Current HIV Research (v.12, #4)

Alcohol abuse and AIDS remain two of the leading public health problems, not only in the United States but throughout the world. Approximatelyamongst 5% of the total US population, abuses alcohol and this statistic has been fairly consistent during recent years. However, the prevalence of alcoholabuse among HIV-positive individuals has been estimated to be between 29 and 60% in the US [1]. Alcohol use has also been implicated as an importantrisk factor in HIV transmission. In addition, the incidence of HIV infection has been found to be associated with the overall level of alcohol consumption.In a meta-analysis study, drinkers were found to be at a 77% higher risk of HIV-infection than non-drinkers [2]. In another meta-analysis of studiesconducted in Africa, the HIV incidence among alcohol-users was found to be 70% higher than non-users [3]. Over the last decade, several elegant studieshave shown that alcohol consumption enhances virus replication and accelerates the onset of SIV-induced AIDS in macaques [4-6]. A general consensusis emerging that alcohol consumption may promote virus replication and accelerate the onset of clinical disease. This accelerated onset of disease can beattributed to the fact that alcohol is known to adversely affect the immune system. Alcohol adversely affects the central nervous system and HIVassociatedneurological disorders are known to play an important role in overall HIV pathogenesis. In several studies, alcohol has been shown toexacerbate the CNS effects of HIV-1 on ventricular volumes in the brains of infected individuals. The effect on white matter is associated with pathologieslike myelin pallor, gliosis and multinucleated giant cells which were found to be much more pronounced in HIV+ individuals who consumed alcohol [7].In view of these data, it is reasonable to believe that alcohol abuse is likely to influence the health status of patients infected with HIV.This issue of Current HIV Research presents a collection of 8 original research and review articles that focus on the effects of alcohol abuse on HIVpathogenesis in clinical situations as well as in various model systems. In a very interesting article, Agudelo, Nair and colleagues report the presence of aDRD2 polymorphism in 165 HIV-infected alcohol abusers. In another study conducted by Miguez- Burbano and colleagues, levels of brain derivedneurotophic factor were found to be inversely correlated with alcohol consumption among HIV+ individuals, suggesting compromised neuroplasticity inthese patients. The study by Thayer and colleagues establishes a correlation between risky sexual behavior, frequency of alcohol use and dorsal defaultmode network connectivity strength which is one of the four connectivity networks in the brain. In yet another elegant study conducted in the African-American population, Sales and colleagues also showed a positive correlation between alcohol use and risky sexual behavior.In the area of basic research, Mastrogiannis and colleagues report the very interesting finding that alcohol enhances HIV-1 replication in macrophages; thisprovides definitive evidence for increased virus replication due to alcohol consumption. Their study provides novel information that alcohol suppressesseveral miRNAs (28, 125b, 150, 198, 223, 382) APOBEC3G, APOBEC3H, IFN regulatory factor 7 and retinoic acid-inducible gene I, all of which areknown to be involved in HIV replication.There are 3 reviews which provide current information in the area of HIV and alcohol research. The reviews by Molina et al. and Amedee et al. provide acomprehensive overview of advances in the field with particular emphasis on non-human primate modes. These reviews will be immensely helpful to thereaders in terms of our current understanding of alcohol abuse and HIV pathogenesis. The last review deals with alcohol and its impact on both HIV andHCV infection. Approximately 25% of HIV-infected patients are co-infected with hepatitis C virus (HCV), therefore the information covered in thisreview will be useful for researchers involved in studying co-infection. Since the detailed characterization of HCV infection of the CNS is relatively new,this is an area of research that should see extensive growth in the coming years.

