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ABSTRACT: The effects of RU-486, a glucocorticoid antagonist, on HIV infection and replication in depressed and nondepressed women were studied using ex vivo models of HIV infection. RU-486 treatment of cells decreased HIV reverse transcriptase activity of monocyte-derived macrophages in a model of acute infectivity. RU-486 also decreased HIV viral replication in the chronically-infected T-cell line ACH-2, but not in the promonocyte cell line U1. No differences were associated with depression status. Thus, glucocorticoid antagonism may suppress HIV infectivity and replication ex vivo. Studies to determine the role of glucocorticoid antagonists in the host defense against HIV should be performed.
The Journal of neuropsychiatry and clinical neurosciences 03/2013; 25(1):51-7. · 2.34 Impact Factor
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The Lancet 08/2011; 378(9792):664-5; author reply 666. · 38.28 Impact Factor
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ABSTRACT: A number of recent investigations have focused on the treatment needs of injection drug users (IDUs); especially with regard
to gender and ethnic/ racial differences. The results of those studies indicate that female IDUs represent a large portion
of the addicted population, and have particular treatment needs that differ from their male counterparts. In addition, those
treatment needs often vary among ethnic and racial groups. In order to elucidate the service needs of IDUs, data is presented
from a recent study that compares the gender and racial differences in characteristics and service utilization of subjects
in methadone treatment. The results of that study parallel other research, and indicate that gender and racial differences
are important factors to consider in the development of effective treatment programs.
06/2011: pages 329-358;
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ABSTRACT: Efficacy studies of investigational HIV vaccines require enrollment of individuals at 'high risk' for HIV. This paper examines participation in HIV vaccine trials among women at 'high risk' for HIV acquisition. In-depth interviews were conducted with 17 African-American women who use crack cocaine and/or exchange sex for money/drugs to elicit attitudes toward medical research and motivators and deterrents to HIV vaccine trial participation. Interviews were digitally recorded and transcribed; data were coded and compiled into themes. Most women expressed favorable attitudes toward medical research in general. Motivators for trial participation included compensation; personal benefits including information, social services, and the possibility that the trial vaccine could prevent HIV; and altruism. Deterrents included: dislike of needles; distrust; concern about future consequences of participating. In addition, contingencies, care-giving responsibilities, and convenience issues constituted barriers which could impede participation. Respondents described varied, complex perspectives, and individual cases illustrate how these themes played out as women contemplated trial participation. Understanding factors which influence vaccine research participation among women at 'high risk' can aid sites to tailor recruitment procedures to local contexts. Concerns about future reactions can be addressed through sustained community education. Convenience barriers can be ameliorated by providing rides to study visits when necessary, and/or conducting study visits in accessible neighborhood locations. Women in this sample thought carefully about enrolling in HIV vaccine trials given the structural constraints within which they lived. Further research is needed regarding structural factors which influence personal agency and individuals' thinking about research participation.
Vaccine 06/2011; 29(36):6130-5. · 3.77 Impact Factor
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JAIDS Journal of Acquired Immune Deficiency Syndromes 04/2011; 56(5):e129-30. · 4.43 Impact Factor
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ABSTRACT: Drug use continues to be a major factor fueling the global epidemic of HIV infection. This article reviews the current literature on the ability of drug treatment programs to reduce HIV transmission among injection and noninjection drug users. Most data come from research on the treatment of opiate dependence and provide strong evidence on the effectiveness of medication-assisted treatment for reducing the frequency of drug use, risk behaviors, and HIV infections. This has been a consistent finding since the epidemic began among diverse populations and cultural settings. Use of medications other than methadone (such as buprenorphine/naloxone and naltrexone) has increased in recent years with promising data on their effectiveness as HIV prevention and as new treatment options for communities heavily affected by opiate use and HIV infection. However, few treatment interventions for stimulant abuse and dependence have shown efficacy in reducing HIV risk. The cumulative literature provides strong support of drug treatment programs for improving access and adherence to antiretroviral treatment. Drug users in substance abuse treatment are significantly more likely to achieve sustained viral suppression, making viral transmission less likely. Although there are challenges to implementing drug treatment programs for maximum impact, the scientific literature leaves no doubt about the effectiveness of drug treatment as an HIV prevention strategy.
