Biomedical subjects

David S Metzger

Publications and source records attributed to David S Metzger.

15 recordsLinked to original sources

PubMed2006

Naltrexone inhibits alcohol-mediated enhancement of HIV infection of T lymphocytes.

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.

Adult↗

PubMed2006

A randomized trial of audio computer and in-person interview to assess HIV risk among drug and alcohol users in Rio De Janeiro, Brazil.

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.

Adolescent↗

PubMed2006

Acceptability of audio computer-assisted self-interview (ACASI) among substance abusers seeking treatment in Rio de Janeiro, Brazil.

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.

Adolescent↗

PubMed2006

How should HIV vaccine efficacy trials be conducted? Diverse U.S. communities speak out.

Developing an effective vaccine remains a critical long-term approach to HIV prevention. Every efficacy trial should be responsive to the concerns of participating communities because the successful development of an HIV preventive vaccine will require long-term involvement of people who have been marginalized and who distrust the government and biomedical research. Using qualitative interviews and purposive sampling, we elicited recommendations regarding how vaccine efficacy trials should be conducted from 90 members of communities that have been disproportionately affected by HIV/AIDS: injection drug users, gay men, and African Americans. The most common recommendation was for complete disclosure of all aspects of the trial. Other themes included participant and community education, who to include in trials, preventing harm, trust, community involvement, researcher attributes, and respect for participants. Developing positive, respectful and collaborative experiences with community members will facilitate vaccine research because negative experiences and unfavorable community reactions can greatly impede success in future trials.

AIDS Vaccines↗

PubMed2005

CD8+ T cell depletion amplifies hepatitis C virus replication in peripheral blood mononuclear cells.

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.

Antiviral Agents↗

PubMed2005

Morphine withdrawal enhances hepatitis C virus replicon expression.

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.

Cell Line↗

PubMed2005

Alcohol suppresses IL-2-induced CC chemokine production by natural killer cells.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Adult↗

PubMed2005

Decreasing international HIV transmission: the role of expanding access to opioid agonist therapies for injection drug users.

AIMS: To examine the role of expanded access to opioid agonist treatment as a means to decrease international HIV transmission. DESIGN: Review of the English language literature via Medline. MEASUREMENTS: Estimates of prevalence rates for injection drug use, HIV infection and treatment effect sizes for changes in opioid use, opioid injection, needle-sharing, injection-related HIV risk behavior and cost. FINDINGS: An estimated 12.6 million injection drug users internationally accounted for 10% of the 4.2 million new HIV infections in 2003. Ninety-three of the 136 countries (68%) that report injection drug use identify HIV infection related to this behavior. Observational studies of methadone treatment demonstrate decreases in opioid use, opioid injection, needle-sharing and lower rates of HIV prevalence and incidence. The effectiveness of buprenorphine in demonstrating similar findings is expected, although implementations and research are still emerging. The cost-effectiveness of opioid agonist treatment has been established. The barriers to international adoption of opioid agonist treatment, despite the research evidence and international guidelines, are discussed. CONCLUSIONS: Untreated opioid dependence leads to HIV transmission, on an international level. Opioid agonist treatments are associated with reductions in the frequency of opioid use, fewer injections and injection-related HIV risk behaviors and lower rates of HIV prevalence and incidence. Despite international recommendations, treatment for opioid-dependent injection drug users with methadone and buprenorphine is limited. Research, implementation efforts and political strategies to expand access to opioid agonist treatment are needed in order to combat the spread of HIV, especially in the developing world.

Buprenorphine↗

PubMed2004

Homelessness and HIV risk behaviors among injection drug users.

