Current HIV Research - Volume 12, Issue 4, 2014

Alcohol abuse and AIDS remain two of the leading public health problems, not only in the United States but throughout the world. Approximately amongst 5% of the total US population, abuses alcohol and this statistic has been fairly consistent during recent years. However, the prevalence of alcohol abuse 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 important risk 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 studies conducted in Africa, the HIV incidence among alcohol-users was found to be 70% higher than non-users [3]. Over the last decade, several elegant studies have shown that alcohol consumption enhances virus replication and accelerates the onset of SIV-induced AIDS in macaques [4-6]. A general consensus is emerging that alcohol consumption may promote virus replication and accelerate the onset of clinical disease. This accelerated onset of disease can be attributed to the fact that alcohol is known to adversely affect the immune system. Alcohol adversely affects the central nervous system and HIVassociated neurological disorders are known to play an important role in overall HIV pathogenesis. In several studies, alcohol has been shown to exacerbate the CNS effects of HIV-1 on ventricular volumes in the brains of infected individuals. The effect on white matter is associated with pathologies like 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 HIV pathogenesis in clinical situations as well as in various model systems. In a very interesting article, Agudelo, Nair and colleagues report the presence of a DRD2 polymorphism in 165 HIV-infected alcohol abusers. In another study conducted by Miguez- Burbano and colleagues, levels of brain derived neurotophic factor were found to be inversely correlated with alcohol consumption among HIV+ individuals, suggesting compromised neuroplasticity in these patients. The study by Thayer and colleagues establishes a correlation between risky sexual behavior, frequency of alcohol use and dorsal default mode 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; this provides definitive evidence for increased virus replication due to alcohol consumption. Their study provides novel information that alcohol suppresses several miRNAs (28, 125b, 150, 198, 223, 382) APOBEC3G, APOBEC3H, IFN regulatory factor 7 and retinoic acid-inducible gene I, all of which are known 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 a comprehensive overview of advances in the field with particular emphasis on non-human primate modes. These reviews will be immensely helpful to the readers in terms of our current understanding of alcohol abuse and HIV pathogenesis. The last review deals with alcohol and its impact on both HIV and HCV infection. Approximately 25% of HIV-infected patients are co-infected with hepatitis C virus (HCV), therefore the information covered in this review 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.

According to a survey from the HIV Cost and Services Utilization Study (HCSUS), approximately 53% of HIV-infected patients reported drinking alcohol and 8% were classified as heavy drinkers. The role of alcohol as a risk factor for HIV infection has been widely studied and recent research has found a significant association between heavy alcohol consumption and lower levels of CD4 T cells among HIV-infected alcoholics. Although there is evidence on the role of alcohol as a risk factor for HIV transmission and disease progression, there is a need for population studies to determine the genetic mechanisms that affect alcohol’s role in HIV disease progression. One of the mechanisms of interest is the dopaminergic system. To date, the effects of dopamine on HIV neuroimmune pathogenesis are not well understood; however, dopaminergic neural degeneration due to HIV is known to occur by viral invasion into the brain via immune cells, and modulation of dopamine in the CNS may be a common mechanism by which different types of substances 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 HIV patients with alcohol dependence has not been systematically explored. In the current study, DRD2 Taq1A and C957T SNP genotyping analyses were performed in 165 HIV-infected alcohol abusers and the results were examined with immune status and CD4 counts.

The populations at risk for HIV infection, as well as those living with HIV, overlap with populations that engage in heavy alcohol consumption. Alcohol use has been associated with high-risk sexual behavior and an increased likelihood of acquiring HIV, as well as poor outcome measures of disease such as increased viral loads and declines in CD4+ T lymphocytes among those living with HIV-infections. It is difficult to discern the biological mechanisms by which alcohol use affects the virus:host interaction in human populations due to the numerous variables introduced by human behavior. The rhesus macaque infected with simian immunodeficiency virus has served as an invaluable model for understanding HIV disease and transmission, and thus, provides an ideal model to evaluate the effects of chronic alcohol use on viral infection and disease progression in a controlled environment. In this review, we describe the different macaque 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 in immune cell populations that potentiate SIV replication. They also demonstrate a significant impact of chronic alcohol use on SIV-disease progression and survival. These studies highlight the utility of the rhesus macaque in deciphering the biological effects of alcohol on HIV disease. Future studies with this well-established model will address the biological influence of alcohol use on susceptibility to HIV, as well as the efficacy of anti-retroviral therapy.