Alcohol Abuse and HIV Infection: Role of DRD2 by Marisela Agudelo, Pradnya Khatavkar, Adriana Yndart, Changwon Yoo, Rhonda Rosenberg, Jessy G. Devieux, Robert M. Malow, Madhavan Nair (234-242).
According to a survey from the HIV Cost and Services Utilization Study (HCSUS), approximately 53% ofHIV-infected patients reported drinking alcohol and 8% were classified as heavy drinkers. The role of alcohol as a riskfactor for HIV infection has been widely studied and recent research has found a significant association between heavyalcohol consumption and lower levels of CD4 T cells among HIV-infected alcoholics. Although there is evidence on therole of alcohol as a risk factor for HIV transmission and disease progression, there is a need for population studies todetermine the genetic mechanisms that affect alcohol's role in HIV disease progression. One of the mechanisms ofinterest is the dopaminergic system. To date, the effects of dopamine on HIV neuroimmune pathogenesis are not wellunderstood; however, dopaminergic neural degeneration due to HIV is known to occur by viral invasion into the brain viaimmune cells, and modulation of dopamine in the CNS may be a common mechanism by which different types ofsubstances of abuse impact HIV disease progression. Although previous studies have shown an association of D(2)dopamine receptor (DRD2) polymorphisms with severity of alcohol dependence, the expression of this allele risk on HIVpatients with alcohol dependence has not been systematically explored. In the current study, DRD2 Taq1A and C957TSNP genotyping analyses were performed in 165 HIV-infected alcohol abusers and the results were examined withimmune status and CD4 counts.

Chronic Alcohol Abuse and HIV Disease Progression: Studies with the Non-Human Primate Model by Angela M. Amedee, Whitney A. Nichols, Spencer Robichaux, Gregory J. Bagby, Steve Nelson (243-253).
The populations at risk for HIV infection, as well as those living with HIV, overlap with populations thatengage in heavy alcohol consumption. Alcohol use has been associated with high-risk sexual behavior and an increasedlikelihood of acquiring HIV, as well as poor outcome measures of disease such as increased viral loads and declines inCD4+ T lymphocytes among those living with HIV-infections. It is difficult to discern the biological mechanisms bywhich alcohol use affects the virus:host interaction in human populations due to the numerous variables introduced byhuman behavior. The rhesus macaque infected with simian immunodeficiency virus has served as an invaluable model forunderstanding HIV disease and transmission, and thus, provides an ideal model to evaluate the effects of chronic alcoholuse on viral infection and disease progression in a controlled environment. In this review, we describe the differentmacaque models of chronic alcohol consumption and summarize the studies conducted with SIV and alcohol.Collectively, they have shown that chronic alcohol consumption results in higher levels of plasma virus and alterations inimmune cell populations that potentiate SIV replication. They also demonstrate a significant impact of chronic alcohol useon SIV-disease progression and survival. These studies highlight the utility of the rhesus macaque in deciphering thebiological effects of alcohol on HIV disease. Future studies with this well-established model will address the biologicalinfluence of alcohol use on susceptibility to HIV, as well as the efficacy of anti-retroviral therapy.

Brain Derived Neurotrophic Factor and Cognitive Status: The Delicate Balance Among People Living with HIV, with and without Alcohol Abuse by Maria Jose Míguez-Burbano, Luis Espinoza, Nicole Ennis Whitehead, Vaughn E. Bryant, Mayra Vargas, Robert L. Cook, Clery Quiros, John E. Lewis, Asthana Deshratan (254-264).
Introduction: The advent of combination antiretroviral therapy(cART) has lead to a significant reduction inmorbidity and mortality among people living with HIV(PLWH). However, HIV-associated neurocognitive disorders(HAND) still remain a significant problem. One possible mechanism for the persistence of these disorders is through theeffect of HIV on brain-derived neurotrophic factor (BDNF). BDNF is influenced by various factors including hazardousalcohol use (HAU), which is prevalent among PLWH. This study attempts to elucidate the relationships between HAU,BDNF and HAND.;Methods: Cross-sectional analyses were conducted on a sample of 199 hazardous alcohol users and 198 non-HAU livingwith HIV. Members of each group were matched according to sociodemographic characteristics and CD4 count. Researchprocedures included validated questionnaires, neuropsychological assessments and a blood sample to obtain BDNF andimmune measurements.;Results: Hazardous alcohol users showed either significantly lower or significantly higher BDNF levels compared to theNon-hazardous (OR=1,4; 95% CI: 1-2.1, p = 0.003). Therefore, for additional analyses, subjects were categorized basedon BDNF values in: Group 1 < 4000, Group 2: 4001-7,999 (reference group), and Group 3 for those >8,000 pg/mL.Groups 1 and 3 performed significantly worse than those in Group 2 in the domains of processing speed, auditory-verbaland visuospatial learning and memory. Multivariate analyses confirmed that HAU and BDNF are significant contributorsof HAND.;Conclusion: Our findings offer novel insights into the relationships between BDNF, and alcohol use among PLWH. Ourresults also lend support to expanding clinical movement to use BDNF as an intervention target for PLWH, in those withevidence of deficiencies, and highlight the importance of including HAUat the inception of clinical trials.

