Current HIV Research - Volume 14, Issue 5, 2016

If we have any hope of achieving a cure for HIV infection, close attention to the cell types capable of getting infected with HIV is necessary. Of these cell types, astrocytes are the most ideal cell type for the formation of such a reservoir. These are long-lived cells with a very low turnover rate and are found in the brain and the gastrointestinal tract. Although astrocytes are evidently resistant to infection of cell-free HIV in vitro, these cells are efficiently infected via cell-tocell contact by which immature HIV virions bud off lymphocytes and have the ability to directly bind to CXCR4, triggering the process of fusion in the absence of CD4. In this review, we closely examine the evidence for HIV infection of astrocytes in the brain and the mechanisms for viral entry and regulation in this cell type, and discuss an approach for controlling this viral reservoir.

HIV infection among AIDS patients is associated with dysfunctions in the central nervous system (CNS) at the late stages of the disease. HIV Tat protein is released extracellularly from the productively infected cells and play important role in successful HIV replication and activates the neighboring uninfected cells in the bystander fashion. The structural flexibility of Tat protein is one of the unique features, responsible for the diverse functions. The RNA binding ability and interacting domains are very important characteristic of the HIV-Tat protein. HIV Tat protein adversely affects the integrity of the blood brain barrier by a variety of mechanisms. Such compromise in the integrity of the blood brain barrier could affect the neuro-immune interactions within the brain, which results to the neuroinflammation.

Background: Over the past three decades, the clinical presentation of HIV infection of the Central Nervous System (CNS) has evolved. Prior to wide spread use of effective antiretroviral therapy (ART), more than a third of infected individuals exhibited a range of neurocognitive and motor deficits that frequently progressed to severe dementia and paralysis. However, the use of ART has significantly decreased the prevalence of severe forms of HIV-1 associated neurocognitive disorders (HAND). Studies of neurocognitive dysfunction have reported variable prevalence, ranging from 21% to 77.6%, defined primarily by mild to moderate neurocognitive impairment. HIV-associated chronic inflammation and associated neurotoxicity of long term ART, as well as the aging of the HIV-infected population, likely influence the pathogenesis of HAND. Despite significant research efforts directed towards a better understanding of the mechanisms underlying HIV neuropathogenesis, definitive causal pathophysiology of HAND and thus effective prevention or treatment remain elusive. Furthermore, HIV therapeutic research now includes efforts to effect a cure, by eliminating or silencing HIV within infected cells, which must include efforts to target the latently infected cells within the CNS. Conclusion: Prevention and treatment of the neurological complications of HIV, and eradication of persistent virus from the CNS compartment are major priorities for the HIV-CNS research. Here we give an overview of the progress of research on HIV-CNS disease, define new challenges and research areas, and highlight domestic and global priorities.

Background: One of the major complications of Human Immunodeficiency Virus (HIV) infection is the development of HIV-Associated Neurocognitive Disorders (HANDs) in approximately 50-60% of HIV infected individuals. Despite undetectable viral loads in the periphery owing to anti-retroviral therapy, neuroinflammation and neurocognitive impairment are still prevalent in HIV infected individuals. Several studies indicate that the central nervous system (CNS) abnormalities observed in HIV infected individuals are not a direct effect of viral replication in the CNS, rather these neurological abnormalities are associated with amplification of HIV specific signals by unknown mechanisms. We propose that some of these mechanisms of damage amplification are mediated by gap junction channels, pannexin and connexin hemichannels, tunneling nanotubes and microvesicles/exosomes. Objective: Our laboratory and others have demonstrated that HIV infection targets cell to cell communication by altering all these communication systems resulting in enhanced bystander apoptosis of uninfected cells, inflammation and viral infection. Here we discuss the role of these communication systems in HIV neuropathogenesis. Conclusion: In the current manuscript, we have described the mechanisms by which HIV “hijacks” these host cellular communication systems, leading to exacerbation of HIV neuropathogenesis, and to simultaneously promote the survival of HIV infected cells, resulting in the establishment of viral reservoirs.

