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Viral and cellular factors underlying neuropathogenesis in HIV associated neurocognitive disorders (HAND)

Vasudev R Rao, Arthur P Ruiz, Vinayaka R Prasad

AIDS Research and Therapy · 2014 · Review

doi:10.1186/1742-6405-11-13 (opens in a new tab)

Abstract

As the HIV-1 epidemic enters its fourth decade, HIV-1 associated neurological disorders (HAND) continue to be a major concern in the infected population, despite the widespread use of anti-retroviral therapy. Advancing age and increased life expectancy of the HIV-1 infected population have been shown to increase the risk of cognitive dysfunction. Over the past 10 years, there has been a significant progress in our understanding of the mechanisms and the risk factors involved in the development of HAND. Key events that lead up to neuronal damage in HIV-1 infected individuals can be categorized based on the interaction of HIV-1 with the various cell types, including but not limited to macrophages, brain endothelial cells, microglia, astrocytes and the neurons. This review attempts to decipher these interactions, beginning with HIV-1 infection of macrophages and ultimately resulting in the release of neurotoxic viral and host products. These include: interaction with endothelial cells, resulting in the impairment of the blood brain barrier; interaction with the astrocytes, leading to metabolic and neurotransmitter imbalance; interactions with resident immune cells in the brain, leading to release of toxic cytokines and chemokines. We also review the mechanisms underlying neuronal damage caused by the factors mentioned above. We have attempted to bring together recent findings in these areas to help appreciate the viral and host factors that bring about neurological dysfunction. In addition, we review host factors and viral genotypic differences that affect phenotypic pathological outcomes, as well as recent advances in treatment options to specifically address the neurotoxic mechanisms in play.

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From PubMed Central, U.S. National Library of Medicine, as current on Oct 24, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

1HIV associated neurocognitive disorders (HAND) are a potential consequence of HIV-1 infection, and about half of all adults with AIDS suffer from neurological complications related to HIV-1. HIV-1 infection plays a pivotal role in HAND by generating products that lead to neurological damage in the central nervous system (CNS). HAND includes a spectrum of neurological disorders ranging from asymptomatic neurocognitive impairment (ANI), an intermediate form termed mild neurocognitive disorder (MND) and the severe form, HIV associated dementia (HAD). The relationship between the prevalence of these forms to each other and their occurrence in the overall population of HIV-1-infected individuals can be depicted in a pyramidal form, with the total number of HIV-1-infected individuals forming the base, with the upper layers having progressively fewer numbers of patients exhibiting ANI, MND and HAD. As the availability of highly active anti-retroviral therapy (HAART) has become more widespread worldwide, HIV-1-infected individuals are living longer. Although the incidence and prevalence of HAD have been reduced in the era of HAART, the prevalence of HAND overall is actually increasing worldwide. The increased lifespan of treated patients results in a chronic exposure of the brain to HIV-1 virions and viral proteins leading to inflammation, as well as a concomitant chronic inflammation in the peripheral immune system, leading to the accumulation of neurological damage. The success of HAART in controlling peripheral viral load is not necessarily accompanied by reduction in the immune activation in the brain.

Overview of HIV neuropathogenesis

2Before embarking on delineating the viral and host factors that play central roles in HAND, it is helpful to have an understanding of the current working model for a mechanistic basis of HIV neuropathogenesis. Infiltration of monocytes into the brain is a hallmark of HAND. Monocyte-derived macrophages (MDM) are one of the major types of cell that are infected by HIV-1 (CD4+ T lymphocytes and dendritic cells being the other two cell types). Once the HIV-1-infected macrophages have established residence in the CNS, they secrete chemokines that establish a chemotaxis gradient across the blood–brain barrier (BBB), which recruits more monocytic cells from the peripheral compartment into the CNS. This influx of HIV-1-infected monocytic cells leads to the infection of other CNS-resident monocytic cells, namely perivascular macrophages and microglia, which in turn results in greater BBB damage and accelerates the rate at which HIV-1-infected and uninfected monocytic cells can enter the brain. Neurons do not support HIV-1-infection or replication, but they do express several cell-surface receptors (CCR5, CXCR4, NMDAR etc.) that render them sensitive to insults by viral proteins (e.g. Tat, gp120), inflammatory cytokines (e.g. TNF-α, IL1β) and small metabolites (e.g. nitric oxide, arachidonic acid, etc.) secreted by immune cells in the brain. The key events that contribute to HAND include direct neuronal apoptosis, dysregulation of key neuronal support cells, and the loss of dendritic arbor.

HIV-1 infection of Macrophages

3The process of HIV-1 infection begins by HIV-1 binding to CD4 receptor on the target cell surface, through the viral envelope protein gp120. This binding induces a conformational change in gp120 that exposes a CD4-binding induced (CD4i) co-receptor binding site, which subsequently binds to either CCR5 or CXCR4 coreceptor. The binding of gp120 to a co-receptor then exposes the fusion peptide in viral protein gp41, which is inserted into the cell membrane and drives fusion of the viral and cell membranes. The co-receptor preference, which is determined primarily by the V3 loop in gp120, designates a given HIV-1 isolate as either an R5 or X4 virus depending upon whether it uses CCR5 or CXCR4 coreceptor. Based on the fact that CCR5Δ32 mutation confers resistance to HIV-1 transmission, the field has come to the conclusion that only R5 viruses are transmissible and are the type of viruses detected systemically early in infection. However, later as the disease progresses, the predominant tropism switches to CXCR4-usage, at least in some of the cases (approximately 50%). CXCR4 usage is associated with faster viral replication and a more rapid CD4+ T-cell decline. However, this switch is not obligatory for disease progression, as exceptions are observed in some parts of the world where non-B subtypes of HIV-1 are prevalent.

4HIV-1 can productively infect both CD4+ T lymphocytes and monocytic cells/macrophages. Infection of monocytic/macrophage cells is primarily by M-tropic viruses driving fusion through the CCR5 coreceptor, but infection by T-tropic viruses through the CXCR4 coreceptor has also been observed. While dendritic cells can also be infected by HIV-1, they do not support robust HIV-1 replication. However, they do play a crucial role in the systemic spread of HIV-1 due to their strategic presence in lymph nodes. HIV-infection leads to a progressive decline in the population of CD4+ T cells, which is due to loss of both infected CD4+ T cells and uninfected cells (bystander killing). However, there is no systemic loss of monocytic cells, either infected or uninfected. It has been reported that monocytic/macrophage-tropic viruses, in addition to bearing gp120 that is able to recognize and bind CCR5 coreceptor, have evolved the capability to infect cells with a lower density of CD4 receptors on the cell surface and a greater fusion activity. Furthermore, macrophages are also characterized by the budding of virions into internal multivesicular bodies, which are vacuoles within the cells, rather than budding through the plasma membrane directly to the external medium. This mechanism allows HIV-1 to ‘hide’ inside the infected macrophages, making macrophages one of the latent reservoirs of HIV-1.

