections, and with the progression of some bacterial infections to sepsis. The increased incidence of infections caused by intracellular bacteria (i.e. Mycobacterium tuberculosis [tuberculosis] and Listeria monocytogenes [meningitis]) among alcoholics is explained in part by impaired phagocytic function.
The combination of alcohol abuse and hepatitis B in a patient is more detrimental than either of the two conditions alone. About 10% to 35% of heavy drinkers develop alcoholic hepatitis. Hepatitis B-infected alcoholics have a greater risk of developing cirrhosis and hepatocellular cancer. Gender also plays a role, with women who abuse alcohol at greater risk for developing alcoholic hepatitis than men. It is clear that effective vaccines to reduce the risk of infection in alcohol abusers are critically needed. However, it has been shown that vaccine efficacy is diminished among people who abuse alcohol.
Viral Replication
In the past, researchers (Bagsara, 1996) demonstrated that alcohol could impair white blood cell responses to HIV. A provocative study that warrants replication found that a single drinking episode depressed certain immune responses of white blood cells taken from healthy volunteers. (Bagsara, 1996) In addition, white blood cells isolated after this drinking episode were more susceptible to HIV infection than were cells isolated from subjects who did not drink, hinting that even occasional alcohol consumption may increase the likelihood of infection upon exposure to HIV. Subsequently, researchers have focused on understanding the role of viral replication in both laboratory cell cultures, including neural cells, and in animal models which focus on mucosal membrane response. (Bean, 2001; Liu, 2003)
Figure 2: Viral life cycle: Early Infection to Death – Researchers are focusing on “set points” early in the life cycle of the virus. These set points may be affected by alcohol use and determine the course of disease. (Bagby et al, 2006). See Recent Publications, Appendix C.)
The pathologic consequences of HIV are a function of the completion of the life cycle of the virus. (NIAAA, 2004) HIV-1 has a complex viral life cycle that utilizes 15 distinct proteins in specific functions, some of which may interact with alcohol. (Figure 3) They are: Gag and Env structural proteins, capsid proteins, nucleocapsid, SU and transmembrane proteins, Pol enzymes, reverse transcriptase, integrase, gene regulatory proteins Tat and Rev and accessory proteins Nef, Vif, Vpr and Vpu. Elevated levels of HIV transcription are regulated, among other things, by nuclear factor kappa B, which is functionally dependent on Tat activation. Thus, cell activities unrelated to HIV infection-inducing signal transduction pathways and ultimately up-regulating transcription factors can enhance HIV transcription. Oxidative stress and certain interleukins have been demonstrated to enhance HIV replication through these pathways. A specific cell activity unrelated to HIV infection is cell activation via alcohol exposure. As observed in alcoholics, elevated levels of TNF contribute to the activation of NF-kB. (Gonzalez-Quintela, 2004; Zeldin, 1996) NF-K B, on the other hand, influences HIV promoter activity. (NIAAA, 2004).
Figure 3: HIV Virus Proteins
The key questions for alcohol/HIV researchers are, “Does alcohol modify expression of HIV proteins or the cellular biology of infected cells to promote or inhibit HIV replication via NF-K B or any other mechanism? Is alcohol a viral “adapter” that can influence and/or modify cellular functions to enhance the replicative capacity of the virus?” Conflicting results have been obtained by those studying HIV replication in isolated peripheral blood mononuclear cells (PBMC). Bagasra and colleagues reported increased HIV-1 p24 levels in vitro in infected peripheral blood mononuclear cells from individuals after a one-dose acute alcohol infusion or binge drinking. (Bagasra,1996) In a different experimental design , no consistent increase in HIV replication after exposure to alcohol was shown. (Fitzpatrick, 1995) Further studies have recently shown that even alcohol concentrations as low as 0.25% increase the number of peripheral blood lymphocytes expressing CXCR4, thereby increasing viral entry 5 to 10 fold. (Bean, 2001; Liu, 2003) Thus, alcohol may facilitate enhanced viral infection by increasing the availability of HIV-1 co-receptor, and the increased intracellular cAMP may also facilitate its replication. Additional studies are needed to resolve the controversy in the field. (Liu, 2003)
Differing research approaches could be used to determine whether alcohol consumption enhances HIV replication. (Pomerantz, 2004) The first could be a clinical study of alcohol consumption and viral load over time. A positive correlation or direct relationship would provide important clinical data to inform patient management. Determining the mechanism of interaction between alcohol and HIV would likely involve molecular studies of the HIV genome to determine the presence of alcohol binding and/or inducible response elements. Such genomic sequences, on exposure to ethanol or its metabolites, could enhance viral replication. This enhancement could be through the recently described (Rampalli, 2003) NF-kb activation/ augmentation of the HIV promoter, LTR, or other regulatory gene (s), such as Tat or Rev. A second approach to determining the role of alcohol in HIV replication is to examine the action of alcohol or its metabolites on tissue-specific cellular metabolism.