JAIDS Journal of Acquired Immune Deficiency Syndromes 12/2010; 55 Suppl 1:S32-6. · 4.43 Impact Factor
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ABSTRACT: Research conducted during the first 20 years of the AIDS epidemic provided a solid foundation of data supporting methadone treatment as HIV prevention. Drug users in methadone treatment were consistently found to reduce the frequency of drug use, risk behaviors, and infections. These data have been consistent over time and across cultural settings and have been used to promote the expansion of drug treatment as a prevention intervention. More recently, data have emerged suggesting the prevention potential of medication-assisted treatments other than methadone (buprenorphine/naloxone and naltrexone). Still, with a few notable exceptions, global drug treatment coverage for opiate injectors remains remarkably low and only a few treatment interventions for stimulant use have shown efficacy in reducing HIV risk. Importantly, more recent data provide support for the role of drug treatment programs in improving access and adherence to antiretroviral treatment and that injection drug users in substance abuse treatment are more likely to achieve sustained viral suppression. While important challenges remain in maximizing its impact, the scientific literature provides strong evidence of the efficacy of drug treatment as an HIV prevention strategy.
Current HIV/AIDS Reports 11/2010; 7(4):220-5.
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ABSTRACT: To test the hypothesis that the selective serotonin reuptake inhibitor (SSRI) citalopram would down-regulate human immunodeficiency virus (HIV) infectivity and that the greatest effects would be seen in people with depression. Depression is a risk factor for morbidity and mortality in HIV/acquired immune deficiency syndrome. Serotonin (5-HT) neurotransmission has been implicated in the pathobiology of depression, and pharmacologic therapies for depression target this system. The 5-HT transporter and 5-HT receptors are widely distributed throughout the central nervous and immune systems. Depression has been associated with suppression of natural killer cells and CD8(+) lymphocytes, key regulators of HIV infection.
Ex vivo models for acute and chronic HIV infection were used to study the effects of citalopram on HIV viral infection and replication in 48 depressed and nondepressed women. For both the acute and chronic infection models, HIV reverse transcriptase activity was measured in the citalopram treatment condition and the control condition.
The SSRI significantly down-regulated the reverse transcriptase response in both the acute and chronic infection models. Specifically, citalopram significantly decreased the acute HIV infectivity of macrophages. Citalopram also significantly decreased HIV viral replication in the latently infected T-cell line and in the latently infected macrophage cell line. There was no difference in down-regulation by depression status.
These studies suggest that an SSRI enhances natural killer/CD8 noncytolytic HIV suppression in HIV/acquired immune deficiency syndrome and decreases HIV viral infectivity of macrophages, ex vivo, suggesting the need for in vivo studies to determine a potential role for agents targeting serotonin in the host defense against HIV.
Psychosomatic Medicine 11/2010; 72(9):925-32. · 3.97 Impact Factor
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ABSTRACT: Increased natural killer (NK) activation has been associated with resistance to HIV-1 infection in several cohorts of HIV-1 exposed, uninfected individuals. Inheritance of protective NK receptor alleles (KIR3DS1 and KIR3DL1) has also been observed in a subset of HIV-1 exposed, uninfected individuals. However, the exact mechanism contributing to NK activation in HIV-1 exposed, uninfected intravenous drug users (EU-IDU) remains to be elucidated.
We investigated the role of both host genotype and pathogen-induced dendritic cell modulation of NK activation during high-risk activity in a cohort of 15 EU-IDU individuals and 15 control, uninfected donors from Philadelphia.
We assessed the activation status of NK cells and dendritic cells by flow cytometry and utilized functional assays of NK-DC cross-talk to characterize the innate immune compartment in EU-IDU individuals.
As previously reported, NK cell activation (CD69) and/or degranulation (CD107a) was significantly increased in EU-IDU individuals compared with control uninfected donors (P = 0.0056, n = 13). Genotypic analysis indicated that the frequency of protective KIR (KIR3DS1) and HLA-Bw4*80I ligands was not enriched in our cohort of EU-IDU individuals. Rather, plasmacytoid dendritic cells (PDC) from EU-IDU exhibited heightened maturation (CD83) compared with control uninfected donors (P = 0.0011, n = 12). When stimulated in vitro, both PDCs and NK cells from EU-IDU individuals maintained strong effector cell function and did not exhibit signs of exhaustion.