5The predominant route of CNS exposure to HIV-1 is through peripheral blood monocytic cells/macrophages that have been infected by virus and transmigrate across the blood–brain barrier (BBB). Peripheral blood monocytes are categorized into classical “resting” monocytes that express only CD14 (CD14++CD16-), intermediate monocytes that maintain high levels of CD14, while gaining CD16 positivity (CD14++ CD16+), and non-classical “activated” monocytes that express high CD16 levels and lower levels of CD14 (CD14+CD16++). The CD16++ subset, while comprising only about 5-10% of the total circulating monocyte population, is overrepresented in the brains of patients with HIV encephalopathy. CD16++ monocytes are more susceptible to HIV infection and support higher levels of viral replication. Additionally, infected CD16++ monocytes have been shown to transmigrate more efficiently across the BBB in response to a chemokine gradient. While CD4+ T lymphocytes have been suggested to play a role in trafficking HIV into the CNS, the vast majority of HIV-1 isolates derived from CNS tissue appear to be of macrophage-tropic lineage.

CNS invasion: disruption of the blood brain barrier

6The BBB is located at all points of interaction between the brain tissue and blood vessels and consists of astrocytic end feet and human brain microvascular endothelial cells (HBMEC). In addition to the barrier created by HBMECs and astrocytes, pericytes envelope the abluminal side of endothelium and increase the selectivity of the barrier. Pericyte density in the brain is much higher than that observed in other organs, thereby constituting an additional barrier. The BBB maintains the sanctity of the brain’s internal environment and provides an important physiologic and immunologic separation between the CNS and the peripheral circulation. HIV-1 infiltrates the BBB early after infection using HIV-infected monocytic cells as a “Trojan horse” for entry into brain. While low numbers of monocytes routinely enter the CNS as part of “immune surveillance” to replenish the population of resident macrophages, infection by HIV-1 increases the adherence of monocytes to endothelial cells, increasing their transmigration across the BBB. The HIV-infected macrophages in the vicinity of the BBB secrete inflammatory cytokines and viral products that damage HBMECs, induce cellular oxidative stress and they also produce chemokines like CCL2 that facilitate the build-up of additional immune cells near the barrier. The interplay between the secreted cytokines, viral products and HBMECs activates endothelial cells and increases surface expression of adhesion molecules on endothelial cells – which in turn accelerates the transmigration of infected macrophages across the BBB.

7HIV-1 proteins Tat and gp120 both directly damage the BBB (Figure 1). Tat is a non-structural viral protein secreted by infected cells. Tat mRNA, Tat protein and antibodies to Tat are detectable in the CNS of HIV-infected patients. Brain endothelial cells, when exposed to HIV-1 Tat, have been shown to alter the expression and distribution of tight junction proteins (claudins & occludins). Tat treatment of HBMECs in vitro up-regulates matrix metallopeptidase-9 (MMP-9), which in turn increases the permeability of brain endothelial cells by degrading occludins. In vitro two-chamber models with HBMECs and astrocytes have also shown HIV-1 Tat causes dysregulation of nitric oxide production in brain endothelial cells and induces secretion of CCL2, a key chemokine responsible for migration of immune cells.

8Even though brain endothelial cells that line the BBB are not productively infected, several in vivo and in vitro studies have demonstrated that envelope glycoprotein gp120 causes a functional impairment at the BBB. The gp120 protein is found on the surface of virions and on infected cells as a homo-trimer, but gp120 is also shed from infected cells and found in soluble form as a monomer. Studies involving HIV-1 gp120 transgenic mice, in which gp120 was expressed in thymocytes and the CNS, revealed that the permeability of the brain capillaries in mice is severely impaired. Kanmogne et al. demonstrated, using a two-chamber BBB model, that the exposure of HBMECs to recombinant HIV-1 gp120 protein (from either X4 and R5 HIV-1 isolates) led to activation of proinflammatory and interferon-inducible genes, increased leukocyte adhesion, decreased trans-endothelial electrical resistance (TEER) and increased migration of monocytes across the barrier. Removal of gp120 resulted in complete restoration of TEER and significant improvement in permeability. Exposure of HBMECs to gp120 in vitro resulted in increased expression of adhesion molecules (ICAM and VCAM), damage to the barrier and a consequent increase in monocyte migration across the monolayer of endothelial cells. There was a dose dependent increase in cytotoxicity of HBMECs when exposed to recombinant gp120, and gp120-mediated HBMEC cytotoxicity has been shown to involve the p38 mitogen-activated protein (MAP) kinase pathway.

9Thus, both HIV-1 proteins gp120 and HIV-1 Tat have been implicated in perturbing the blood–brain barrier. Delineating the precise roles of additional viral and host factors that directly perturb the BBB as well as identifying reliable biomarkers of BBB damage would be crucial to furthering our understanding of the mechanisms driving the pathology specific to the BBB in HAND. Such knowledge will accelerate the development of innovative treatment strategies, specifically aimed at preventing damage to the BBB and reducing the CNS invasion of infected macrophages.

Mechanisms of neuropathogenesis

10Although neurons cannot be infected by HIV-1, neuronal damage is a key feature in the development of HAND Neurons are vulnerable to direct damage by several viral proteins. This vulnerability is mainly mediated through the presence of several neuronal cell surface receptors: the N-methyl-D-Aspartate receptors (NMDAR), the low-density lipoprotein receptor related protein (LRP), chemokine receptors CCR5 and CXCR4, and the dopamine transporter. Glutamate is the most abundant neurotransmitter in the brain, and it is responsible for propagating excitatory signal transmission by binding to NMDAR and opening cation specific channels in the cell membrane, allowing ingress of sodium and calcium ions and the egress of potassium ions. LRP is a receptor involved in cholesterol trafficking in neurons, and also plays a role in signal transmission and inhibition of neuronal apoptosis. Dopamine receptors and transporters are less widespread than NMDAR, but are importantly found in areas of the brain that are prone to high levels of HIV-1 infection, such as the striatum and substantia nigra, which are involved in executive function and the behavioral reward system, and there are lower expression levels of dopamine transporter in the striata of HIV patients with cognitive deficits.

11The two major viral proteins that interact with the above receptors to cause neuronal injury are gp120 and Tat. Both monomeric and oligomeric gp120 have neurotoxic capabilities, and transgenic mice expressing gp120 have a spectrum of neuronal and glial changes resembling abnormalities in brains of HIV-1-infected humans. HIV-1 gp120 directly binds NMDAR on human embryonic neurons and can cause a lethal influx of calcium ions (Figure 2). HIV-1 gp120 can bind to either CCR5 or CXCR4 and induce death in neuroblastoma cells (Figure 2). This apoptosis apparently takes place through a p38-MAPK-mediated signaling cascade. Cognitive testing of gp120 transgenic mice showed age-dependent deficits in open field activity and spatial reference memory tests. The natural ligands of both CCR5 (eg. CCL5, CCL3) and CXCR4 (CXCL12) were found to be neuroprotective against gp120 neurotoxicity. However, CXCL12 displays neurotoxicity after the N-terminal cleavage of a tetrapeptide in CXCL12 by MMP-2. Another factor up-regulated by the interaction of gp120 with CXCR4 is the neuronal nicotinic receptor α7, which increases cellular permeability to [Ca2+] influx and contributes to cell death.