Animal Models
The animal model that most closely resembles human infection with HIV is SIV infection of rhesus monkeys. (Nelson, 2004) SIV is a lentivirus that is genetically related to HIV. SIV is T cell tropic and infects both lymphocytes and macrophages, inducing an immunodeficient state that correlates with the depletion of CD4+ lymphocytes. Infection with SIV results in three stages comparable to HIV human infections (see figure 1): (a) acute infection characterized by high viremia, fever, lethargy and dermal rash; (b) asymptomatic stage with anti-SIV antibody and a decline in CD4 cell count;and (c) AIDS, characterized by substantial CD4 cell depletion and opportunistic infections. Beyond these similarities, an additional advantage of the use of the primate animal model is the ability to establish and monitor specific parameters related to alcohol consumption and HIV infection. These include time and route of infection, timing and quantity of alcohol consumption, assessment of nutritional and behavioral variables, as well as characterization of systemic and organ-specific pathogenesis. Limited data are available using this model (due to a variety of cost and care factors for monkeys; personal communication, Steve Nelson) and studies are needed to determine the interactions among alcohol, immune function, host SIV infection, and disease progression in nonhuman primate infection.
A recent study in Alcoholism: Clinical & Experimental Research (Bagby, 2003; in press) used simian immunodeficiency virus (SIV) infection of rhesus monkeys to examine the combined effects of chronic, binge alcohol consumption on the primary stage of SIV/HIV infection. Researchers found that alcohol consumption may increase host susceptibility to SIV/HIV infection. This study had two primary purposes: 1) to develop an animal model to study the interactive effects of alcohol on HIV disease transmission, pathogenesis, progression and anti-viral therapy; and 2) to examine the effects of alcohol consumption on what is called the 'primary stage' of infection. This stage is extremely difficult to study in humans because it is rare to be able to identify infected people this early.
The investigators adapted the primate model using SIV, which infects rhesus monkeys in the same way that HIV infects humans and produces a disease that is very similar to the human disease. Approximately one week after SIV infection, there was a 64-fold increase of the SIV virus in the blood of the alcohol-treated monkeys compared to the sucrose-treated monkeys. The researchers hypothesized that more cells are infected with virus at this early stage or that infected cells are producing more virus; i.e., that alcohol either increased the number of susceptible cells or increased the infectivity of cells. Alcohol consumption also enhanced lymphocyte turnover (as assessed by expression of the cell cycle protein marker Ki67) in SIV-infected monkeys during the early stage of infection, which may have contributed to the observed increase of virus in the blood.
Immunosuppressive Effects of Alcohol
Clinical Evidence
The physiochemical characteristics of alcohol allow it to interfere and damage most organ systems. In addition to the well-established relationship between alcohol and liver disease, alcohol may increase morbidity and mortality through its impact on immune system function. (Cook, 1998 and Watson, 1994) The clinical manifestation of immune changes caused by alcohol consumption are evident in drinkers, who exhibit increased susceptibility to infectious diseases such as respiratory infections and sepsis. (Cortese, 1992; Esposito, 1984; Jerrels, 1994; Manson, 2004) Infections that may lead to septicemia in the alcoholic include pneumonia, urinary tract infections, and bacterial peritonitis. (NIAAA, 2004) Alcoholics have twice as high a risk for pneumonia-related mortality as non-alcohol users. (Cortese, 1992; Esposito, 1984) The incidence of tuberculosis is also significantly increased by alcohol consumption. (Cook, 1998; Friedman, 1987; Manson, 2004) In animal models, alcohol-consuming mice not only had significantly higher lung organism burdens, their lymphocyte proliferation and production of gamma interferon were decreased. Researchers from Emory University (Holguin, 1998) have reported a number of abnormalities among alcohol users, including impaired alveolar type II pneumocyte function, decreased surfactant production, reduced barrier integrity, and increased apoptosis that could increase the risk of lower respiratory infections in alcohol users. (Kovacks, 2004) Thus, infections in ethanol-consuming individuals who drink large amounts of alcohol are both more frequent and more severe (Cook, 1998), in part because of ethanol-induced dysregulation of the immune system response. Further research is needed on the effects of alcohol on susceptibility to HIV infection, including the relationship of alcohol use-related host defense impairment to infection with opportunistic pathogens such as Mycobacterium tuberculosis, Streptococcus pneumoniae, Pneumocystis carinii and hepatitis C (HCV).
