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Roger J Pomerantz

Publications and source records attributed to Roger J Pomerantz.

82 records · Page 5Linked to original sources
PubMed2002

Lentiviral expression of HIV-1 Vpr induces apoptosis in human neurons.

Our recent studies have demonstrated that extracellular, recombinant human immunodeficiency virus type I (HIV-1) Vpr protein is highly neurotoxic in the microenvironment of differentiated mature human neurons and undifferentiated neuronal precursors. Although most of the direct neurotoxic effects of HIV-1 have been attributed previously to the envelope gene product, gp120, and the Tat regulatory protein, it was demonstrated that Vpr protein caused apoptosis comparable to that induced by gp120 protein in a dose-dependent manner in the neuronal system. Having observed the neurocytopathic effects of extracellular Vpr protein previously, the effects of virally expressed Vpr on nondividing, terminally differentiated human neurons were investigated. An HIV-1-based three-plasmid expression vector system was utilized to study the effects of intracellularly expressed Vpr. These virion preparations were then used to transduce neurons generated from the human neuronal precursor NT2 cell-line. Intracellularly expressed Vpr induced apoptosis within terminally differentiated neurons, as demonstrated by TUNEL assays. Additionally, virions lacking Vpr expression did not significantly induce apoptosis within these neurons. These results suggest that HIV-1 Vpr may also be leading directly to selective neurotoxicity through intracellular expression. Furthermore, human apoptosis gene microarray comparisons exhibited an up-regulation of Bcl-2-related mRNA, as well as other apoptosis genes involved in the mitochondrial apoptotic pathway, for the Vpr-transduced neuronal cells, when compared to Vpr-negative controls. Thus, Vpr delivered intracellularly, as well as extracellularly, is involved in the induction of significant neuronal apoptosis and may be one of the molecular mechanisms in HIV-1-induced encephalopathy.

AIDS Dementia Complex↗
PubMed2002

Central nervous system infections in individuals with HIV-1 infection.

Opportunistic infections of the central nervous system (CNS) are common complications of advanced immunodeficiency in individuals with human immunodeficiency virus type 1 (HIV-1) infection. Neurological disease is the first manifestation of acquired immunodeficiency syndrome (AIDS) in 10% to 20% of symptomatic HIV-1 infection. Prompt diagnosis and treatment of such disorders is critical. Also, in the era of highly active antiretroviral therapy (HAART), these disease states have changed in presentation and epidemiology. Therefore, we review the epidemiology, pathogenesis, clinical features, diagnosis, and management of five common central nervous system disorders in individuals with HIV-1 infection: toxoplasma encephalitis, primary central nervous system lymphoma, cryptococcal meningitis, cytomegalovirus encephalitis, and progressive multifocal leukoencephalopathy.

AIDS-Related Opportunistic Infections↗
PubMed2002

Rhabdovirus-based vectors with human immunodeficiency virus type 1 (HIV-1) envelopes display HIV-1-like tropism and target human dendritic cells.

We describe replication-competent, vaccine strain-based rabies viruses (RVs) that lack their own single glycoprotein and express, instead, a chimeric RV-human immunodeficiency virus type 1 (HIV-1) envelope protein composed of the ectodomain and transmembrane domains of HIV-1 gp160 and the cytoplasmic domain of RV G. The envelope proteins from both X4 (NL4-3)- and R5X4 (89.6)-tropic HIV-1 strains were utilized. These recombinant viruses very closely mimicked an HIV-1- like tropism, as indicated by blocking experiments. Infection was inhibited by SDF-1 on cells expressing CD4 and CXCR4 for both viruses, whereas RANTES abolished infection of cells expressing CCR5 in addition to CD4 in studies of the RV expressing HIV-1(89.6) Env. In addition, preincubation with soluble CD4 or monoclonal antibodies directed against HIV-1 gp160 blocked the infectivity of both G-deficient viruses but did not affect the G-containing RVs. Our results also indicated that the G-deficient viruses expressing HIV-1 envelope protein, in contrast to wild-type RV but similar to HIV-1, enter cells by a pH-independent pathway. As observed for HIV-1, the surrogate viruses were able to target human peripheral blood mononuclear cells, macrophages, and immature and mature human dendritic cells (DC). Moreover, G-containing RV-based vectors also infected mature human DC, indicating that infection of these cells is also supported by RV G. The ability of RV-based vectors to infect professional antigen-presenting cells efficiently further emphasizes the potential use of recombinant RVs as vaccines.

AIDS Vaccines↗
PubMed2002

Eliminating HIV-1 reservoirs.

HIV-1 infection can now be treated effectively in many patients in the developed world, using combination antiretroviral therapeutics, called highly active antiretroviral therapy (HAART). Nevertheless, these regimens do not cure HIV-1 infection. Residual disease is maintained via proviral latency in resting CD4+ T-lymphocytes and possibly monocytes/macrophages. In addition, low-level viral replication continues in a cryptic manner during HAART. As such, a variety of approaches to both activate the latent reservoirs and deplete residual viral replication are being developed. In understanding the molecular pathogenesis of HIV-1 disease, one can potentially target these cellular reservoirs of HIV-1 persistence.