12The viral protein Tat also causes neurotoxicity via multiple pathways. Similar to gp120, Tat can activate NMDA receptors and drive the toxic influx of Ca2+ ions (Figure 3). In addition to calcium dysregulation through the NMDAR, Tat can induce the phospholipase C-driven activation of inositol 1,4,5-triphosphate, which increases the intracellular levels of [Ca2+] by mobilizing stores in the endoplasmic reticulum and contributes to calcium toxicity and cell death. Tat also binds LRP in neurons, causing LRP internalization and a decrease in uptake of natural LRP ligands such as amyloid-β peptide and Apolipoprotein E (Figure 3). The interaction of Tat with LRP can lead to the formation of an apoptosis-promoting complex including postsynaptic density protein-95 (PSD-95), NMDA receptors and neuronal nitric oxide synthase (nNOS). Tat has been found to interfere with the expression of miRNAs in neurons, increasing the levels of CREB-targeting miR-34a and leading to neuronal dysfunction. Tat can also interfere with the ability of dopamine transporter to reuptake dopamine. This likely contributes to the particularly severe damage rendered to dopaminergic-rich regions in the brains of patients with severe HAND.

13Other toxic viral proteins which have been found to activate caspases in neurons include Vpr and Nef. Vpu has been found to form cation-selective ion channels in a lipid bilayer membrane, though this effect has not been observed in neurons. Recently, stress pathways and accumulation of amyloid beta (Aβ) fibrils have been reported to be important in causing neuronal dysfunction. It has been suggested that an integrated stress response (ISR) pathway involving specific ISR proteins may underlie the neuroinflammatory processes observed in HAND. It has also been reported that individuals with HIV encephalitis display a higher levels of intraneuronal Aβ accumulation in comparison with controls, suggesting that HIV impacts the clearance of Aβ in the brain.

14Targeting the above discussed mechanisms of neuronal toxicity could yield therapies that can alleviate the symptoms and improve the quality of life for patients suffering from HAND.

Macrophage and microglial activation

15In addition to toxic viral proteins, HIV-1-infected macrophages and microglia release a variety of neurotoxic host factors that contribute to neuronal injury. These can be broadly categorized as proinflammatory cytokines, chemokines, and small molecules. The proinflammatory cytokines induced by HIV-1-infection of macrophages include TNF-α, IL-1β, IL-6, IL-8 and IFN-α. TNF-α has been shown to also inhibit glutamate uptake by astrocytes, leading to a extracellular buildup of glutamate that can lead to neuronal excitotoxicity. TNF-α has also been found to have a neuroprotective role, through the TNFR2 mediated activation of NF-κB through a PI3 kinase, so its role is more complicated than simply that of a neurotoxin. IL-1β is released from macrophages in response to protein kinases induced by gp120, and both IL-1β and TNF-α were found to dysregulate glutamate production in neurons through the induction of glutaminase. IL-6 is also directly induced in macrophages by gp120, and leads to the formation of large cytoplasmic vacuoles in neurons that disrupt neuronal function. Excess levels of IFN-α have been correlated with severity of HIV dementia. Treatment of MDM with IFN-α (or HIV-1 infection) has been reported to increase glutaminase (GLS1) expression through phosphorylation of STAT1, which was shown to act through GLS1 promoter. In addition to inflammatory cytokines, small molecules released by HIV-1-infected macrophages such as platelet activating factor (PAF) and quinolinic acid play a key role in neurotoxicity via NMDAR dysregulation.

16Microglia are mesoderm-derived cells whose population is established in the brain perinatally. They are responsible for immune surveillance of the CNS, and are the primary source of inflammatory cytokines in the brain. Infected microglia are thought to be the main source of giant multinucleated cells, which are a hallmark of HIV associated dementia and an important source of inflammatory cytokines in the CNS of HIV-1 patients. Microglia are a major source of neuronal excitotoxicity, releasing glutamate in response to HIV-1 infection. Even in patients who are able to effectively control HIV infection via ART, increased microglial activation has been shown to correlate with poorer executive performance. Treatment of fetal human microglia with recombinant Tat induces the production of a number of chemokines, such as CCL2 and CCL5, involved in the development of HAND. Dysregulated chemokines released from microglia have an especially potent impact on neurons, due to the presence of several chemokine receptors on neuronal cell surface, including CCR1, CCR4, CCR5, CCR9/10, CXCR2, CXCR4, and CX3CR1.

Astrocytes: no longer a passive bystander

17Over the past 10 years, a significant amount of research has gone into understanding the extensive role played by astrocytes in the CNS, overturning their previous status as merely space holders, structural scaffolding, and scavengers. Their newly described roles include uptake of neurotransmitters, modulation of synaptic transmission, BBB maintenance, vaso-modulation, and long-term potentiation. The new concept of neuronal-glial intercommunication, where astrocytes play a dynamic role by integrating neuronal inputs and modulating synaptic activity, has helped us better comprehend astrocyte dysfunction in the context of HAND.

18It has been recently shown that astrocytes can be infected by HIV-1 in vitro, and additionally that infected astrocytes can impair BBB function, but the infected astrocytes are rarely seen in patient brain autopsies (although one recent study has shown 20% of the astrocytes are infected in patients with HAD). Furthermore, recombinant Tat protein has been shown to be responsible for the induction of chemokines, cytokines and nitric oxide synthetase in cultured primary human astrocytes. For example, Tat has been shown to induce astrocytes to produce platelet-derived growth factor BB (PDGF-BB), which in turn induces the production of CCL2. HIV-1 Tat can also up-regulate the expression of MMP-9 via MAPK-NF-κB-dependent mechanism, and MMP-9, in turn, disrupts the BBB.

19Exposure of astrocytes to gp120 causes up-regulation of IL-6 and TNF-α, and increases the release of glutamate and potassium, which leads to toxic increases in calcium in neurons and astrocytes. Using Affymetrix microarray analysis, Wang et al. showed that primary human astrocytes, when exposed to HIV-1 or gp120 in vitro, have an impaired ability to transport L-glutamate, and the authors ascribed this defect to transcriptional inhibition of the EAAT2 glutamate transporter gene. More recently, Fernandes et al. have used an animal model to show that gp120 prevents the uptake of extracellular glutamate by astrocytes, leading to a disruption of glutamate-glutamine homeostasis and a consequent impairment of memory. Release of toxic cytokines, inability to take up excess glutamate and damage to the BBB make astrocytes a central offender in the pathogenesis of HAND.