It is also important to consider frequency and duration of exposure to alcohol in relation to infection, as well as other host characteristics impacted by alcohol abuse, such as nutritional status, that can influence susceptibility to AIDS-related illnesses. Alcohol-induced malnutrition can further compromise the human immune system. (Watzl, 1993) Heavy alcohol abuse is associated with high caloric intake derived from alcohol and inadequate intake of protein, vitamins, and minerals, creating a malnutrition/wasting –type syndrome. (Watzl, 1993) Thus, alcoholics may not ingest adequate levels of vitamins and trace elements, such as zinc, iron, selenium, and magnesium, necessary for maintaining a competent immune response.
Laboratory Evidence
Chronic and even acute alcohol consumption results in significant changes in the immune system of experimental animals and humans. (Szabo, 1997; Brodey, 1994) A variety of short and long-term alcohol-induced effects on both cell mediated and humoral immune response have been described (Szabo, 1997; Miguez, 2001; Nair, 1994; Petrovick, 1996), with alcohol exposure linked to impaired host defense through a combination of cellular defects, altered cytokine production, and oxidative stress. (Dominguez, 2001; Isaki & Kresina, 2000; Laso, 1999; Manso, 1997; Starkenburg, 2001; Wang, 1997)
Studies in alcohol users have consistently shown decreased lymphocyte numbers accompanied by impaired function. (Roselle, 1992; Jerrels and Sibley, 1996) Although the mechanism for an ethanol-induced decrease in lymphoid cell number is yet to be defined, reduced antigen presentation and subsequent decreased antigen-dependent T-cell proliferation may be involved. (Brodie, 1994; Szabo, 1999) In a chronic alcohol-consuming animal model, a defect in antigen presentation occurred during the cognitive phase of the immune response when antigen presenting cells (APC) engage uncommitted T helper CD4+ cells. (Szabo, 1999) This defect, however, could not be reproduced when alcohol exposure occurred after the presentation and recognition steps. Specific to HIV, researchers from the University of Nebraska (Haora, 2004) recently demonstrated that elevated ROS following ethanol exposure decreased proteosome activity, and that this impairment could be restored by anti-oxidant supplementation. The data support the notion that HIV-1 infection and alcohol may work in concert to affect antigen presentation. (Haora, 2004) An additional suggested mechanism is programmed cell death, known as apoptosis. (Szabo, 1995; 1997).