Anti-HIV Agents↗
PubMed2001

Reservoirs of human immunodeficiency virus type 1: the main obstacles to viral eradication.

Highly active antiretroviral therapy (HAART) has led to profound decreases in morbidity and mortality rates in human immunodeficiency virus type 1 (HIV-1)-infected persons, at least in the developed world. Many infected persons have plasma levels of HIV-1 RNA that are less than the limits of detection of most clinical assays as a result of combination antiretroviral therapy. Nonetheless, HIV-1 has not been eradicated by HAART. This has been shown to be because of latent HIV-1 replication-competent provirus in resting CD4+ T lymphocytes, cryptic viral replication below the limits of detection of most clinical assays, and, possibly, the presence of viral sanctuary sites. An understanding of these reservoirs for HIV-1 in the setting of virally suppressive HAART will be critical for the development of new approaches to induce HIV-1 remissions and for the exploration of the possibility of viral eradication in the future.

Antiretroviral Therapy, Highly Active↗
PubMedDate not supplied

RNA interference: on the road to an alternate therapeutic strategy!

RNA interference (RNAi) is a newly described natural biological phenomenon mediated by small interfering RNA (siRNA) molecules which target viral mRNA for degradation by cellular enzymes. RNAi has become a method of choice for studying gene function, especially in mammalian systems. With proof-of-concept studies already presented against a wide variety of human pathogens and several innovative methods of delivering the siRNA to a wide variety of primary cells available, the role for siRNA as a potential therapeutic strategy is becoming increasingly clear. This review presents recent advances in this direction.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

Reservoirs, sanctuaries, and residual disease: the hiding spots of HIV-1.

Highly active antiretroviral therapy (HAART) has profoundly decreased morbidity and mortality in human immunodeficiency virus type 1 (HIV-1)-infected individuals, at least in the developed world. Many infected individuals have plasma levels of HIV-1 RNA below the limits of detection of most clinical assays due to combination antiretroviral therapy. Nonetheless, HIV-1 has not been eradicated by HAART. This has been shown recently to be due to latent HIV-1 replication-competent provirus in resting CD4+ T-lymphocytes, cryptic viral replication below the limits of detection of most clinical assays, and viral sanctuary sites. An understanding of these sanctuaries and reservoirs for HIV-1 in the setting of virally suppressive HAART will be critical in developing new approaches to induce HIV-1 remissions or the possibility of viral eradication in the future.

Anti-HIV Agents↗
PubMedDate not supplied

Ludwik Hirszfeld Memorial Lecture: HIV-1 reservoirs: major molecular obstacles to viral eradication.

Over the last 18 years of study in one of our laboratories, we have observed the development of residual disease and latent reservoirs as major problems in the long-term therapy of HIV-1-infected individuals on highly active antiretroviral therapy (HAART). It was shown in the early 1990 's that HAART, as it is presently configured, is unlikely to lead to viral eradication due to several mechanisms of viral persistence. The two general mechanisms involved with persistence during HAART include low-level residual, cryptic replication and proviral latently-infected cells. As such, these are key areas of potential studyfor depletion and, hopefully in the future, eradication of residual disease in patients on suppressive HAART. To deplete these residual disease mechanisms will require multipronged approaches. These will include induction of HIV-1 latent proviruses, suppression of residual viral replication and destruction of long-lived cellular sanctuaries, such astissue-bound macrophages.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

RNA interference:a potential novel therapeutic combating HIV-1 in the central nervous system.

RNA interference (RNAi)is a conserved process by which eukaryotic cells protect their genomes utilizing small, double-stranded RNAs to degrade target RNAs. This occurs in a sequence-specific manner and is different from the interferon effect of larger double stranded RNAs. Post-transcriptional gene silencing by these nucleic acids can lead to degradation of either cellular or viral RNAs. It has been recently shown that double stranded, small interfering RNAs (siRNAs)of 21 to 25 nucleotides can be transfected into relevant cells to target specific RNAs. In addition, utilizing hairpin motifs, siRNAs can be expressed intracellularly using molecular therapeutic vectors. This potent approach has been utilized to both inhibit pathogens, including viruses, as well as to dissect cellular molecular mechanisms via a potent knockout effect. At this time in the HIV-1-pandemic,one of the remaining, most enigmatic, and still vitally important areas of HIV-1 pathogenesis occurs in the central nervous system (CNS).HIV-1-induced encephalopathy remains difficult to treat in the developing world and in parts of the developed world, even in the era of highly active anti-retroviral therapy. As such, novel approaches which could lead to intracellular immunization, and life-long resistance against HIV-1 encephalopathy would be of important impact worldwide. Thus, we now seek to combine our background in molecular therapeutics and RNAi with our long-standing interest in HIV-1 neuropathogenesis to target the CNS using siRNAs.

AIDS Dementia Complex↗