Current HIV Research - Volume 4, Issue 3, 2006

Millions of individuals worldwide have been infected with the human immunodeficiency virus (HIV) and developed the disease known as acquired immunodeficiency syndrome (AIDS). Untreated, the infection can lead to dissolution of both the immunological and central neurological systems. A fraction of the world population of HIV-infected individuals is receiving medications that diminish the peripheral viral burden, but it remains unclear whether drug inaccessibility to the brain and the inability to eliminate existing virus will, in the long-term, lead to increased neurological complications. Preliminary findings indicate that neurological pathologies will remain a consequence of HIV infection. HIV is a lentivirus, a subgroup of retroviruses that uniformly cause CNS disease. Part of this issue of Current HIV Research is focused on our present scientific understanding of neuroAIDS. Nunn provides an overview of neuroAIDS with respect to the scientific and clinical questions being addressed and the present day status of neuroAIDS in the global HIV epidemic [1]. Bell et al. provide an introduction to the component structures and cells of the brain and an overview of their involvement in HIV-induced pathologies [2] and Banks et al. summarize the major role that the blood brain barrier (BBB) plays in establishing and maintaining virus within the CNS and the consequential dysfunction [3]. Dunfee et al. discuss neurotropism of HIV and the dynamic interactions between the evolving virus and the macrophage/microglial brain cells [4]. Ciborowski and Gendelman discuss the central role of mononuclear phagocytes in the development of HIVassociated dementia (HAD) and describe approaches to define the molecular events and biomarkers for HAD [5]. Neurological diseases and productive lentiviral replication in the CNS occur in both rodent and primate macrophages. Zink et al. describe the characterized members of the lentiviral genus that infect varied animals, their similarities and differences and how they may serve as models for understanding HIV infection [6]. Kaul and Lipton describe the complex cellular interplay that potentially contributes to neuronal death in association with HIV-1 disease and discuss recent and prospective approaches for therapy and prevention of HAD [7]. Lastly, Schwartz and Major [8] compare the clinical syndromes of AIDS-dementia complex (ADC) in adults and HIV-associated progressive encephalopathy (PE) in pediatric patients, and they discuss the potential role of neural progenitors in HIV-mediated brain disease. As co-editors of this issue of Current HIV Research, we are very grateful for the time and effort that all of the authors and coauthors have committed to each review article. Furthermore, we hope that the reader will be stimulated by this collection of insightful review articles. REFERENCES [1] Nunn MF. (2006). NeuroAIDS: A Neuroscience Problem with Global Impact. Current HIV Research. 4:245-247. [2] Bell JE, Anthony IC, Simmonds P. (2006). Impact of HIV on Regional & Cellular Organisation of the Brain. Current HIV Research. 4: 249-257. [3] Banks WA, Ercal N, Price TO. (2006). The Blood-Brain Barrier in NeuroAIDS. Current HIV Research. 4: 259-266. [4] Dunfee R, Thomas E, Gorry PR, Wang J, Ancuta P, Gabuzda D. (2006). Mechanisms of HIV-1 Neurotropism. Current HIV Research. 4: 267-278. [5] Ciborowski P, Gendelman HE. (2006). Human Immunodeficiency Virus-Mononuclear Phagocyte Interactions: Emerging Avenues of Biomarker Discovery, Modes of Viral Persistence and Disease Pathogenesis. Current HIV Research. 4: 279-291. [6] Zink MC, Laast VA, Helke KL, Brice AK, Barber SA, Clements JE, Mankowski JL. (2006). From Mice to Macaques - Animal Models of HIV Nervous System Disease. Current HIV Research. 4: 293-305. [7] Kaul M, Lipton SA. (2006). Mechanisms of Neuronal Injury and Death in HIV-1 Associated Dementia. Current HIV Research. 4: 307-318. [8] Schwartz L, Major EO. (2006). Neural Progenitors and HIV-1- Associated Central Nervous System Disease in Adults and Children. Current HIV Research. 4: 319-327.