Alcohol effects on T cell proliferation are dose-dependent and seem to be associated with inhibition of early signaling events of calcium mobilization and/or decreased interleukin production. (Brodie, 1994) Even acute alcohol intoxication can suppress inflammatory responses in normal subjects. (Dingle, 1997; Szabo, 1999) Recent findings indicate that the ethanol-suppressed response is mediated through Toll-like receptors (TLRs). (Dai, 2005) Current research on cytokine imbalance produced by alcohol is leading to new insights into the regulation of the immune system in alcoholics. The nature of the APC-T helper cell interaction helps to determine the effector response; i.e., cell- mediated (Th1) or humoral (Th2). Cytokine expression after exposure of normal human monocytes and murine splenic cells to alcohol is shifted toward Th2 dominance. (Laso, 1999; Wang, 1997) This polarization to Th2 is further enhanced in alcoholics, since levels of pro-oxidants such as glutathione, which plays an integral role in determining the Th1/Th2 maturational pathway of an immune response (NIAAA, 2004), are depleted in alcoholics. These experimental observations are of concern in HIV/AIDS, since high levels of TH2 interleukins have been associated with increased oxidative stress-induced damage and increased viral replication, as well as increased prevalence of opportunistic infections. (Isaki & Kresina, 2000; Laso, 1999; Szabo, 1999) In simian immunodeficiency virus (SIV)-infected animals, alcohol has been shown to suppress TNF-α and lead to increased susceptibility to secondary infections. (Stoltz, 2000)
Alcohol, HIV Infection and the Central Nervous System (CNS)
Higher rates of alcohol use are often reported among HIV+ individuals when compared to the general population. (Penkover, 1995; NIAAA, 2004) The combination of heavy alcohol use and HIV infection is also associated with increased neuropsychiatric impairment. Whether alcohol interacts with HIV neuroinvasion to increase synergistic cell death is under investigation. Neuropsychological testing indicates, however, that there is decreased motor and visuomotor speed and generally poorer executive functioning. In addition, heavy alcohol use and poor executive functioning is associated with reduced adherence, suggesting that planning functions impacted by the synergistic interaction may mediate behaviors such as adherence.
In addition to causing major dysregulation of the immune system, HIV infection profoundly affects the CNS. Viral invasion of the brain has been documented as early as two weeks post-infection, a time well before seroconversion can be determined. (NIAAA, 2004) Autopsy reports have confirmed neuropathological abnormalities in as many as 90% of patients with AIDS. (Meyerhoff, 2002) Consistent with these observations of CNS damage, HIV-associated cognitive/motor complex, characterized by psychomotor slowing, memory deficits, and behavior changes, is thought to afflict between 15% and 40% of AIDS patients, and to be the clinical correlate of HIV encephalitis.
Despite the widespread recognition of the devastating effects of HIV on neural tissue and brain function, the mechanism(s) underlying these pathologies remain unclear. Penetration of the virus into the CNS arena appears to be critical, however, as neurobehavioral deficits correlate with viral load. Mounting evidence points to the ability of HIV or HIV-infected mononuclear cells to gain access to the CNS compartment by penetrating the blood-brain barrier (BBB). The cerebral microvessel endothelium is the major cellular element of the BBB and comprises the primary limitation to passage of substances from the blood to the brain. Brain Microvessel Endothelial Cells (BMECs) possess unique features that distinguish them from cells of peripheral endothelium, and these may significantly limit the paracellular flux through the BBB, posing a major impediment to invasion of the brain by both microorganisms and circulating leukocytes. The lack of fenestrae in BMECs, as well as the presence of specific membrane-associated transport systems, further restricts the transcellular movement of materials from blood to brain. (NIAAA, 2004) It stands to reason that modulation of any of these BBB properties could significantly impact the ability of HIV to enter the CNS and cause destruction of neural tissue.
While many factors could potentially alter BBB integrity and function and thus facilitate HIV access to the brain, particular attention should be given to alcohol. Alcohol has been linked to increases in BBB permeability to various tracers. Using proton magnetic resonance imaging (MRI), Thomsen demonstrated in humans that alcohol induces transient opening of the BBB. Thus, alcohol has the potential to heighten susceptibility to and progression of HIV-related CNS disease. Potential routes by which alcohol may facilitate HIV entry into the brain include augmented expression of pro-inflammatory cytokines, modulation of membrane permeability and inter-endothelial junctions, and stimulation of viral replication. (NIAAA, 2004) Alcohol may also act in concert with HIV-1 proteins (gpl20, Tat) and/or cytokines present in the circulation of HIV-1 infected patients to accelerate HIV-1 disease progression. In support of this concept, interaction of Tat protein with alcohol has been confirmed in an animal model. Belmadani and colleagues (2001), however, suggested that moderate ethanol consumption is neuroprotective by reducing excitotoxicity induced by Gp120. A study examining the metabolic effects of advanced HIV infection and alcohol use using breakdown products of membrane-molecules and magnetic resonance spectroscopy studies provides evidence that chronic alcohol use may exacerbate some metabolic injury in the brains of HIV-infected individuals. (Meyerhoff, 2003) Given the widespread use of alcohol and rapidly growing HIV-infected population, there is an urgent need to delineate the role of alcohol in the development of HIV-related CNS disease.
