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Current HIV research [journal]
- Editorial: Impact of Alcohol on HIV Related Issues in Human Population or Model System. [Journal Article]
- Curr HIV Res 2014; 12(4):233.
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 . 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 . In another meta-analysis of studies conducted in Africa, the HIV incidence among alcohol-users was found to be 70% higher than non-users . 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 . 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.
- Editorial: The Monocyte/Macrophage in the Pathogenesis of AIDS: The Next Frontier for Therapeutic Intervention in the CNS and Beyond: Part II. [Journal Article]
- Curr HIV Res 2014; 12(3):163.
In the previous issue of Current HIV Research, we introduced a series of research and review articles (Part I) emphasizing the role of macrophages in the pathogenesis of AIDS and CNS diseases, as well as implications for therapeutic intervention. We present several additional articles, in Part II of this issue, further emphasizing the importance of host-virus interactions in disease and consideration for avenues of therapy and new investigation. An interesting mechanism of host dysregulation of gene expression is demonstrated here by Duan et al. where HIV-1 Tat protein impairs factalkine gene expression, leading to impaired microglial-neuronal interactions and concomitant activation of inflammation (i.e. the NFkB pathway) . It is interesting to speculate that Tat, through fractalkine dysregulation, may alter the retention and migration properties of peripheral derived macrophages, and thereby contributes to the pathogenesis of HIV in CNS as well as the reservoir of infection. At the same time, down-modulation of the host-factor, heme oxygenase (HO-1), permits increased release of macrophage derived glutamate, which in turn can exert toxic effects on neurons. This mechanism, as well as pharmacological modulation of HO-1 and neurotoxicity, suggests that pharmacological HO-modulation may have therapeutic efficacy, as discussed in the paper by Ambegaokar , in HIV induced CNS disorders as well as in other diseases associated with neurotoxicity. The monocyte/macrophage system is of interest in the context of HIV replication as macrophages provide an important reservoir of HIV infection and contribute to immune dysregulation. Upon differentiation macrophages become highly susceptible to HIV infection, relative to monocytes. The paper by Alijawai et al. demonstrates how modulation of the Wnt/βcatenin signaling pathway can serve as a restriction mechanism in monocytes, with down-modulation of β-catenin upon differentiation . The authors further pointed out that Wnt ligands could be involved in the suppression of post integration HIV replication events in macrophages exposed to soluble factors produced by monocytes. As such, pharmacological intervention with the Wnt/β-catenin signaling pathway could be used to suppress HIV replication, or alternatively, to activate latent reservoirs of HIV infection. Peripheral derived monocytes/macrophages and/or activated microglia play prominent roles in the pathogenesis of HIV in CNS, as discussed throughout part I and II of this thematic issue. The alteration of the myeloid lineage in the setting of HIV infection and increased organ invasion is not limited to the CNS, at least in the setting of encephalitis. Here, our group demonstrates macrophage invasion into visceral tissues in patients with HIV encephalitis, with evidence of underlying renal disease. It is apparent that altered monocyte/macrophage homeostasis tissue invasion in HIV infection contribute to comorbid conditions in AIDS according to Fischer et al. . As tissue invasion in patients with AIDS, but without encephalitis, also appears to be increased, altered macrophage trafficking may play an important role in immune dysfunction and comorbidities in patients with HIV infection and AIDS. It is likely that strategies directed to specific pathways dysregulated in HIV infection, or through utilization of strategies to normalize immune polarization, activation, and/or migration into tissues may be important, not only to address CNS associated manifestations of HIV infection, but also to treat comorbidities involving altered myeloid homeostasis and trafficking. In the coming years, studies in these directions should provide insights and novel therapeutic strategies, well beyond the context of HIV infection.
- A Novel Integrase Targeting Agent to Explore the Future Prospective of HIV Eradication: Dolutegravir. [JOURNAL ARTICLE]
- Curr HIV Res 2014 Aug 7.
Out of the 15 discrete proteins encoding the total amount of genetic information in the chromosomes of human immunodeficiency virus type 1; three perform the vital enzymatic functions i.e. a reverse transcription, an integration, and proteolysis. The HIV integrase is the new validated drug target against AIDS amongst all essential enzymes due to the lack of the human homologue. In last few years quite, a few but potent inhibitors inhibiting HIV-1 integrase have been recognized and hence have gained a state-of-the-art for treating the infection caused by HIV-1. The greater understanding of HIV-integrase biological structure has further lead to continuous efforts for the proposal of novel inhibitors targeting diverse steps in the progression of integration with the primary goal to overcome resistance due to the rapid occurrence of integrase mutations in the treated patients. This review is focused on various aspects of the recently approved HIV-integrase inhibitor "dolutegravir", its efficacy, safety profiles with the clinical data and molecular modeling studies highlighting its importance over the already approved HIV-integrase inhibitors.