Biomedical Consequences of Alcohol Use Disorders in the HIV-Infected Host by Patricia E. Molina, Gregory J. Bagby, Steve Nelson (265-275).
Alcohol abuse is the most common and costly form of drug abuse in the United States. It is well known thatalcohol abuse contributes to risky behaviors associated with greater incidence of human immunodeficiency virus (HIV)infections. As HIV has become a more chronic disease since the introduction of antiretroviral therapy, it is expected thatalcohol use disorders will have an adverse effect on the health of HIV-infected patients. The biomedical consequences ofacute and chronic alcohol abuse are multisystemic. Based on what is currently known of the comorbid andpathophysiological conditions resulting from HIV infection in people with alcohol use disorders, chronic alcohol abuseappears to alter the virus infectivity, the immune response of the host, and the progression of disease and tissue injury,with specific impact on disease progression. The combined insult of alcohol abuse and HIV affects organ systems,including the central nervous system, the immune system, the liver, heart, and lungs, and the musculoskeletal system.Here we outline the major pathological consequences of alcohol abuse in the HIV-infected individual, emphasizing itsimpact on immunomodulation, erosion of lean body mass associated with AIDS wasting, and lipodystrophy. We concludethat interventions focused on reducing or avoiding alcohol abuse are likely to be important in decreasing morbidity andimproving outcomes in people living with HIV/AIDS.

Differences in Sexual Risk Behaviors Between Lower and Higher Frequency Alcohol-Using African-American Adolescent Females by Jessica McDermott Sales, Jennifer L. Monahan, Carolyn Brooks, Ralph J. DiClemente, Eve Rose, Jennifer A. Samp (276-281).
Background: To examine differences between lower and higher frequency alcohol users in sexual behaviorsand psychosocial correlates of risk for HIV among young African-American females.;Methods: Data were collected from sexually active African-American females aged 15-20 years, seeking services at aSTD clinic in Atlanta, GA, to assess sexual behavior, correlates of risk, and a non-disease biological marker ofunprotected vaginal sex.;Results: Number of drinking occasions was significantly related to three of four psychosocial correlates and with all selfreportingsexual behavior measures. Also, heavier drinking per occasion was associated with the presence of semen invaginal fluid.;Conclusion: Non-abuse levels of drinking were related to increased sexual risk-taking in this sample of young African-American females. Incorporating messages about the intersection of alcohol use and sexual decision making intoHIV/STD prevention programs would strengthen STD prevention messaging in this vulnerable population.