Previous alcohol abuse may create a point of vulnerability that is exacerbated by the effects of the virus on the brain. In contrast, in the absence of HIV infection a past history of chronic alcohol abuse, combined with current abstinence from alcohol, appears to cause no significant lasting cognitive impairment (although detectable cognitive impairment may remain as a result of chronic heavy drinking). In the presence of HIV, however, several researchers have hypothesized that in some cases there may be enough impairment of cognitive function to make the brain more susceptible to the damaging impact of a second, independent process. (Green, 2004) The known risk of cognitive decline in HIV infection has prompted attempts to identify risk factors for this decline. Numerous studies have reported deficits in memory and learning, slower reaction times, and decreased speed in decision-making in HIV- infected patients. (Antunes, 2004; McArthur 2003; Ohio State Research, 2004) The most severe cognitive changes, which sometimes progress to the point of dementia, are almost always reported in the latest stages of the illness, but some research (Ohio State Research, 2004) has demonstrated that asymptomatic HIV-positive patients may experience subtle cognitive impairments that influence their daily activities.
AIDS Dementia/Cognitive Impairment
Several studies (Fein, 1995; Meyerhoff, 1995; Meyerhoff, 2001; Pfefferbaum, 2002, in press. See Appendix C) have raised the possibility of increased vulnerability to cognitive impairment and HIV/AIDS Dementia (HAD) development and progression in patients with HIV and alcohol co-morbidity. Durvasula and colleagues recently reported that alcohol use exacerbated adverse HIV effects on sequential reaction time. (Durvasula, 2001) Meyerhoff and colleagues add an additional piece of information by demonstrating synergistic effects of heavy alcohol use and HIV infection on both motor and visuomotor speed. Similar results were obtained by Rothlind and colleagues, with the most robust group differences observed between those with comorbidity ( HIV+ heavy drinking) and the seronegative control group (light drinking). Heavy drinking showed robust effects on measures of working memory, balance, and executive function.
Neuropathological and neuropsychological studies (Durvasula, 2001; Meyerhoff, 2001) have indicated that certain brain regions are affected by both HIV infection and chronic alcohol abuse. There has been little research on how extremely heavy drinking affects the clinical outcomes related to neurological impairment and HIV disease. Initial studies (Pfefferbaum, 2002) demonstrated a potentially additive or synergistic effect of alcohol use and HIV disease on cognitive performance. The current studies focus on brain and underlying neural metabolic mechanisms which may interact to lead to cell death in specific regions of the brain. These studies (Durvasula, 2001; Meyerhoff, 2001) include subjects who drink heavily, on average at least 100 drinks per month over many years, and are being treated for HIV. Magnetic resonance spectroscopy studies (Meyerhoff, 2001) of both HIV-positive and HIV-negative people who were either heavy or light drinkers found that chronic alcohol abuse exacerbates some metabolic injury in the brains of HIV-infected people, although this effect may be less pronounced in patients receiving effective antiretroviral therapy.
B. Past Biomedical Research Priorities for Alcohol and HIV/AIDS*:
NIAAA biomedical research on basic, applied, and preclinical studies to address the biological interactions between alcohol and HIV pathogenesis has focused in the past on:
· Effects of alcohol on viral burden, immune function, organ pathogenesis and neuropsychological function in HIV infected individuals.
· Effects of alcohol consumption on seroconversion and progression of disease in defined cohorts, including biological endpoints which relate to both alcohol abusing populations (e.g., MCV, CDT, liver function enzymes) and AIDS-specific measures (e.g., viral load, CD4+ and CD8+ levels).
· Mechanism(s) of enhanced progression of liver disease by alcohol consumption in individuals infected with HIV and/or co-infected with HCV/HIV.
· Drug-drug interactions between alcohol and antiretroviral drugs and altered pharmacology due to alcohol consumption.
· Alcohol use-related host defense impairment and opportunistic infection caused by pathogens such as Mycobacterium tuberculosis, Streptococcus pneumoniae, Pneumocystis carinii and hepatitis C (HCV).
· Interaction between alcohol and HIV proteins in neurodegeneration, organ pathogenesis and immune deficiency in animal models of HIV infection.
· Preventive interventions against tissue injury related to alcohol and HIV-related illnesses including neurological, hepatic, cardiac, and metabolic processes.