- Efficacy, Tolerability and Virological Consequences of Long-term Use of Unboosted Atazanavir plus 2 NRTIs in HIV-infected Patients. [JOURNAL ARTICLE]
- Curr HIV Res 2014 Aug 7.
Switch to unboosted atazanavir (ATV) is an attractive option due to convenience and tolerability in HIV-positive patients. With limited available data we investigated the determinants of long-term efficacy and the consequences of virological failure of unboosted atazanavir-based regimens. Methods: Retrospective analysis in two Italian large outpatient clinics including demographic, immunovirological, resistance and pharmacokinetic data. Results: 249 patients receiving atazanavir (400 mg once-daily) plus 2 NRTIs were included; 163 were males (65.5%) and median age was 47 years (42-51.5). Median CD4+ T-cell count was 396/uL (261-583); 146 (58.6%) presented a viral load <50 copies/mL. Over a median follow up of 157 weeks (106-203) 193 patients (77.5%) were still on treatment with 10 (4%) and 2 (0.8%) stopping for virological failure or toxicity, respectively. Ten patients with virological failure presented newly selected resistance associated mutations (RAMs) for NRTIs (2/10) or ATV (4/10, one I50L). Total cholesterol and triglycerides showed significant decreases at 48 [-4 mg/dL and -41 mg/dL] and 96 weeks [-14 mg/dL and -54 mg/dL] as compared to baseline. At multivariate analysis a genotypic sensitivity score ≤1, atazanavir RAMs >1 and suboptimal adherence were independently associated with virological failure; in lamivudine/emtricitabine-treated patients the presence of M184V (without other NRTI RAMs) was not associated with virological failure. Conclusions: Unboosted-atazanavir containing regimens were efficacious (with uncommon virological failures) and well-tolerated (with improvements in lipid profile over time) treatments in HIV-positive patients. Isolated M184V in lamivudine/emtricitabine recipients was not associated with higher failure rates supporting the use of functional ATV-based dual therapies as maintenance strategies.
- Editorial: The Monocyte/Macrophage in the Pathogenesis of AIDS: The Next Frontier for Therapeutic Intervention in the CNS and Beyond: Part I. [Journal Article]
- Curr HIV Res 2014; 12(2):75-6.
Monocytes, macrophages, and microglia, play multiple roles in the pathogenesis of HIV infection. In addition to providing a tissue reservoir of infection, HIV infected and non-infected macrophages enter and accumulate in the Central Nervous System, where virus infection spreads to resident glial cells including astrocytes and microglia. This process contributes to the secretion of toxic molecules and inflammatory cytokines, which contribute to neuronal damage and promote a spectrum of HIVassociated neurological disorders ranging from HIV dementia to asymptomatic neurocognitive impairment. There appears to be an alteration in the dynamics of monocyte/macrophage subsets as a result of HIV infection, with resulting alterations in immune polarization status. It is likely that such alterations contribute to T cell dysfunction in HIV infection and may present important challenges to immune therapeutic and vaccine-based eradication strategies. As the macrophage/microglial reservoir of HIV infection is long-lived and not susceptible to the direct action of current anti-retroviral compounds (as cells already infected), this reservoir likely accumulates in infected persons over-time and may thereby provides an important target for therapeutic strategies aimed at HIV eradication and/or the treatment of HIV associated neurocognitive disorders. In the articles of this issue, experts have provided insights and perspectives regarding host-viral interaction mechanisms and specific molecular pathways involved in HIV induced inflammation, oxidative stress and neuronal injury. The articles within this Hot Topic issue, represent a series of review articles as well as original research papers. The areas covered represent diverse, yet related areas of investigation regarding HIV infection, virus induced alterations gene expression in infected cells, effects on cells of the blood brain barrier, neural injury and protection, and identify new avenues for therapeutic intervention. The monocyte/macrophage lineage, including microglia, are infected by HIV by a process that predominantly involves "R5" virus, interacting with the cellular coreceptor CCR5. The inability of X4 viruses to transmit de novo are unclear, but their appearance during the course of disease progression might suggest they are immunologically unfit and immune dysregulation would be required for successful CXCR4 tropic virus propagation in vivo. If this is the case, effects of HIV in polarizing macrophages toward M2 function may be a critical step in viral pathogenesis as well as persistence. As R5 virus appears critical for transmission and prominent in the pathogenesis of HIV induced CNS disease, the identification of determinants involved in infection through various coreceptors are of major importance, particularly in view of the association with evolution toward X4 tropic virus with AIDS progression. In the paper by Aiamkitsumrit, bioinformatics approaches to the prediction