This article uses data from an 8-year study of injection drug users to examine whether homelessness independently influenced the likelihood of engaging in human immunodeficiency virus (HIV) risk behaviors. Fixed effects regression analyses are used to estimate the associations between four different housing contexts and four different behaviors related to transmitting HIV infections. Results showed that 16% of the study group experienced homelessness at some point during the study, and that homelessness was significantly associated with a higher likelihood of frequenting shooting galleries (odds ratio = 2.05), but did not have a significant effect on sharing syringes, sharing other injection drug paraphernalia, or participating in paid sex. These results provide limited support for positing homelessness as independently associated with increased levels of HIV-related risk behavior among injection drug users and highlights the need for more research that examines the housing dynamics among this population.

Adolescent↗

PubMed2003

Human immunodeficiency virus prevention and the potential of drug abuse treatment.

Since first recognition of the scope of the acquired immunodeficiency syndrome epidemic among the drug-using community, substance abuse treatment has been viewed as playing an important role in preventing new infections. In the past 20 years, many studies have documented significantly lower rates of drug use, drug-related risk behaviors, and human immunodeficiency virus (HIV) infections among drug users who remain in treatment programs. There is also growing evidence that drug detoxification alone is insufficient to provide protection from HIV infection. These findings have important implications for users of cocaine and noninjection drugs, as well as heroin injectors. Despite strong evidence of effectiveness and widespread support for the important public health role of drug treatment, its impact has been compromised by limited availability and acceptability. The available data clearly establish drug abuse treatment as HIV prevention, yet without expansion of existing treatment programs and the continued development of treatments for addiction to cocaine and other widely used stimulants, its public health potential cannot be realized.

Cocaine-Related Disorders↗

PubMed2003

Morphine enhances HIV infection of neonatal macrophages.

Perinatal transmission of HIV accounts for almost all new HIV infections in children. There is an increased risk of perinatal transmission of HIV with maternal illicit substance abuse. Little is known about neonatal immune system alteration and subsequent susceptibility to HIV infection after morphine exposure. We investigated the effects of morphine on HIV infection of neonatal monocyte-derived macrophages (MDM). Morphine significantly enhanced HIV infection of neonatal MDM. Morphine-induced HIV replication in neonatal MDM was completely suppressed by naltrexone, the opioid receptor antagonist. Morphine significantly up-regulated CCR5 receptor expression and inhibited the endogenous production of macrophage inflammatory protein-1beta in neonatal MDM. Thus, morphine, most likely through alteration of beta-chemokines and CCR5 receptor expression, enhances the susceptibility of neonatal MDM to HIV infection, and may have a cofactor role in perinatal HIV transmission and infection.

Analgesics, Opioid↗

PubMed2003

Randomized, controlled evaluation of a prototype informed consent process for HIV vaccine efficacy trials.

Procedures must be developed to ensure that valid informed consent is obtained from participants in HIV vaccine efficacy trials. A prototype informed consent process was evaluated among 4,892 persons at high risk for HIV infection in the HIV Network for Prevention Trials Vaccine Preparedness Study (VPS), a prospective cohort study of HIV seroincidence in eight U.S. metropolitan areas. Twenty percent of VPS participants were selected at random to undergo the prototype informed consent process at VPS month 3. Participants' knowledge of 10 key HIV vaccine trial concepts and willingness to participate in HIV vaccine efficacy trials were assessed and compared at baseline and semiannually thereafter for 18 months. Knowledge of HIV vaccine trial concepts was low at baseline. Participation in the prototype process was associated with substantial and sustained increases in knowledge (relative risks for the 10 items, 1.04-2.26), which were of similar magnitude across HIV risk groups, race/ethnicity, and educational levels. It is recommended that the prototype informed consent process be adopted for future HIV vaccine efficacy trials as well as for clinical trials in other research areas.

AIDS Vaccines↗

PubMed2003

Alcohol potentiates hepatitis C virus replicon expression.