Neuroprotective factors

20Macrophages, microglia and even neurons themselves produce a number of neuroprotective mediators of inflammation. Neurotoxicity seen in HAND is the net result of the effects of neurotoxic insults and the action of neuroprotective host factors. In the quest to define neurotoxic agents responsible for HAND, the neuroprotective processes often go unnoticed. Platelet derived growth factor (PDGF) confers neuroprotection against gp120 toxicity by stimulating the PI3K/Akt pathway, and the pretreatment of neuronal cells with PDGF-CC abrogated Tat-mediated neurotoxicity by mitigating apoptosis and neurite loss. Astrocytes exposed to HIV-1 or chronically infected with HIV-1 express the tissue inhibitor of metalloproteinases-1 (TIMP-1), which is shown to have a neuroprotective role when primary human neurons are exposed to HIV-1. It has also been reported that exposure of astrocytes to HIV-1 gp120 induces the expression of nuclear factor erythroid-derived 2-related factor 2 (Nrf2), which plays a role in the stimulation of anti-oxidant defensive enzymes.

21Fractalkine (FKN/CX3CL1) is a chemokine produced by neurons, and it plays an important role in communication with microglia, which abundantly expresses the FKN receptor CX3CR1 (neurons also express this receptor but less abundantly). FKN plays an important role in neuroprotection and helps reduce gp120 toxicity via activation of ERK1/2 and CREB (this effect was seen both in the presence and absence of co-cultivated glial cells). Increased levels of FKN were found in the neurons of patients with HIV encephalitis, and FKN was found to potently drive the migration of monocytes across an in vitro trans-well system, as well as inhibit the neurotoxic effects of Tat protein in rat cerebellar neurons. Also the chemokine CCL3L1 protects against gp120 neurotoxicity by phosphorylation of CREB, which promotes the transcription of the cell-survival gene bcl-2. The routes of action of these host mediators against viral neurotoxins may offer potential avenues of therapeutic intervention that capitalize on existing pathways of neuroprotection.

Host genetic determinants of neurotoxicity

22Several important host gene polymorphisms have been associated with an effect on the transmission of HIV-1 and/or AIDS disease progression (e.g., CCR5-Δ32, CCL31). Similarly, several host gene polymorphisms have been linked with effects on the susceptibility to neurocognitive impairment. A point mutation identified in CCR2 (V64I) that had been associated with slower immunosuppressive disease progression, has also been shown to be specifically associated with a slower progression of neurocognitive impairment. This V64I variant was not associated with a difference in plasma or CSF viral load, suggesting that its impact could be mediated through a mis-regulation of the inflammatory response rather than through differences in viral replication. A polymorphism in the TNF-α gene increases its production in response to bacterial LPS, and this allele has been found in an increased frequency of patients with HAD. An allele of CCL2, 2578G confers a 50% reduction in risk of acquiring HIV-1 infection. However, the same allele, subsequent to HIV infection, was also associated with a 4.5 fold increased risk of HAD. This 2578G allele resulted in a greater transcriptional output of CCL2, which could exacerbate the development of HAND by increasing the influx of monocytic cells in response to CNS infection.

HAND co-morbidity with drugs of abuse

23Neurocognitive disease in HIV-patients can be greatly exacerbated by abuse of drugs such as opiates, methamphetamine and cocaine. Injection drug users (IDUs) are at particular risk, as injection drug use remains an important route of HIV-1 transmission. In addition, HIV-patients addicted to drugs of abuse are less likely to adhere to antiretroviral drug regimens. Opioid abuse is associated with faster HIV-1 disease progression, including increased risks of neurocognitive problems. While the “typical” opioid abuser has previously been perceived as a heroin IDU, there is a growing problem with the rising numbers of people abusing prescription opiates – a 2008 report indicated that while 400,000 Americans used heroin within one year, an estimated 12 million Americans abused prescription opiates within the same timeframe. The mechanisms of opioid-mediated injury in conjunction with HIV-CNS infection are well documented. μ-opiod receptor (MOR) is one of the primary routes of opiod signaling. While morphine itself leads to the down-regulation of MOR in cultured microglia, treatment of microglia with morphine and Tat reverses this down-regulation, providing a potential feed-forward mechanism of higher numbers of MOR at the cell-surface available to propagate further morphine-Tat mediated neurotoxicity. Doxycycline-inducible Tat transgenic mice (that express HIV-1 Tat in astrocytes) that were administered both doxycycline and morphine showed a marked decrease in the density of dendritic spines in the striatum, compared with mice given either doxycycline or morphine alone. PDGF-BB was also able to protect human neurons from synergistic Tat/morphine damage by inhibiting production of ROS and caspase-3 through the activation of the PI3K pathways.

24Morphine also acts synergistically with gp120 to promote neuronal death through p38 MAP kinase signaling. Mice that were transgenic for gp120 and subjected to morphine withdrawal failed to normalize oxidative capacity compared with non-transgenic mice subjected to morphine withdrawal. The same study also found failure to recover from synaptic damage in gp120-transgenic mice experiencing withdrawal compared with non-transgenic mice. Tat-induced release of CCL2 from astrocytes is further enhanced by morphine, and can increase the chemotactic migration of a microglial cell line towards affected astrocytes. HIV-1 patients using opiates were found to have higher levels of microglial activation in their brains. There is also evidence of opioid use having an effect on HIV-1 infection and replication: morphine significantly enhanced the infectivity of human macrophages, possibly by an increase in CCR5 expression. A more recent study showed that treatment of monocytes with morphine down-regulated several anti-HIV-1 microRNAs, which rendered the monocytes more susceptible to infection. Administration of morphine to rhesus macaques before infection with SIV resulted in a higher viral set point compared with a non-morphine control group.

25Methamphetamine (METH) use has been found to exacerbate brain injury and neuronal loss in HIV-1 patients, particularly in populations of interneurons in dopamingeric areas (DA) where the drug acts on the behavioral reward system. METH potentiates a Tat-mediated decrease in dopaminergic release in the cultured human fetal neurons. In the human neuroblastoma cell line SH-SY5Y, treatment with both METH and Tat produced significantly higher levels of both apoptosis and formation of autophagosomes than either factor by itself. In cultured human astrocytes, METH was found to potentiate the gp120-mediated release of the pro-inflammatory cytokine IL-6, mediated through the PI3K/Akt and NF-κB pathways. Treatment of METH on astroglioma cells transfected with a Tat expression construct exacerbated Tat-induced down-regulation of the neuroprotective factor β-catenin. Furthermore, HIV-patients using METH were found to have significantly higher viral loads than non-METH users. This was found to be a result of the interference of METH with antiretroviral therapy. METH also interferes with the normal antigen processing and phagocytic functions of macrophages, enhances the susceptibility of macrophages to HIV-1 infection by up-regulation of CCR5 and increases HIV-1 replication in CD4 T cells and monocytes.