Background: While the advancement of highly active antiretroviral therapy (HAART) has transformed the course of HIV/AIDS from a death sentence to a manageable chronic condition, the prevalence of a constellation of neurological disorders collectively termed as HIV-associated neurocognitive disorders (HAND) continues to persist in these patients. HAND is characterized by cognitive dysfunction, depression, impaired memory and/or deficits in motor skills. The underlying factors leading to HAND have been the subject of extensive research and are thought to be associated with HIV infection in the CNS combined with robust immune activation of resident cells of the CNS. In addition, there is a strong correlation between chronic substance abuse and the manifestation of HAND. Among the various commonly abused drugs, cocaine has been extensively studied for its ability to exacerbate the neuropathogenesis of HAND. Ample evidence suggests that cocaine not only facilitates viral replication in macrophages and microglia, but also inflicts deleterious effects on various other cells of the CNS, thereby contributing to the potentiation of HAND. Cocaine has been shown to enhance the permeability of the blood-brain barrier (BBB) through various mechanisms including direct pro-apoptotic effects on brain endothelial cells, systemic induction of inflammatory factors which have been demonstrated to down-regulate tight junction proteins and via up-regulation of several endothelial adhesion molecules leading to accelerated breach of the BBB and increased influx of HIV-infected leukocytes into the CNS. Cocaine also enhances viral replication in CNS astrocytes and promotes astrogliosis via astrocyte activation and proliferation. Furthermore, cocaine also exacerbates neuroinflammatory responses by mediating microglial activation and migration. In addition to cellular injury mediated by inflammatory responses, cocaine also directly affects the brain reward system by disrupting the homeostasis of neurotransmitters such as dopamine and acetylcholine and works synergistically with viral proteins such as tat and gp120 to promote neuronal injury. Conclusion: This review highlights previous studies in the field on the role of cocaine in the progression of HAND and gives an overview of the major signaling pathways in the CNS that are involved in this process.

Background: HIV-1 enters the CNS within two weeks after peripheral infection and results in chronic neuroinflammation that leads to HIV associated neurocognitive disorders (HAND) in more than 50% of infected people. HIV enters the CNS by transmigration of infected monocytes across the blood brain barrier. Intravenous drug abuse is a major risk factor for HIV-1 infection, and opioids have been shown to alter the progression and severity of HAND. Methadone and buprenorphine are opioid derivates that are used as opioid maintenance therapies. They are commonly used to treat opioid dependency in HIV infected substance abusers, but their effects on monocyte migration relevant to the development of cognitive impairment are not well characterized. Conclusion: Here, we will discuss the effects of opioids and opioid maintenance therapies on the inflammatory functions of monocytes and macrophages that are related to the development of neuroinflammation in the context of HIV infection.

Background: It is well established that antiretroviral therapy (ART), while highly effective in controlling HIV replication, cannot eliminate virus from the body. Therefore, the majority of HIV-1-infected individuals remain at risk for developing AIDS due to persistence of infected reservoir cells serving as a source of virus re-emergence. Several reservoirs containing replication competent HIV-1 have been identified, most notably CD4+ T cells. Cells of the myeloid lineage, which are the first line of defense against pathogens and participate in HIV dissemination into sanctuary organs, also serve as cellular reservoirs of HIV-1. In latently infected resting CD4+ T cells, the integrated copies of proviral DNA remain in a dormant state, yet possess the ability to produce replication competent virus after cellular activation. Studies have demonstrated that modification of chromatin structure plays a role in establishing persistence, in part suggesting that latency is, controlled epigenetically. Conclusion: Current efforts to eradicate HIV-1 from this cell population focus primarily on a "shock and kill" approach through cellular reactivation to trigger elimination of virus producing cells by cytolysis or host immune responses. However, studies revealed several limitations to this approach that require more investigation to assess its clinical application. Recent advances in gene editing technology prompted use of this approach for inactivating integrated proviral DNA in the genome of latently infected cells. This technology, which requires a detailed understanding of the viral genetics and robust delivery, may serve as a powerful strategy to eliminate the latent reservoir in the host leading to a sterile cure of AIDS.

Background: There is a strong correlation between the use and abuse of illicit drugs and the spread of Human Immunodeficiency Virus (HIV). It is well established that illicit drugs users are a high risk population for infection with HIV with an increased rate of HIV transmission and replication. Cocaine, amphetamine, methamphetamine, heroin and morphine stand out as the most frequently abused illicit drugs and their use correlates well with HIV infection and AIDS progression. Notably, the high incidence of HIV infection in illicit drug abusers is primarily due to high risk activities such as needle sharing and unprotected sex. Several studies have also demonstrated that drugs of abuse increase viral RNA concentrations by enhancing HIV replication, in particular in the central nervous system (CNS). The CNS is a common target for both drugs of abuse and HIV, and their synergistic action accelerates neuronal injury and cognitive impairment. In order to generate complete genomic transcripts, HIV gene expression has to progress through both the initiation and elongation phases of transcription, which requires coordinated action of different transcription factors. Conclusion: In this review, we will provide the latest updates of the molecular mechanisms that regulate HIV transcription and discuss how drugs of abuse, such as cocaine, amphetamine, methamphetamine, heroin and morphine, modulate those mechanisms to upregulate HIV transcription and eventually HIV replication.