Early in the HIV/AIDS epidemic, it was recognized that there were many syndrome-defining illnesses involving the nervous system, including peripheral neuropathies and dementia, opportunistic infections of the central nervous system (CNS) such as cryptococcal and tubercular meningitis, and progressive multifocal leukencephalopathy (PML). Fast on the heels of the discovery of HIV-1 as the causative agent for AIDS, several studies pointed to the viral envelope glycoprotein gp120 as a principal suspect for neuropathology [1,7]. The neurotoxic potential of other viral proteins has also been demonstrated, most notably Tat, however the mechanisms for delivery of these viral proteins into the central nervous system remain unclear [10]. The obvious vehicle for virus delivery to the brain would be an HIV infected T-cell, the predominant source for HIV in the periphery, yet it has been difficult to demonstrate the presence of these cells in CNS tissue. Instead, infected perivascular macrophages and microglia are often found in brain tissue from patients with viral encephalitis or HIV-associated dementia (HAD) [15,17]. Although there is clearly neuronal loss in HAD, neurons and oligodendrocytes are not infected directly by HIV. Astrocytes can be infected but without the production of virus. This profile of cellular tropism in CNS infection is consistent with several other animal lentiviruses that infect monocytic cells exclusively over T-cells [2]. The background outlined above will be discussed in much more detail in the articles to follow. While macrophages/monocytes and activated glial cells have recently taken center stage in the study of the neuropathogenesis of HIV, several key questions in HIV neurovirology remain. First, what is the mechanism by which HIV causes neuronal cell death? It remains unclear whether HAD is the product of a chronic neuroinflammatory environment set up in the course of HIV infection, or is due instead to the direct toxicity of viral gene products. Both mechanisms may ultimately be important. It is possible that traffic of HIV-infected monocytes into the CNS early in the course of the disease establishes a chronic inflammatory environment and activation of the innate immune system. This inflammation would lead to the eventual recruitment of other components of the cellular immune response to the brain, including T-cells and the potent neurotoxic viral strains that infect them. Breakdown of the neuroprotective blood-brain barrier some time in the course of disease may also be important for neuropathogenesis. Studies of animal models for neuroAIDS such as SIV infection in the macaque [3,18] or a recently developed HIV/MLV chimera which can infect the CNS of mice [11] will surely provide important answers toward understanding the mechanisms of HIV neuropathogenesis. A second question, the focus of significant efforts in neuroAIDS, is whether the CNS can serve as an immunologically and therapeutically privileged reservoir for harboring HIV. Many current anti-retroviral drugs may have limited diffusion or transport across the blood-brain barrier into the CNS [9]. Do drug-resistant viruses develop in this environment, and if so, can HIV from the CNS affect the course of patient treatment and outcomes? A recent study from Hawaii has demonstrated that patients with HAD receiving highly active antiretroviral therapy (HAART) had significantly higher levels integrated HIV provirus in peripheral blood mononuclear cells when compared to matched HAD-negative controls [14]. This finding suggests the possibility that the CNS could serve as a source of HIV-infected monocytes when there is active replication of HIV in the brain. If the CNS is a reservoir for active viral replication it is hoped that this virus can be eliminated through the development of improved HAART components with better CNS penetration or other therapeutic strategies eliminating HIV-infected cells. It is also unclear whether there is latent, non-replicating virus within the CNS. The non-productive infection of astrocytes or perhaps brain progenitor cell populations might provide such a host for latent HIV [6]. Will HAART therapy will eventually eliminate the neurological complications of AIDS? With the advent of protease inhibitors and combination therapy for HIV the landscape of HIV/AIDS neurological disorders has certainly changed. In the developed world, where HAART therapy is widely available, the incidence of opportunistic infections in the CNS of AIDS patients has declined with the rebound of their immune function. Over the past decade the incidence of HAD has also decreased. Despite these successes, some studies suggest the overall prevalence of HAD may be increasing as patients survive longer living with HIV/AIDS [4]. Peripheral neuropathies also remain a problem for patients [5]........

There are many excellent reviews of HIV infection of the nervous system. However these all assume that the reader has a working knowledge of the structure and cellular architecture of the brain. It may be that specialised brain vocabulary represents an unwelcome hurdle for those scientists with expert knowledge of the effects of HIV in other cell systems and who wish to extend that interest to the brain. This review provides an introduction to the component structures and cells of the brain and an overview of their involvement in HIV/AIDS. HIV infection leads to death through its capacity to progressively devastate the immune system. Current anti-HIV therapy has achieved considerable success in halting and partially reversing this process. In the absence of treatment, the breakdown of immunity is marked by declining CD4 counts and increasing vulnerability to opportunistic infections. In parallel with these effects on the lymphoid system, the nervous system is frequently the site of an initially stealthy infection which leads ultimately to symptomatic disease in a significant proportion of HIV infected individuals. The most feared manifestation of central nervous system (CNS) involvement is dementia. Unfortunately, serial CD4 counts and measurement of blood viral load do not serve to identify or monitor early infection of brain tissue. Since effective anti-HIV therapy has not achieved eradication of virus from lymphoid tissues, and anti-HIV drugs do not enter the nervous system easily, it is hardly surprising that HIV infection of the nervous system continues to cause clinical problems. Even in treatmentcompliant patients, a measurable degree of cognitive impairment may develop, signalling previous or present HIV-related brain injury. The cause of HIV associated dementia and cognitive disability remains poorly understood. Perhaps most significantly, the long-term consequences of clinically occult brain infection are unknown and will require further investigation.

