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Current HIV research [journal]
- Drug Resistance Mutations from Whole Blood Proviral DNA among Patients on Antiretroviral Drugs in Zimbabwe. [JOURNAL ARTICLE]
- Curr HIV Res 2014 Oct 16.
Introduction: There are more than 500 000 HIV-infected people on antiretroviral treatment (ART) in Zimbabwe with very limited laboratory monitoring. To ensure effective treatment and prevent transmission of drug resistance, affordable treatment monitoring is needed to guide individual treatment. Methods: 125 whole blood samples from patients on first-line ART were investigated for drug resistance mutations using an in-house genotypic testing method. Patients had been on HIV reverse transcriptase inhibitors only, with some having been on both HIV and TB treatment. DNA was extracted from whole blood, amplicons were generated by nested PCR and sequenced. Drug resistance mutations were determined using the Stanford HIV drug resistance database. Exact statistics were used to investigate relationships between drug resistance and predisposing factors. Results: From 125 samples, 108 were successfully analyzed for drug resistance mutations. 11 of the 108 sequences had drug resistance mutations; predominantly M184V and Y181C. For a 100-cell increase in CD4 count, the odds of being resistant were 60% lower than those with the baseline CD4 count (p=0.04, CI: 0.34-0.98). There was no association between concurrent HIV/TB treatment and drug resistance (p=0.41). Discussion and conclusion: Although plasma samples are recommended for genotypic testing, the cost of analyzing plasma RNA makes it less feasible in resource limited settings. Lower cost DNA drug resistance testing from whole blood samples was assessed as a treatment-monitoring tool among patients followed by CD4 and clinical monitoring only. The infrequent detection of resistance and higher CD4 is consistent with effective first-line treatment. Further investigation of proviral DNA as a tool to identify drug resistance mutations is warranted.
- Monocytes are Susceptible to Chronic, Highly Productive HIV Infection. [JOURNAL ARTICLE]
- Curr HIV Res 2014 Oct 16.
Peripheral blood monocytes of HIV-infected individuals carry virus, constituting one potential reservoir. However, most studies of infection in tissue culture find monocytes refractory to HIV replication, suggesting that culture conditions limit the relative susceptibility of this target cell. We employed a tissue culture system optimized for maintenance of human monocytes without differentiation and compared HIV infection efficiency of monocytes and fully differentiated monocyte derived macrophages (MDM). We tested direct virus-cell fusion, expression of cell lineage markers, and productive HIV infection in fresh monocytes, monocytes after varying periods of supportive culture, and fully differentiated MDM comparing cells from individual donors. Fresh, uncultured monocytes allowed modest HIV fusion, however one week culture was sufficient to allow efficient fusion and an increase in expression of CD14, CD16, CD33, and CD105. Compared to freshly isolated monocytes, monocytes infected after a few days in culture produced p24 more quickly, but the peaks of production were similar. Fresh monocytes were highly susceptible to productive HIV infection in supportive culture, roughly equal to MDM from the same donor in expression of extracellular p24 up to five weeks after infection. Taken together our findings indicate that monocytes are biologically capable of supporting chronic, highly productive HIV infection, a capacity that may reflect their status in HIV-infected persons.
- 2´,3´-Dialdehyde of ATP, ADP, and Adenosine Inhibit HIV-1 Reverse Transcriptase and HIV-1 Replication. [JOURNAL ARTICLE]
- Curr HIV Res 2014 Aug 25.
The 2´3´-dialdehyde of ATP or oxidized ATP (oATP) is a compound known for specifically making covalent bonds with the nucleotide-binding site of several ATP-binding enzymes and receptors. We investigated the effects of oATP and other oxidized purines on HIV-1 infection and we found that this compound inhibits HIV-1 and SIV infection by blocking early steps of virus replication. oATP, oxidized ADP (oADP), and oxidized Adenosine (oADO) impacts the natural activity of endogenous reverse transcriptase enzyme (RT) in cell free virus particles and are able to inhibit viral replication in different cell types when added to the cell cultures either before or after infection. We used UFLC-UV to show that both oADO and oATP can be detected in the cell after added in the extracellular medium. oATP also suppresses RT activity and replication of the HIV-1 resistant variants M184V and T215Y. We conclude that oATP, oADP and oADO display anti HIV-1 activity that is at in least in part due to inhibitory activity on HIV-1 RT.
- 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, Research Support, N.I.H., Extramural]
- 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, Research Support, N.I.H., Extramural]
- 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.