Increased maturation of PDCs is associated with heightened NK activation in EU-IDU individuals suggesting that both members of the innate compartment may contribute to resistance from HIV-1 infection in EU-IDU.
AIDS (London, England) 09/2010; 24(14):2151-60. · 4.91 Impact Factor
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ABSTRACT: CD56(+) T cells are abundant in liver and play an important role in host innate immunity against viral infections, including hepatitis C virus (HCV) infection, a common infection among heroin abusers. We thus investigated the in vivo impact of heroin use or heroin use plus HCV infection on the CD56(+) T cell frequency and function.
A total of 37 heroin users with (17) or without (20) HCV infection and 17 healthy subjects were included in the study. Although there was no significant difference in CD56(+) T cell frequency in PBMCs among three study groups, CD56(+) T cells isolated from the heroin users had significantly lower levels of constitutive interferon-gamma (IFN-gamma) expression than those from the normal subjects. In addition, when stimulated by interleukin (IL)-12, CD56(+) natural T cells from HCV-infected heroin users produced significantly lower levels of IFN-gamma than those from the normal subjects. This diminished ability to produce IFN-gamma by CD56(+) T cells was associated with the increased plasma HCV viral loads in the HCV-infected heroin users. Investigation of the mechanisms showed that although heroin use or heroin use plus HCV infection had little impact on the expression of the key positive regulators (IL-12 receptors, STAT-1, 3, 4, 5, JAK-2, and TYK-2) in IL-12 pathway, heroin use or heroin use plus HCV infection induced the expression of suppressor of cytokine signaling protein-3 (SOCS-3) and protein inhibitors of activated STAT-3 (PIAS-3), two key inhibitors of IL-12 pathway.
These findings provide compelling in vivo evidence that heroin use or heroin use plus HCV infection impairs CD56(+) T cell-mediated innate immune function, which may account for HCV infection and persistence in liver.
PLoS ONE 01/2010; 5(3):e9602. · 4.09 Impact Factor
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ABSTRACT: Although both monocytes and macrophages possess essential requirements for HIV-1 entry, peripheral blood monocytes are infrequently infected with HIV-1 in vivo and in vitro. In contrast, tissue macrophages and monocyte-derived macrophages in vitro are highly susceptible to infection with HIV-1 R5 tropic strains. We investigated intracellular anti-HIV-1 factors that contribute to differential susceptibility of monocytes/macrophages to HIV-1 infection. Freshly isolated monocytes from peripheral blood had significantly higher levels of the anti-HIV-1 microRNAs (miRNA, miRNA-28, miRNA-150, miRNA-223, and miRNA-382) than monocyte-derived macrophages. The suppression of these anti-HIV-1 miRNAs in monocytes facilitates HIV-1 infectivity, whereas increase of the anti-HIV-1 miRNA expression in macrophages inhibited HIV-1 replication. These findings provide compelling and direct evidence at the molecular level to support the notion that intracellular anti-HIV-1 miRNA-mediated innate immunity may have a key role in protecting monocytes/macrophages from HIV-1 infection.
Blood 12/2008; 113(3):671-4. · 9.90 Impact Factor
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JAIDS Journal of Acquired Immune Deficiency Syndromes 04/2008; 47 Suppl 1:S1-4. · 4.43 Impact Factor
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JAIDS Journal of Acquired Immune Deficiency Syndromes 04/2008; 47 Suppl 1:S47-8. · 4.43 Impact Factor
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ABSTRACT: Racial differences in the prevalence and incidence of HIV infection and AIDS diagnoses in the United States are striking. These differences have been recognized for nearly 20 years, yet they are not well investigated. In this article, we examine 15 factors identified in the sexually transmitted infection (STI) literature to explain the presence of racial/ethnic disparities in STIs. We review findings from these studies and offer suggestions for future research, with the goal of further understanding and reducing disparities in HIV. In general, the STI literature shows that an evaluation of individual behavior is necessary but insufficient on its own to account for racial/ethnic disparities in STIs. Population parameters should be included within models that traditionally include individual-level factors. The 15 factors can be categorized into 3 broad overarching themes: behavioral, prevention participation, and biologic explanations of differentials in STI transmission and infection. Future research that focuses on only 1 of the 15 factors discussed in this review, to the exclusion of others, is likely to yield poor outcomes. Conversely, an emphasis on the interactions of several factors is more likely to produce effective public health interventions and reductions in HIV transmission.