26Cocaine is also known to accelerate the pathology of HAND. The drug binds the dopamine transporter and reduces the rate of dopamine uptake. Cocaine potentiates Tat-mediated neurotoxicity through the action at D1 receptors, Cocaine administration to SHIV-infected simian macrophages enhanced viral replication through increases in NF-κB signaling and IL-10, and cultured human endothelial cells exposed to cocaine experienced an up-regulation in adhesion molecules, resulting in increased monocyte transmigration across the BBB.

27Interestingly, according to recent studies cannabinoids (CB) appear to actually mediate a degree of neuroprotection in the context of CNS-HIV-1 damage. Synthetic CBs acting on the CB2 receptor (CB2-R) were able to mitigate gp120-induced damage in both human dopaminergic neurons and CB-2R expressing microglia, and a CB2 agonist was found to rescue deficits in neurogenesis seen in gp120-expressing transgenic mice.

Viral genetic determinants

28HIV-1 is phylogenetically divided into four groups: M, N, O and P, each representing a successful zoonotic event from primates – group M being the most widespread. Group M is further divided into subtypes A, B, C, D, F, G, H, J, K as well as a number of circulating recombinant forms (CRFs) of these subtypes. The global distribution of HIV-1 subtypes is region-specific, with a given geographical region correlating with the presence of a distinct subtype, a CRF or a particular combination of subtypes and CRFs. Such a highly region-specific distribution is thought to be due either to a founder effect, to host-population genetics selecting for specific subtypes of HIV-1, or a combination of both. Region-specific subtype-distribution has allowed researchers to correlate region-specific disease severity to subtype-specific viral gene polymorphisms, as documented in clinical studies. For example, reports from India, where HIV-1 subtype C is the predominant subtype, pointed to a lower incidence (0 - 4%) of severe forms of HAD, in contrast to geographic regions where subtype B HIV-1 is prevalent, which reported pre-HAART incidence levels of 15 - 30%.

29Our laboratory previously investigated whether genetic differences between the circulating isolates are responsible for the wide variation in incidence of HAD in different geographic regions. We reported that a majority (88%) of HIV-1 subtype C isolates worldwide have a Tat protein with a Cys31Ser polymorphism that disrupts a dicysteine motif, which is a key element of Tat protein’s homology to β-chemokines (Figure 4). In contrast, the Tat proteins encoded by 99% of non-subtype C HIV-1 isolates maintained a C31 residue at that position. We demonstrated that Tat protein of subtype C HIV-1 isolates with a C31S polymorphism is defective for monocyte chemotaxis function in vitro. As the infiltration of monocytic cells to the brain is a hallmark of HAD and plays a central role in triggering the inflammatory onslaught on neurons, we hypothesized that the C31S polymorphism in Tat protein of subtype C HIV-1 isolates contributes to the mechanistic basis for low incidence of HAD reported in India, as fewer monocytic cells would migrate to brain and result in little neuronal damage.

30In subsequent studies, several other groups have showed that recombinant subtype C Tat protein has a decreased potential for direct neurotoxicity and a decreased ability to induce inflammatory chemokine and cytokines. In order to examine whether the C31S polymorphism is associated with biological differences in neuropathogenesis, we compared cognitive dysfunction and pathological changes induced by representative subtype C and B isolates in a SCID mouse HIV encephalitis (SCID-HIVE) model. This allowed us to compare two genetically distinct HIV-1 isolates employing a single host genetic background. These studies revealed that subtype C isolates with a C31S polymorphism have lower potential to cause neuropathology and cognitive dysfunction (Figure 4). In primary monocytes, subtype B Tat was found to induce higher amounts of pro-inflammatory factors than subtype C Tat, such as TNF, IL-6, CCL2, and IDO (an enzyme in the kynurenine pathway that leads to production of neurotoxic quinolinic acid). HIV-1 TatB has also been shown to disrupt the integrity of brain microvascular endothelial cells to a greater extent compared to Tat C. Also, TatB, compared with TatC, can induce higher levels of IDO in human primary astrocytes, and TatB also induces higher levels of CCL2 in microglia and primary astrocytes than TatC (this higher CCL2 induction was specifically associated with the presence of the dicysteine motif) (Figure 4). Astroglioma cells that were either transfected with a Tat expression construct or treated with recombinant Tat showed a decrease in β-catenin, a transcriptional co-activator in the Wnt signaling pathway involved in neuroprotection. This β-catenin decrease was specific to the dicysteine motif in Tat, as neither TatC nor a TatB mutant with a disrupted dicysteine motif (C30G) were able to bring about this decrease.

31The low incidence of HAD caused by subtype C HIV-1 in India was further corroborated by the absence of HAD in Ethiopia, as measured by neurocognitive tests using International HIV Dementia (IHD) scale. Subtype C HIV-1 is also widespread in the Southern African countries. Interestingly, however, recent cohort studies in South Africa and Botswana, where C is the predominant subtype, showed that the incidence of HAD is much higher than that in India at 25 and 38% respectively. In light of our earlier findings indicating reduced neuropathogenicity for subtype C HIV-1, we were intrigued by the increased incidence data reported for subtype C HIV-1 cohorts in Southern Africa. While it may be generally assumed that subtype C HIV-1 from different regions of the world are highly related, studies on the phylogenetic and molecular clock analysis of gp120 sequences of Indian HIV-1 isolates have shown that their origin in India occurred much later than that of South African subtype C HIV-1. Therefore, we initiated a multi-site study to investigate phylogenetic differences between Southern African (South Africa and Zambia) and South Asian (India and Bangladesh) subtype C HIV-1 isolates. Our results showed that, with respect to both the whole virus genome sequence as well as sequences encoding Tat protein, the Indian HIV-1C isolates are genetically distinct from those in Southern Africa. More importantly, HIV-1C isolates with an intact dicysteine motif in Tat protein (C31) were quite rare (2 - 3%) in India, while they were significantly more frequent in the Southern African countries (11 - 26%). Thus, the frequency of HIV-1C isolates with a C31 in Tat broadly paralleled the incidence of HAD in these countries. Neurocognitive tests in SCID-HIVE mice, using a representative subtype C from Southern Africa (HIV-11084i) with an intact dicysteine motif in Tat (C31) and comparing it to subtype C from India (HIV-1IndieC1) lacking an intact dicysteine motif in Tat (C31S), showed that mice exposed to subtype C from Southern Africa exhibited significantly greater cognitive dysfunction compared to subtype C from India, especially when the testing paradigm presented a higher level of memory load. These findings lead to three main conclusions. One, intra-subtype variation exists and such variation can involve viral genes in HIV-1 that play a direct role in neurotoxicity. Two, it is more accurate to correlate differential disease outcomes in two geographical regions being compared, to differences in neurovirulence signatures rather than to differences in subtypes as a whole. Three, once further confirmed in a clinical study, it should be possible to perform a genetic screening in a subtype C HIV-1 epidemic for Tat genotype to gauge the risk of neurological dysfunction at the time of initial diagnosis.