Alcohol consumption accelerates liver damage and diminishes the anti-hepatitis C virus (HCV) effect of interferon alfa (IFN-alpha) in patients with HCV infection. It is unknown, however, whether alcohol enhances HCV replication and promotes HCV disease progression. The availability of the HCV replicon containing hepatic cells has provided a unique opportunity to investigate the interaction between alcohol and HCV replicon expression. We determined whether alcohol enhances HCV RNA expression in the replicon containing hepatic cells. Alcohol, in a concentration-dependent fashion, significantly increased HCV replicon expression. Alcohol also compromised the anti-HCV effect of IFN-alpha. Investigation of the mechanism(s) responsible for the alcohol action on HCV replicon indicated that alcohol activated nuclear factor kappaB (NF-kappaB) promoter. Caffeic acid phenethyl ester (CAPE), a specific inhibitor of the activation of NF-kappaB, abolished alcohol-induced HCV RNA expression. In addition, naltrexone, an opiate receptor antagonist, abrogated the enhancing effect of alcohol on HCV replicon expression. In conclusion, alcohol, probably through the activation of NF-kappaB and the endogenous opioid system, enhances HCV replicon expression and compromises the anti-HCV effect of IFN-alpha. Thus, alcohol may play an important role in vivo as a cofactor in HCV disease progression and compromise IFN-alpha-based therapy against HCV infection.

Antidotes↗

PubMed2003

HIV prevention among injection drug users: the need for integrated models.

Opportunistic infections (OIs) were first recognized among injection drug users (IDUs) in New York City in 1981. By the mid-1980s, OIs had become associated with HIV infection, and attention began to focus on efforts to prevent HIV transmission among IDUs. Since then, a range of prevention strategies has been implemented and evaluated in an attempt to reduce the spread of HIV infection among drug users. These prevention strategies include (1) HIV testing and counseling and educational and behavioral interventions delivered through community outreach; (2) condom, bleach, and needle distribution and syringe access and exchange programs; (3) substance abuse treatment; and, more recently, (4) prevention interventions targeting HIV-positive IDUs. Data from evaluations of these strategies over the past 20 years have provided substantial evidence of effectiveness and have helped to inform network-based and structural interventions. Despite the cumulative empirical evidence, however, research findings have yet to be widely disseminated, adopted, and implemented in a sustained and integrated fashion. The reasons for this are unclear, but point to a need for improved communications with program developers and community planners to facilitate the implementation and evaluation of integrated intervention strategies, and for collaborative research to help understand policy, legal, economic, and local barriers to implementation.

Community Health Services↗

PubMed2002

Alcohol potentiates HIV-1 infection of human blood mononuclear phagocytes.

BACKGROUND: Acute and chronic alcohol abuse impairs various functions of the immune system and thus has been implicated as a cofactor in HIV infection. The mechanisms by which alcohol affects the function of human immune cells that are the targets for HIV are unknown. METHODS: Human blood monocyte-derived macrophages (MDM) were incubated with or without alcohol (10-40 mM) for 24 hr and then infected with HIV for 24 hr. Culture supernatants were harvested for HIV reverse transcription assay. HIV entry receptor (CCR5, CD4, and CXCR4) expression was determined by reverse transcription-polymerase chain reaction and flow cytometry assays. Beta-chemokines were analyzed using enzyme-linked immunosorbent assay. Different HIV strains (Bal, SF-162, 89.6, and UG024) were used for infection experiments. In addition, ADA (macrophage-tropic strain) and murine leukemia virus envelope-pseudotyped HIV infection was carried out. RESULTS: Although alcohol had little effect on HIV T-lymphocyte-tropic strain infection, it significantly enhanced HIV R5 strain infection in MDM. The enhancing effect of alcohol on the HIV R5 strain was further evidenced by the observation that the R5 (ADA) strain envelope-pseudotyped HIV infection is markedly increased by alcohol, whereas murine leukemia virus envelope-pseudotyped HIV infection was not affected. Alcohol significantly up-regulated CCR5 receptor expression and inhibited the endogenous production of beta-chemokines by MDM. CONCLUSION: Alcohol, through the down-regulation of beta-chemokine production and the up-regulation of CCR5 receptor expression, enhances HIV R5 strain infection of MDM and may have an important role as a cofactor in the progression of HIV disease.

Cells, Cultured↗