JAIDS Journal of Acquired Immune Deficiency Syndromes 04/2008; 47 Suppl 1:S20-7. · 4.43 Impact Factor
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ABSTRACT: Acute and chronic alcohol abuse impairs various functions of the immune system and thus, has been implicated as a cofactor in the immunopathogenesis of human immunodeficiency virus (HIV) disease progression. We determined whether naltrexone, an opioid receptor antagonist widely used in the treatment of alcoholism, inhibits alcohol-mediated enhancement of HIV infection of T cells. Alcohol enhanced HIV infection of peripheral blood lymphocytes (PBL) and a human lymphoid cell line (CEMX174). Alcohol increased HIV X4 envelope (Env), not murine leukemia virus Env-pseudotyped infection of CEMX174 cells. Naltrexone antagonized the enhancing effect of alcohol on HIV infection of PBL and CEMX174 cells. The specific mu-opioid receptor antagonist, Cys2, Tyr3, Arg5, Pen7 (CTAP) amide, also blocked the enhancing effect of alcohol on HIV infection. Investigation of the underlying mechanism for the alcohol action showed that alcohol significantly increased endogenous beta-endorphin production and induced mu-opioid receptor mRNA expression in PBL and CEMX174 cells. The role of beta-endorphin in alcohol-mediated enhancement of HIV infection was indicated by the observations that naltrexone and CTAP antagonized ether alcohol- or exogenous beta-endorphin-mediated enhancement of HIV infection. These findings suggest a biological mechanism for the potential therapeutic benefit of naltrexone in treating HIV-infected alcoholics.
Journal of Leukocyte Biology 07/2006; 79(6):1166-72. · 4.99 Impact Factor
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ABSTRACT: This study compares drug patterns and prevalence of risk behaviors in a randomized trial using two methods of administration, Audio Computer-Assisted Self-Interview (ACASI) and Interviewer-Administered Questionnaire (IAQ), among drug users seeking treatment in a drug treatment center. We randomized 735 participants: 367 to ACASI and 368 to IAQ. No significant difference in sociodemographic variables were found between subjects in the two arms of the study. Those interviewed by ACASI were more likely to report use on 7 of 10 substances assessed. Rates of reporting of sexual risk behaviors (male-to-male and commercial sex) were higher among participants in the ACASI arm. ACASI seems to be a key resource in improving the reporting of sensitive data in Brazil, as it has been in prior international studies.
Journal of Substance Abuse Treatment 05/2006; 30(3):237-43. · 3.14 Impact Factor
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ABSTRACT: This study aimed to determine the acceptability of the ACASI approach to risk assessment and the impact of personal preference regarding mode of interview on reporting risk behaviors among drug users entering treatment in Rio de Janeiro, Brazil. We assessed 268 substance users who completed the ACASI arm in a randomized trial comparing the ACASI with the Interviewer-Administered Questionnaire (IAQ). The vast majority of interviewees (90.7%) reported no problem using the computer, and 37.3% felt that their privacy was best protected by the ACASI (vs. 16.4% who preferred the IAQ). Nearly half (45.5%) reported that the computer interview would produce more "honest" answers, whereas 30.6% selected the IAQ. In the adjusted regression analysis, problems using the computer were associated only with lower educational level (p<0.05). We found no evidence that preference had an impact on reporting risk behaviors or drug use. Our study showed both good feasibility and acceptability of the ACASI for interviewing drug users in Brazil. The findings extend our understanding of the role of the ACASI method by suggesting the utility of this approach in assessing HIV risk among low-to middle-income drug users in a cultural setting quite different from previous studies.