Introduction: The advent of combination antiretroviral therapy(cART) has lead to a significant reduction in morbidity 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 the effect of HIV on brain-derived neurotrophic factor (BDNF). BDNF is influenced by various factors including hazardous alcohol 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 living with HIV. Members of each group were matched according to sociodemographic characteristics and CD4 count. Research procedures included validated questionnaires, neuropsychological assessments and a blood sample to obtain BDNF and immune measurements. Results: Hazardous alcohol users showed either significantly lower or significantly higher BDNF levels compared to the Non-hazardous (OR=1,4; 95% CI: 1-2.1, p = 0.003). Therefore, for additional analyses, subjects were categorized based on 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-verbal and visuospatial learning and memory. Multivariate analyses confirmed that HAU and BDNF are significant contributors of HAND. Conclusion: Our findings offer novel insights into the relationships between BDNF, and alcohol use among PLWH. Our results also lend support to expanding clinical movement to use BDNF as an intervention target for PLWH, in those with evidence of deficiencies, and highlight the importance of including HAUat the inception of clinical trials.

Alcohol abuse is the most common and costly form of drug abuse in the United States. It is well known that alcohol 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 that alcohol use disorders will have an adverse effect on the health of HIV-infected patients. The biomedical consequences of acute and chronic alcohol abuse are multisystemic. Based on what is currently known of the comorbid and pathophysiological conditions resulting from HIV infection in people with alcohol use disorders, chronic alcohol abuse appears 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 its impact on immunomodulation, erosion of lean body mass associated with AIDS wasting, and lipodystrophy. We conclude that interventions focused on reducing or avoiding alcohol abuse are likely to be important in decreasing morbidity and improving outcomes in people living with HIV/AIDS.

Background: To examine differences between lower and higher frequency alcohol users in sexual behaviors and 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 a STD clinic in Atlanta, GA, to assess sexual behavior, correlates of risk, and a non-disease biological marker of unprotected vaginal sex. Results: Number of drinking occasions was significantly related to three of four psychosocial correlates and with all selfreporting sexual behavior measures. Also, heavier drinking per occasion was associated with the presence of semen in vaginal 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 into HIV/STD prevention programs would strengthen STD prevention messaging in this vulnerable population.

Approximately 25% of the HIV-1 positive population is also infected with HCV. The effects of alcohol on HIV-1 or HCV infection have been a research topic of interest due to the high prevalence of alcohol use in these infected patient populations. Although it has long been known that HIV-1 infects the brain, it has only been a little more than a decade since HCV infection of the CNS has been characterized. Both viruses are capable of infecting and replicating in microglia 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 these agents 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 infected with either HIV-1 or HCV, or those who use alcohol, exhibit metabolic abnormalities in the CNS that result in altered levels of n-acetyl aspartate, choline and creatine in various regions of the brain. Treatment of HIV/HCV co-infection in alcohol users is complicated by drug-drug interactions, as well as the effects of alcohol on drug metabolism. The drugdrug interactions 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.

Alcohol use is a major risk factor associated with unprotected sexual behavior, leading to higher risk of sexually transmitted infections (STI) including the human immunodeficiency virus (HIV). Emerging largely crosssectional data suggest functional network connectivity strength is associated with problematic alcohol use, and as evidence supports a relationship between risky sexual behaviors and alcohol use, we hypothesized that functional connectivity might be associated with both categories of risk behavior. As part of a sexual risk reduction intervention study, juvenile justice-involved adolescents (N = 239) underwent a baseline functional magnetic resonance imaging scan and completed questionnaires about their alcohol use and risky sexual behavior at 3-month intervals over 12 months of follow up. To test both cross-sectional and longitudinal relationships between alcohol use and sexual risk behaviors, we estimated a parallel process latent growth model that simultaneously modeled the trajectories of alcohol use and sexual risk behavior. Functional connectivity strength was included as an exogenous variable to evaluate its relationship with level of risk and change in risk over time in both behaviors. Associations were found between baseline alcohol use and risky sex, and between longitudinal trajectories of alcohol use and risky sex. Network functional connectivity strength of the dorsal default mode network was associated with initial and longitudinal alcohol use, which may suggest that selfawareness of the effects of alcohol could serve as a useful target to decrease subsequent risky sexual behavior in adolescence.

Alcohol consumption or alcohol abuse is common among pregnant HIV+ women and has been identified as a potential behavioral risk factor for the transmission of HIV. In this study, we examined the impact of alcohol on HIV infection of cord blood monocyte-derived macrophages (CBMDM). We demonstrated that alcohol treatment of CBMDM significantly enhanced HIV infection of CBMDM. Investigation of the mechanisms of alcohol action on HIV demonstrated 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 IFN regulatory factors was associated with reduced expression of type I IFN. These experimental findings suggest that maternal alcohol consumption may facilitate HIV infection, promoting vertical transmission of HIV.