HIV-1, HCV and Alcohol in the CNS: Potential Interactions and Effects on Neuroinflammation by Peter S. Silverstein, Santosh Kumar, Anil Kumar (282-292).
Approximately 25% of the HIV-1 positive population is also infected with HCV. The effects of alcohol onHIV-1 or HCV infection have been a research topic of interest due to the high prevalence of alcohol use in these infectedpatient populations. Although it has long been known that HIV-1 infects the brain, it has only been a little more than adecade since HCV infection of the CNS has been characterized. Both viruses are capable of infecting and replicating inmicroglia and increasing the expression of proinflammatory cytokines and chemokines, including IL-6 and IL-8.Investigations focusing on the effects of HIV-1, HCV or alcohol on neuroinflammation have demonstrated that theseagents are capable of acting through overlapping signaling pathways, including MAPK signaling molecules. In addition,HIV-1, HCV and alcohol have been demonstrated to increase permeability of the blood-brain barrier. Patients infectedwith either HIV-1 or HCV, or those who use alcohol, exhibit metabolic abnormalities in the CNS that result in alteredlevels of n-acetyl aspartate, choline and creatine in various regions of the brain. Treatment of HIV/HCV co-infection inalcohol users is complicated by drug-drug interactions, as well as the effects of alcohol on drug metabolism. The drugdruginteractions between the antiretrovirals and the antivirals, as well as the effects of alcohol on drug metabolism,complicate existing models of CNS penetration, making it difficult to assess the efficacy of treatment on CNS infection.

Exploring the Relationship of Functional Network Connectivity to Latent Trajectories of Alcohol Use and Risky Sex by Rachel E. Thayer, Erika Montanaro, Barbara J. Weiland, Tiffany J. Callahan, Angela D. Bryan (293-300).
Alcohol use is a major risk factor associated with unprotected sexual behavior, leading to higher risk ofsexually transmitted infections (STI) including the human immunodeficiency virus (HIV). Emerging largely crosssectionaldata suggest functional network connectivity strength is associated with problematic alcohol use, and asevidence supports a relationship between risky sexual behaviors and alcohol use, we hypothesized that functionalconnectivity might be associated with both categories of risk behavior. As part of a sexual risk reduction interventionstudy, juvenile justice-involved adolescents (N = 239) underwent a baseline functional magnetic resonance imaging scanand completed questionnaires about their alcohol use and risky sexual behavior at 3-month intervals over 12 months offollow up. To test both cross-sectional and longitudinal relationships between alcohol use and sexual risk behaviors, weestimated a parallel process latent growth model that simultaneously modeled the trajectories of alcohol use and sexualrisk behavior. Functional connectivity strength was included as an exogenous variable to evaluate its relationship withlevel of risk and change in risk over time in both behaviors. Associations were found between baseline alcohol use andrisky sex, and between longitudinal trajectories of alcohol use and risky sex. Network functional connectivity strength ofthe dorsal default mode network was associated with initial and longitudinal alcohol use, which may suggest that selfawarenessof the effects of alcohol could serve as a useful target to decrease subsequent risky sexual behavior inadolescence.

Alcohol Enhances HIV Infection of Cord Blood Monocyte-Derived Macrophages by Dimitrios S. Mastrogiannis, Xu Wang, Min Dai, Jieliang Li, Yizhong Wang, Yu Zhou, Selin Sakarcan, Juliet Crystal Pena, Wenzhe Ho (301-308).
Alcohol consumption or alcohol abuse is common among pregnant HIV+ women and has been identified as apotential behavioral risk factor for the transmission of HIV. In this study, we examined the impact of alcohol on HIVinfection of cord blood monocyte-derived macrophages (CBMDM). We demonstrated that alcohol treatment of CBMDMsignificantly enhanced HIV infection of CBMDM. Investigation of the mechanisms of alcohol action on HIVdemonstrated that alcohol inhibited the expression of several HIV restriction factors, including anti-HIV microRNAs,APOBEC3G and APOBEC3H. Additionally, alcohol also suppressed the expression of IFN regulatory factor 7 (IRF-7)and retinoic acid-inducible gene I (RIG-I), an intracellular sensor of viral infection. The suppression of these IFNregulatory factors was associated with reduced expression of type I IFN. These experimental findings suggest thatmaternal alcohol consumption may facilitate HIV infection, promoting vertical transmission of HIV.