Drug and Alcohol Dependence 04/2006; 82 Suppl 1:S103-7. · 3.38 Impact Factor
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ABSTRACT: We previously demonstrated that morphine enhances hepatitis C virus (HCV) replication in human hepatic cells. Here we describe the impact of morphine withdrawal (MW), a recurrent event during the course of opioid abuse, on HCV replicon expression in human hepatic cells. MW enhanced both viral RNA and protein expression in HCV replicon cells. Blocking opioid receptors by treatment with naloxone after morphine cessation (precipitated withdrawal, PW) induced greater HCV replicon expression than MW. Investigation of the mechanism responsible for MW- or PW-mediated HCV enhancement showed that both MW and PW inhibited the expression of endogenous interferon-alpha (IFN-alpha) in the hepatic cells. This down-regulation of intracellular IFN-alpha expression was due to the negative impact of MW or PW on IFN-alpha promoter activation and on the expression of IFN regulatory factor 7 (IRF-7), a strong transactivator of the IFN-alpha promoter. In addition, both MW and PW inhibited the anti-HCV ability of recombinant IFN-alpha in the hepatic cells. These in vitro observations support the concept that opioid abuse favors HCV persistence in hepatic cells by suppressing IFN-alpha-mediated intracellular innate immunity and contributes to the development of chronic HCV infection.
American Journal Of Pathology 12/2005; 167(5):1333-40. · 4.89 Impact Factor
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ABSTRACT: Natural killer (NK) cells are a critical component of the host innate immune system. We investigated whether alcohol impairs NK cell function, particularly production of CC chemokines induced by interleukin (IL)-2, the natural ligands for CCR5 receptor.
Primary NK cells and NK cell line (YTS) were cultured with or without alcohol (10 to 80 mM) for three hours. The culture supernatants were then harvested and used to treat human peripheral blood monocyte-derived macrophages and a HeLa cell line, which expresses CD4, CCR5, and CXCR4 receptors (MAGI cells). CC chemokine expression by YTS and primary NK cells treated with or without alcohol was analyzed with the real-time RT-PCR and ELISA. [Ca(2)(+)]i and Western blot assays were used to determine calcium-mediated intracellular signaling pathway and NF-kappaB p65 expression. HIV strains (Bal and UG024) were used to infect macrophages and MAGI cells. In addition, ADA (macrophage-tropic strain) and murine leukemia virus (MLV) envelope-pseudotyped HIV infection was carried out in macrophages. HIV infectivity was determined by HIV reverse transcriptase (RT) and beta-galactosidase activity assays.
Alcohol inhibited IL-2-induced CC chemokine (CCL3 and CCL4) expression by NK cells. Functional tests demonstrated that this reduced expression of CC chemokines was associated with diminished anti-HIV ability of NK cells. Alcohol also reduced the ability of NK cells to response to CCL3-mediated chemotaxis. Alcohol inhibited IL-2-induced NF-kappaB p65 protein expression and calcium mobilization by NK cells.
Alcohol, through the inhibition of IL-2-induced NF-kappaB p65 protein expression and intracellular calcium mobilization, suppressed NK cell production of CC chemokines. This suppression of CC chemokine production was associated with diminished anti-HIV activity of NK cells. Thus, by inhibiting NK cell-mediated innate immunity against HIV, alcohol consumption may have a cofactor role in the immunopathogenesis of HIV disease.
Alcoholism Clinical and Experimental Research 10/2005; 29(9):1559-67. · 3.34 Impact Factor
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ABSTRACT: We investigated the ability of CD8+ T cells to inhibit hepatitis C virus (HCV) replication in peripheral blood mononuclear cells (PBMCs). PBMCs isolated from 11 of 20 HCV-infected subjects had no detectable HCV RNA. Removal of CD8+ T cells from these PBMCs resulted in detection of HCV RNA, and depletion of CD8+ T cells from PBMCs that had detectable HCV RNA amplified HCV replication. Reconstitution of CD8- PBMCs with autologous CD8+ T cells led to inhibition of HCV replication. Interferon-gamma produced by CD8+ T cells was partially responsible for CD8+ T cell-mediated noncytotoxic anti-HCV activity in PBMCs. This noncytotoxic anti-HCV activity was confirmed in HCV replicon cells. Supernatants from CD8+ T cell cultures inhibited HCV RNA expression in the replicon cells. These findings may have important implications for the immunopathogenesis of HCV in both immune and hepatic cells and are relevant to the development of host innate immunity-based anti-HCV interventions.
The Journal of Infectious Diseases 10/2005; 192(6):1093-101. · 6.41 Impact Factor