of viral tropism are discussed . The processes whereby monocytes differentiate into specific subsets appear to be dysregulated in AIDS, promoting altered immune polarization and expansion of CD16+ monocytes. CD16+ monocytes are preferentially infected by HIV and have increased capacity to cross the blood barrier, responding to specific cytokines and promoting CNS dysfunction, as review by Williams et al. . HIV encephalitis and consequent neuronal injury has been studied by a number of laboratories and it is clear that virus infection, macrophage/microglial activation, as well as macrophage transmigration of the blood brain barrier are important in the disease progress. It has been poorly understood, however, to what extent, alterations in macrophage/microglial activation and/or trafficking lead to minor neurocognitive impairment in HIV infection. This is currently an important issue, where minor neurocognitive impairment remains prominent in the setting of antiretroviral therapy. Results from Tavazzi et al.  here demonstrate that inflammation, in the absence of any obvious CNS infection is evident in both morphologic and phenotypic markers in CNS tissue from patients with minor neurocognitive disorders. The findings emphasize the likely importance of the physical interface, i.e. the blood brain barrier and perivascular region, between the CNS and the periphery in neuroAIDS in the current era of antiretroviral therapy. It will be also be of interest to determine how microglial activation reflects some of the altered dysregulation pathways described in this issue. Once inside target cells, HIV induced dysregulation of host gene expression plays an important role in the disease progress, amplified by autocrine and paracrine mechanisms. The paper by Lynn Pulliam  suggests the dual role of virus induced interferon alpha as an important initiator of the immune response, but also having deleterious effects in the setting of chronic infection. Thus, the activation of type I interferon, to which HIV appears to be resistant, may be an important aspect of immune dysregulation during the chronic phase of HIV infection. Interferon alpha secretion leads to a specific "alarm signature" which is likely important for further investigation regarding pathogenesis, development of diagnostics, as well as new targets for therapy. 76 Current HIV Research, 2014, Vol. 12, No. 2 Editorial One mechanism which may account for the indirect effects of HIV infection leading to neuronal injury, appears to be involved in the increased production and secretion of potentially neurotoxic cathepsin B, with altered interactions of cystatin B in patients with HIV infection and neurocognitive disorders, as reviewed by Rivera et al. . Another inflammatory mediator likely involved in the pathogenesis of HIV infection and CNS disorders via microglial production and receptor interactions appears to be mediated by the neurokinin, substance P (SP). As substance P appears to have immune polarizing properties on the myeloid lineage, and promotes inflammation and virus replication, it likely plays a role in both immune dysfunction and neuroAIDS. The modeling and simulation to support clinical investigation with an SP antagonist are discussed in the paper by Barrett et al. . Altered macrophage biology in HIV infection obviously presents unique opportunities for therapeutic intervention. In view of the topics and issues raised by the authors contributing here in Part I and in the next issue, Part II, of this Hot Topic issue, it is likely that strategies targeting monocytes/macrophages and microglia will have broad implications with relevance to AIDS, as well as a wide range of end-organ diseases. We hope that the research and review articles in this two-part issue will promote significant interest in further research in this area.
- Alcohol Abuse and HIV Infection: Role of DRD2. [Journal Article]
- Curr HIV Res 2014; 12(4):234-42.
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.
- Chronic Alcohol Abuse and HIV Disease Progression: Studies with the Non-Human Primate Model. [Journal Article]
- Curr HIV Res 2014; 12(4):243-53.
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.
- Brain Derived Neurotrophic Factor and Cognitive Status: The Delicate Balance Among People Living with HIV, with and without Alcohol Abuse. [Journal Article]
- Curr HIV Res 2014; 12(4):254-64.
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.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.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.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.
- Biomedical Consequences of Alcohol Use Disorders in the HIV-Infected Host. [Journal Article]
- Curr HIV Res 2014; 12(4):265-75.
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.
- Differences in Sexual Risk Behaviors Between Lower and Higher Frequency Alcohol-Using African-American Adolescent Females. [JOURNAL ARTICLE]
- Curr HIV Res 2014 Jul 21.
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 ages 15-20 years, seeking services at a STD clinic in the 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 self-report 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.