32Additional genetic determinants in Tat, other than C31, that play a crucial role in the pathogenesis of HAND are unknown, but are likely to exist. Further studies on differential neuropathogenesis potential of HIV-1 variants in different geographic regions will be informative. Similarly, considering the fact that gp120 causes neuropathogenesis via multiple pathways, it is also possible that there are genetic differences in gp120 between viral variants in their ability to cause HAND via gp120-mediated neurotoxicity. Identification of such variants and their impact on the pathogenesis of HAND will help dissect the various types of neurotoxic insults involving different cellular receptors and develop better therapeutics and/or diagnostics.

Treatment modalities for HAND

33HAART significantly lowers the viral load in both the periphery and the CNS, and has been crucial in significantly decreasing the incidence and prevalence of severe forms of HAND. However, recent clinical studies and a meta-analysis in patients on HAART revealed milder forms of neurological dysfunction (ANI & MND) in greater than half of HIV-positive patients. In studies examining individuals with ART-controlled HIV viremia, HIV DNA in PBMCs correlated with regional brain atrophy highlighting the contribution of peripheral viral reservoirs to CNS pathology. Even the modified HAART regimens that include drugs with better CNS penetration effectiveness (CPE) scores, termed neuro-HAART, have had limited success among patients. Researchers have suggested various approaches to targeting latent CNS HIV reservoirs and sources of neuroinflammation such as cytokines, chemokines and oxidative stress that are in play inside the CNS and are refractory to antiretrovirals. Use of anti-inflammatory and anti-excitotoxic drugs like Minocycline (second-generation tetracycline derivative) and Memantine (voltage-dependent, open channel NMDAR blocker), that can cross the BBB at substantial levels and that have been shown to be neuroprotective in SCID HIVE mice and SIV models, are currently being investigated as adjuvants to treat HAND. Several neuroprotective factors, both endogenous (as discussed above) and exogenous (e.g., pDING;) are also being proposed as alternate treatments, with a focus towards eliminating neuroinflammation caused by exposure to HIV-1. Intra-nasal delivery of neurotropic protective factors such as insulin, IGF-1 and neurotrophin has been shown to mitigate many of the behavioral and pathological deficits in gp120 transgenic mice. In vitro studies, using innovative delivery techniques such as gold and lipid based nano-particles, have been shown to be effective in delivering HAART and anti-inflammatory/anti-excitotoxic agents across the blood brain barrier to specifically target CNS reservoirs. NanoART treatments in humanized mice reduced viral loads and protected CD4 T-cell populations. Natalizumab, a monoclonal antibody against alpha-4-integrin known to block trafficking of leukocytes across the blood–brain barrier, has been shown to be effective in preventing HIV-1 infected cells from breaching the BBB in a SIV model by Campbell and colleagues. These new and innovative treatments, in combination with Neuro-HAART, could be useful in treating HAND in the aging at-risk HIV-1 infected population. Thus, current approaches to intervention of HAND include not only the careful choice of antiretrovirals with better CNS penetration and efficacy, but also the future use of neuroprotective agents or the modulation of neuroprotective host factors.

Conclusions

34Our precise understanding of host factors that mediate the neurotoxic insult launched by exposure of CNS to HIV-1-infected cells, HIV-1 or specific HIV-1 proteins has increased in the recent past. In addition to increased knowledge about the pathways of neurotoxicity, we are also learning about the regional genetic variations in viral genes leading to intra-clade, region specific differences in disease severity. The discussion above clearly indicates that numerous opportunities exist to specifically block the neurotoxicity of viral and host proteins as well as potential neuroprotective factors that could be augmented to help alleviate the negative impact of HIV-1 on the brain.

Abbreviations

35CNS: Central nervous system; HAND: HIV-1 associated neurological disorders; ANI: Asymptomatic neurocognitive impairment; MND: Mild neurocognitive disorder; HAD: HIV-1 associated dementia; HAART: Highly active anti-retroviral therapy; ART: Anti-retroviral therapy; BBB: Blood-brain barrier; HBMEC: Human brain microvascular endothelial cells; MAP: Mitogen-activated protein; NMDAR: N-methyl-D-Aspartate receptors; LRPR: Lipoprotein receptor related protein receptors; PAF: Platelet activating factor; PDGF: Platelet derived growth factor; CRFs: Circulating recombinant forms; SCID-HIVE: SCID mouse HIV-1 encephalitis; CPE: CNS penetration effectiveness.

Competing interests

36The authors declare that they have no competing interests.

Authors’ contributions

37All three authors wrote sections of the manuscript. VRR developed the arrangement of the various sections and VRP was responsible for the integration of the sections. All authors read and approved the final manuscript.