Nearly every aspect of blood-brain barrier (BBB) function is involved in or affected by HIV-1. The disruption of the BBB tends to be minimal and is not likely the mechanism by which infected immune cells and virus enter the brain. Instead, immune cells, virus and viral proteins likely activate brain endothelial cells and enable their own passage across the BBB by way of highly regulated processes such as diapedesis and adsorptive endocytosis. Viral proteins and cytokines can enter the CNS from the blood and provide a mechanism by which HIV-1 can affect CNS function independent of viral transport. Brain endothelial cells can also secrete neuroimmunoactive substances when stimulated by HIV-1, gp120, and Tat. Efflux systems such as p-glycoprotein transport anti-virals in the brain-to-blood direction, thus hampering effective accumulation of drug by the CNS. Overall, the BBB plays a major role in establishing and maintaining virus within the CNS and neuroAIDS.

Human immunodeficiency virus type 1 (HIV) infects macrophages and microglia in the CNS and frequently causes neurocognitive impairment. Although antiviral therapy generally reduces the viral load in the CNS and improves HIV-associated neurological dysfunction, most current antiviral drugs have poor CNS penetrance and cannot completely suppress viral replication. Furthermore, drug-resistance mutations can evolve independently in the CNS. Thus, a longlived viral reservoir persists in macrophages and microglia in the brain despite antiviral therapy. This review discusses mechanisms underlying the neurotropism of HIV, focusing on the role of the HIV envelope glycoproteins and their interactions with CD4 and the chemokine receptors CCR5 and CXCR4. We review data from studies of neurotropic HIV derived from the brains of patients with HIV-associated neurocognitive impairment as well as studies of nonhuman primate models. Understanding mechanisms that underlie HIV neurotropism and neurovirulence is critical for development of therapeutics to inhibit CNS infection and preventing neurological injury in HIV-infected individuals.

Mononuclear phagocytes (MP; bone marrow monocyte-derived macrophages, histiocytes, alveolar macrophages, Kupffer cells, perivascular macrophages, and microglia) function as sentry and surveillance cells by acting as debris scavengers, killers of microbial pathogens, and regulators of immune responses. Interestingly, these same cells are reservoirs and vehicles of dissemination for the human immunodeficiency virus (HIV). How virus alters the MP immunoregulatory activities so it can complete its own life cycle and affect disease is only recently being unravelled. Physiologic, anatomic and functional changes also underlie virus-MP interactions and include multinucleated giant cell formation, changes in ion channel expression and cell volume, and robust secretory responses with the production of numerous secretory factors affecting tissue injury. The balance between such MP activities and ability to both mobilize an adaptive immune response to thwart viral growth underlies the progression of viral infection and clinical disease. This review serves to discuss the functions of MP in HIV disease by bringing together what is known with what remains unknown. The advent of functional genomics and proteomics has opened the ways to address the intricacies of viral-host interactions and has provided new avenues for therapeutic interventions and disease monitoring that takes advantage of specific intracellular relationships between the virus and its host cell.

Lenviviral diseases of animals have been recognized for over a century, long before HIV was recognized as the cause of AIDS. All lentiviruses cause neurological disease and productive virus replication in the CNS occurs exclusively in cells of macrophage lineage. The ability to molecularly engineer the inoculum virus, to sample the brain at many different time points from acute through terminal infection and to correlate in vivo with in vitro findings are significant advantages of animal models of HIV CNS disease. The lentiviruses can be divided into two pathogenetic groups - those that cause immunosuppression, including the lentiviruses of humans (HIV), non-human primates (SIV), cats (FIV), and cattle (BIV), and those that cause immunoproliferation, including the lentiviruses of horses (EIAV), sheep (OvLV) and goats (CAEV). Despite extensive study, no rodent lentivirus has been identified, prompting development of alternate strategies to study lentiviral pathogenesis using rodents. The immunosuppressive lentiviruses most closely recapitulate the disease manifestations of HIV infection, and both SIV and FIV have contributed significantly to our understanding of how HIV causes both central and peripheral nervous system disease.