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Garvey LJ Pavese N Politis M Ramlackhansingh A Brooks DJ Taylor-Robinson SD Winston A Increased microglia activation in neurologically asymptomatic HIV-infected patients receiving effective ARTAids2014 1116772
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Expression of CX3CR1 chemokine receptors on neurons and their role in neuronal survival · 2000
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Perez-Alvarez A Araque A Astrocyte-neuron interaction at tripartite synapsesCurr Drug Targets2013 111112201224
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Wang Z Trillo-Pazos G Kim SY Canki M Morgello S Sharer LR Gelbard HA Su ZZ Kang DC Brooks AI Fisher PB Volsky DJ Effects of human immunodeficiency virus type 1 on astrocyte gene expression and function: potential role in neuropathogenesisJ Neurovirol2004 11Suppl 12532
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Fernandes SP Edwards TM Ng KT Robinson SR HIV-1 protein gp120 rapidly impairs memory in chicks by interrupting the glutamate-glutamine cycleNeurobiol Learn Mem2007 11118
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Platelet-derived growth factor CC-mediated neuroprotection against HIV Tat involves TRPC-mediated inactivation of GSK 3beta. · 2012
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Reddy PV Gandhi N Samikkannu T Saiyed Z Agudelo M Yndart A Khatavkar P Nair MP HIV-1 gp120 induces antioxidant response element-mediated expression in primary astrocytes: role in HIV associated neurocognitive disorderNeurochem Int2012 115807814
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Meucci O Fatatis A Simen AA Bushell TJ Gray PW Miller RJ Chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicityProc Natl Acad Sci U S A1998 11241450014505
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Tong N Perry SW Zhang Q James HJ Guo H Brooks A Bal H Kinnear SA Fine S Epstein LG Dairaghi D Schall TJ Gendelman HE Dewhurst S Sharewr LR Gelbard HA Neuronal fractalkine expression in HIV-1 encephalitis: roles for macrophage recruitment and neuroprotection in the central nervous systemJ Immunol2000 11313331339
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Chun H Hao W Honghai Z Ning L Yasong W Chen D CCL3L1 prevents gp120-induced neuron death via the CREB cell signaling pathwayBrain Res2009 117588
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Dean M Carrington M Winkler C Huttley GA Smith MW Allikmets R Goedert JJ Buchbinder SP Vittinghoff E Gomperts E Donfield S Vlahov D Kaslow R Saah A Rinaldo C Detels R O’Brien SJ Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVESci (New York, NY)1996 11528318561862
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Gonzalez E Kulkarni H Bolivar H Mangano A Sanchez R Catano G Nibbs RJ Freedman BI Quinones MP Bamshad MJ Murthy KK Rovin BH Bradley W Clark RA Anderson SA O’Connell RJ Agan BK Ahuja SS Bologna R Sen L Dolan MJ Ahuja SK The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibilitySci (New York, NY)2005 11571414341440
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Smith MW Dean M Carrington M Winkler C Huttley GA Lomb DA Goedert JJ O’Brien TR Jacobson LP Kaslow R Buchbinder S Vittinghoff E Vlahov D Hoots K Hoots K Hilgartner MW O’Brien SJ Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City CohortSci (New York, NY)1997 115328959965
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Singh KK Ellis RJ Marquie-Beck J Letendre S Heaton RK Grant I Spector S CCR2 polymorphisms affect neuropsychological impairment in HIV-1-infected adultsJ Neuroimmunol2004 111–2185192
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112.
Quasney MW Zhang Q Sargent S Mynatt M Glass J McArthur J Increased frequency of the tumor necrosis factor-alpha-308 A allele in adults with human immunodeficiency virus dementiaAnn Neurol2001 112157162
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Gonzalez E Rovin BH Sen L Cooke G Dhanda R Mummidi S Kulkarni H Bamshad MJ Telles V Anderson SA Walter EA Stephan KT Deucher M Mangano A Bologna R Ahuja SS Dolan MJ Ahuja SK HIV-1 infection and AIDS dementia are influenced by a mutant MCP-1 allele linked to increased monocyte infiltration of tissues and MCP-1 levelsProc Natl Acad Sci U S A2002 11211379513800
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El-Bassel N Shaw SA Dasgupta A Strathdee SA Drug use as a driver of HIV risks: re-emerging and emerging issuesCurr Opin HIV AIDS2014 112150155
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115.
Substance Abuse and Mental Health Services AdministrationResults from the 2007 National survey on drug use and health: National findings. (Office of Applied Studies, NSDUH series H-34DHHS Publication No. SMA 08–4343)2008 Rockville, MD: Substance Abuse and Mental Health Services Administration, Office of Applied Studies - U.S. Department of Health and Human Services
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Pert CB Snyder SH Opiate receptor: demonstration in nervous tissueScience1973 11407710111014
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117.
Turchan-Cholewo J Dimayuga FO Ding Q Keller JN Hauser KF Knapp PE Bruce-Keller AJ Cell-specific actions of HIV-Tat and morphine on opioid receptor expression in gliaJ Neurosci Res2008 11921002110
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Fitting S Xu R Bull C Buch SK El-Hage N Nath A Knapp PE Hauser KF Interactive comorbidity between opioid drug abuse and HIV-1 Tat: chronic exposure augments spine loss and sublethal dendritic pathology in striatal neuronsAm J Pathol2010 11313971410
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119.
Malik S Khalique H Buch S Seth P A growth factor attenuates HIV-1 Tat and morphine induced damage to human neurons: implication in HIV/AIDS-drug abuse casesPLoS One2011 113e18116
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Hu S Sheng WS Lokensgard JR Peterson PK Morphine potentiates HIV-1 gp120-induced neuronal apoptosisJ Infect Dis2005 116886889
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Bandaru VV Patel N Ewaleifoh O Haughey NJ A failure to normalize biochemical and metabolic insults during morphine withdrawal disrupts synaptic repair in mice transgenic for HIV-gp120J Neuroimmune Pharmacol2011 114640649
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El-Hage N Wu G Wang J Ambati J Knapp PE Reed JL Bruce-Keller AJ Hauser KF HIV-1 Tat and opiate-induced changes in astrocytes promote chemotaxis of microglia through the expression of MCP-1 and alternative chemokinesGlia2006 112132146
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Arango JC Simmonds P Brettle RP Bell JE Does drug abuse influence the microglial response in AIDS and HIV encephalitis?Aids2004 11Suppl 1S69S74
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124.
Guo CJ Li Y Tian S Wang X Douglas SD Ho WZ Morphine enhances HIV infection of human blood mononuclear phagocytes through modulation of beta-chemokines and CCR5 receptorJ Investig Med2002 116435442
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125.
Wang X Ye L Zhou Y Liu MQ Zhou DJ Ho WZ Inhibition of anti-HIV microRNA expression: a mechanism for opioid-mediated enhancement of HIV infection of monocytesAm J Pathol2011 1114147
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126.
Kumar R Torres C Yamamura Y Rodriguez I Martinez M Staprans S Donahoe RM Kraiselburd E Stephens EB Kumar A Modulation by morphine of viral set point in rhesus macaques infected with simian immunodeficiency virus and simian-human immunodeficiency virusJ Virol2004 11201142511428
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Langford D Adame A Grigorian A Grant I McCutchan JA Ellis RJ Marcotte TD Masliah E Patterns of selective neuronal damage in methamphetamine-user AIDS patientsJ Acquir Immune Defic Syndr2003 115467474
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128.
Maragos WF Young KL Turchan JT Guseva M Pauly JR Nath A Cass WA Human immunodeficiency virus-1 Tat protein and methamphetamine interact synergistically to impair striatal dopaminergic functionJ Neurochem2002 114955963
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129.
Qi L Gang L Hang KW Ling CH Xiaofeng Z Zhen L Wai YD Sang PW Programmed neuronal cell death induced by HIV-1 tat and methamphetamineMicrosc Res Tech2011 111211391144