Infection with the human immunodeficiency virus-1 (HIV-1) and acquired immunodeficiency syndrome (AIDS) remain a persistent and even growing health problem worldwide. Besides its detrimental systemic effects on the immune system, HIV-1 seems to enter the brain very soon after peripheral infection and can induce severe and debilitating neurological problems that include behavioral abnormalities, motor dysfunction and frank dementia. Infected peripheral immune cells, in particular macrophages, appear to infiltrate the CNS and provoke a neuropathological response involving all cell types in the brain. Both viral and host factors, such as the viral strain and the response of the host's immune system, strongly influence the course of HIV-1 disease. Moreover, HIV-1-dependent disease processes in the periphery have a substantial effect on the pathology developing in the central nervous system (CNS), although the brain eventually harbors a distinctive viral population of its own. In the CNS, HIV-1 also initiates activation of chemokine receptors, inflammatory mediators, extracellular matrix-degrading enzymes and glutamate receptor-mediated excitotoxicity, all of which can activate numerous downstream signaling pathways and disturb neuronal and glial function. Although there have been substantial improvements in the control of viral infection in the periphery, an effective therapy for HIV-1 associated dementia (HAD) is still not in sight. This article will review recently identified injurious mechanisms potentially contributing to neuronal death in association with HIV-1 disease and discuss recent and prospective approaches for therapy and prevention of HAD.

The human immunodeficiency virus type 1 (HIV-1) is a neurotrophic lentivirus that enters and infects the central nervous system (CNS) of adults and children, giving rise to the clinical syndromes of AIDS-dementia complex (ADC) in adults and HIV-1-associated progressive encephalopathy (PE) in pediatric patients. The clinical presentation and progression of neuroAIDS in the developing brain of children is distinct from that seen in adult patients. Neuroimaging, and upon autopsy, neuropathological findings corresponding to clinical disease in pediatric patients include impaired brain growth, reactive gliosis, myelin pallor, calcifications of the basal ganglia, cortical and cerebral atrophy with neuronal loss and ventricular enlargement, and abnormalities of cerebral vasculature. Although there is some overlap with neuropathologic findings in adult patients, ADC in adults is more typically a late development, often complicated by opportunistic infections of the CNS. The neuropathogenesis of ADC and PE is incompletely understood. One population of CNS cells critical for brain development and response to injury and inflammation are neural progenitors cells, and it has therefore been suggested that these cells may be involved in the neuropathogenesis of ADC, and especially PE. This review examines the neurobiology of neural progenitor cells and the possibility that HIV-1 infection of neural progenitors, exposure of neural progenitors to virus, viral products, or progenitor exposure to HIV-1 associated neuroinflammatory substances and neurotoxins might contribute to the neuropathogenesis of AIDS in adults and children. That some of the clinical differences between ADC and PE might, in part, be explained by differences in neural progenitor involvement will also be considered.

Non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTI) are an integral part of combination therapy comprising three classes of antiretroviral drugs for the management of HIV/AIDS. NNRTIs are chemically diverse compounds that bind to a common allosteric site of HIV-1 RT and noncompetitively inhibit DNA polymerization. Resistance to NNRTIs arises rapidly upon drug treatment and results from mutation of the amino acids lining the HIV-1 RT binding pocket. Nevertheless, rationally designed NNRTIs deduced from changes in binding pocket size, shape, and residue character that result from clinically observed NNRTI resistance mutations exhibit broad-spectrum anti-HIV-1 activity. Notably, membrane permeable tight binding NNRTIs have utility as topical microbicides since they are capable of blocking cell-free and cell-associated mucosal HIV-1 infection without metabolic activation. This review summarizes the discovery of highly potent tight binding phenethyl-thiazolyl-thiourea (PETT) derivatives targeting the NNI binding pocket of HIV-1 RT. These NNRTIs were rationally designed by molecular docking using a composite binding pocket constructed by superimposing the crystal structure coordinate data of several NNI/RT ligand-binding site complexes. Molecular modeling and score functions such as molecular surface area, the buried surface, and binding affinity values were used to analyze how drug-resistant mutations would change the RT binding pocket shape, volume, and chemical make-up of these NNRTIs, and how these changes could affect drug binding. Several ligand derivatization sites were identified for docked compounds that fit the binding pocket. The best fit was determined by calculating an inhibition constant (Ludi Ki) of the docked compound for the composite binding pocket. Compounds with a Ludi Ki of >1 μM were identified as the most promising tight binding NNRTIs. This review highlights novel lipophilic thiourea NNRTIs that display high binding affinity and selective indices with robust anti-HIV-1 activity against the wild type as well as drug-resistant isolates carrying multiple RT gene mutations. The increasing prevalence of drug-escape mutants among recent HIV seroconverters makes the discovery of these broad-spectrum thiourea NNRTIs useful as a component of topical microbicide for the prevention of mucosal HIV transmission.

Acquired immunodeficiency syndrome (AIDS), a degenerative disease of the immune and central nervous systems, is an enormous world-wide health threat. No cure has been found, and research is aimed at developing chemotherapy against the causative agent, human immunodeficiency virus (HIV). Chemotherapy for AIDS has progressed steadily in the past decade. However, new, effective, and less toxic chemotherapeutic agents are still needed. Plants, particularly anti-infective or immunomodulating herbal medicines, can serve as sources of new active leads to be further developed as anti-AIDS drug candidates. A lot of structurally different natural coumarins were found to display potent anti-HIV activity and continued progress is anticipated in the discovery of new leads and in the development of these agents as potential anti-AIDS drug candidates. Recent studies based on the account of various coumarins from plant sources and their analogs- synthetic coumarins, indicate that some of them serve as potent nonnucleoside RT-inhibitors, another as inhibitors of HIV-integrase or HIV-protease. The current review demonstrates the variety of coumarins of natural plant origin and synthetic coumarins having unique mechanism of action to one of the most important stage of HIV replication (RTinhibition). The merits of selecting potential anti-HIV agents to be used in rational combination drugs design and structure- activity relationships are discussed. The scientific community is looking actively for new drugs and combinations for treatment of HIV infection effective for first-line treatment, as well as against drug-resistant mutants.

Variability, both at the population (interhost) as well as at the individual (intrahost) level is a key property of HIV that stems mainly from the inherent infidelity of the reverse transcriptase enzyme that the virus uses to transcribe its RNA genome into DNA so that it may be integrated into the human genetic material and propagated along with it. The lack of proofreading mechanisms, high turnover of virions, and propensity for recombination also contribute to the extensive variability of HIV. These parameters provide the virus quasispecies with an impressive capacity to adapt to immunologic, pharmacologic or other selection pressures and have important implications for the diagnosis of new infections, the monitoring of antiretroviral treatment response, and effective vaccine(s) design. Herein, we discuss in detail the global genetic variation of HIV-1 infection.

Highly active retroviral therapy (HAART) has been in widespread use in the United States since 1996. We sought to determine how the use of HAART influenced survival among patients with acquired immunodeficiency syndrome (AIDS) and primary central nervous system (CNS) non-Hodgkin's lymphoma (NHL). We used the populationbased San Diego and Orange County cancer registry to identify 94 patients with both AIDS and CNS NHL diagnosed 1994-1999, of whom 31 were diagnosed 1996-1999. We performed Kaplan-Meier analyses to compare survival between patients who received HAART at NHL diagnosis or thereafter versus untreated patients and Cox proportional hazard models for adjusted survival. Among the patients diagnosed with NHL in 1996-1999, seven (23%) were taking HAART at the time of NHL diagnosis. Median survival was eight months for those who received HAART at the time of lymphoma diagnosis or after, versus one month for untreated patients. HAART, radiation therapy, and better performance status were associated with improved survival. We conclude that HAART prolongs survival in AIDS-related CNS NHL.

There is a continued need to develop inexpensive and effective drugs specific for novel targets of human immunodeficiency virus type 1 (HIV-1). The HIV-1 nucleocapsid p7 (NCp7) protein plays a critical role in early and late stages of the virus life cycle and possesses two highly conserved retroviral zinc fingers that are essential for its function. We have previously shown that zinc finger inhibitors (ZFI) based on the S-acyl 2-mercaptobenzamide thioester (SAMT) chemotype specifically target HIV NCp7 and are effective at reducing levels of infectious virus in an HIV-1-transgenic mouse model. Here, we did an initial proof-of-concept study to test the potential of a lead SAMT compound to reduce virus infectivity in the simian immunodeficiency virus (SIV) nonhuman primate model. SAMT-19 had potent antiviral and virucidal effects against the primary pathogenic isolate SIV/DeltaB670 and was non-cytotoxic in vitro. Cynomolgus macaques were infected intrarectally with SIV/DeltaB670 and treated with a low dose of SAMT-19 by continuous infusion from day 8 to day 28 post infection. Monkeys in the treatment group had significantly lower levels of infectious virus in peripheral blood mononuclear cells during the course of therapy as compared to monkeys in the control group, although therapy had no demonstrable effect on virus load. SAMT-19 therapy did not alter liver, kidney or immunologic function and was well tolerated by all treated monkeys. These data demonstrate that SAMT-19 is safe and virucidal in the nonhuman primate model. Further studies directed at optimizing SAMT bioavailability and pharmacokinetics likely will result in enhanced therapeutic efficacy of this promising HIV therapeutic.