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130.
Shah A Silverstein PS Kumar S Singh DP Kumar A Synergistic cooperation between methamphetamine and HIV-1 gsp120 through the P13K/Akt pathway induces IL-6 but not IL-8 expression in astrocytesPLoS One2012 1112e52060
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131.
Sharma A Hu XT Napier TC Al-Harthi L Methamphetamine and HIV-1 Tat down regulate beta-catenin signaling: implications for methampetamine abuse and HIV-1 co-morbidityJ Neuroimmune Pharmacol2011 114597607
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132.
Ellis RJ Childers ME Cherner M Lazzaretto D Letendre S Grant I Increased human immunodeficiency virus loads in active methamphetamine users are explained by reduced effectiveness of antiretroviral therapyJ Infect Dis2003 111218201826
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133.
Methamphetamine Inhibits Antigen Processing, Presentation, and Phagocytosis · 2008
Corrected
134.
Liang H Wang X Chen H Song L Ye L Wang SH Wang YJ Zhou L Ho WZ Methamphetamine enhances HIV infection of macrophagesAm J Pathol2008 11616171624
Not in our library10.2353/ajpath.2008.070971 (opens in a new tab)
135.
Toussi SS Joseph A Zheng JH Dutta M Santambrogio L Goldstein H Short communication: Methamphetamine treatment increases in vitro and in vivo HIV replicationAIDS Res Hum Retroviruses2009 111111171121
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136.
Aksenov MY Aksenova MV Nath A Ray PD Mactutus CF Booze RM Cocaine-mediated enhancement of Tat toxicity in rat hippocampal cell cultures: the role of oxidative stress and D1 dopamine receptorNeurotoxicology2006 112217228
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137.
Dhillon NK Williams R Peng F Tsai YJ Dhillon S Nicolay B Gadgil M Kumar A Buch SJ Cocaine-mediated enhancement of virus replication in macrophages: implications for human immunodeficiency virus-associated dementiaJ Neurovirol2007 116483495
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Yao H Kim K Duan M Hayashi T Guo M Morgello S Prat A Wang J Su TP Buch S Cocaine hijacks sigma1 receptor to initiate induction of activated leukocyte cell adhesion molecule: implication for increased monocyte adhesion and migration in the CNSJ Neurosci2011 111659425955
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139.
Hu S Sheng WS Rock RB CB2 Receptor agonists protect human dopaminergic neurons against damage from HIV-1 gp120PLoS One2013 1110e77577
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140.
Avraham HK Jiang S Fu Y Rockenstein E Makriyannis A Zvonok A Masliah E Avraham S The cannabinoid CB2 receptor agonist AM1241 enhances neurogenesis in GFAP/Gp120 transgenic mice displaying deficits in neurogenesisBr J Pharmacol2014 112468479
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141.
Hemelaar J Gouws E Ghys PD Osmanov S Isolation W-UNfH, Characterisation: Global trends in molecular epidemiology of HIV-1 during 2000–2007Aids2011 115679689
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142.
Tebit DM Nankya I Arts EJ Gao Y HIV diversity, recombination and disease progression: how does fitness “fit” into the puzzle?AIDS Rev2007 1127587
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143.
Gupta JD Satishchandra P Gopukumar K Wilkie F Waldrop-Valverde D Ellis R Ownby R Subbakrishna DK Desai A Kamat A Ravi V Rao BS Satish KS Kumar M Neuropsychological deficits in human immunodeficiency virus type 1 clade C-seropositive adults from South IndiaJ Neurovirol2007 113195202
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144.
Satishchandra P Nalini A Gourie-Devi M Khanna N Santosh V Ravi V Desai A Chandramuki A Jayakumar PN Shankar SK Profile of neurologic disorders associated with HIV/AIDS from Bangalore, south India (1989–96)Indian J Med Res2000 111423
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145.
Langford TD Letendre SL Larrea GJ Masliah E Changing patterns in the neuropathogenesis of HIV during the HAART eraBrain Pathol2003 112195210
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146.
Sacktor N Lyles RH Skolasky R Kleeberger C Selnes OA Miller EN Becker JT Cohen B McArthur JC HIV-associated neurologic disease incidence changes: multicenter AIDS Cohort Study, 1990–1998Neurology2001 112257260
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147.
Ranga U Shankarappa R Siddappa NB Ramakrishna L Nagendran R Mahalingam M Mahadevan A Jayasuryan N Satishchandra P Shankar SK Prasad VR Tat protein of human immunodeficiency virus type 1 subtype C strains is a defective chemokineJ Virol2004 11525862590
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148.
Albini Ferrini S Benelli R Sforzini S Giunciuglio D Aluigi MG HIV-1 Tat protein mimicry of chemokinesProc National Academy of Sciences - PNAS1998 11221315313158
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149.
Mishra M Vetrivel S Siddappa NB Ranga U Seth P Clade specific differences in neurotoxicity of human immunodeficiency virus-1 B and C Tat of human neurons: significance of dicysteine C30C31 motifAnn Neurol2008 113366376
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150.
Campbell GR Watkins JD Singh KK Loret EP Spector SA Human immunodeficiency virus type 1 subtype C Tat fails to induce intracellular calcium flux and induces reduced tumor necrosis factor production from monocytesJ Virol2007 111159195928
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151.
Rao VR Neogi U Talboom JS Padilla L Rahman M Fritz-French C Gonzalez-Ramirez S Verma A Wood C Ruprecht RM Ranga U Azim T Joska J Eugenin E Shet A Bimonte-Nelson H Tyor WR Prasad VR Clade C HIV-1 isolates circulating in Southern Africa exhibit a greater frequency of dicysteine motif-containing Tat variants than those in Southeast Asia and cause increased neurovirulenceRetrovirology2013 1161
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152.
Li W Huang Y Reid R Steiner J Malpica-Llanos T Darden TA Shankar SK Mahadevan A Satishchandra P Nath A NMDA receptor activation by HIV-Tat protein is clade dependentJ Neurosci2008 11471219012198
Not in our library10.1523/jneurosci.3019-08.2008 (opens in a new tab)
153.
Gandhi N Saiyed Z Thangavel S Rodriguez J Rao KV Nair MP Differential effects of HIV type 1 clade B and clade C Tat protein on expression of proinflammatory and antiinflammatory cytokines by primary monocytesAIDS Res Hum Retroviruses2009 117691699
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154.
Wong JK Campbell GR Spector SA Differential induction of interleukin-10 in monocytes by HIV-1 clade B and clade C Tat proteinsJ Biol Chem2010 11241831918325
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155.
Rao VR Sas AR Eugenin EA Siddappa NB Bimonte-Nelson H Berman JW Ranga U Tyor WR Prasad VR HIV-1 clade-specific differences in the induction of neuropathogenesisJ Neurosci2008 11401001010016
Not in our library10.1523/jneurosci.2955-08.2008 (opens in a new tab)
156.
Gandhi N Saiyed ZM Napuri J Samikkannu T Reddy PV Agudelo M Khatavkar P Saxena SK Nair MP Interactive role of human immunodeficiency virus type 1 (HIV-1) clade-specific Tat protein and cocaine in blood–brain barrier dysfunction: implications for HIV-1-associated neurocognitive disorderJ Neurovirol2010 114294305
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157.
Samikkannu T Saiyed ZM Rao KV Babu DK Rodriguez JW Papuashvili MN Nair MP Differential regulation of indoleamine-2,3-dioxygenase (IDO) by HIV type 1 clade B and C Tat proteinAIDS Res Hum Retroviruses2009 113329335
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158.
Henderson LJ Sharma A Monaco MC Major EO Al-Harthi L Human immunodeficiency virus type 1 (HIV-1) transactivator of transcription through its intact core and cysteine-rich domains inhibits Wnt/beta-catenin signaling in astrocytes: relevance to HIV neuropathogenesisJ Neurosci2012 11461630616313
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159.
Joska JA Fincham DS Stein DJ Paul RH Seedat S Clinical correlates of HIV-associated neurocognitive disorders in South AfricaAIDS Behav2010 112371378
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Joska JA Westgarth-Taylor J Myer L Hoare J Thomas KG Combrinck M Paul RH Stein DJ Flisher AJ Characterization of HIV-Associated Neurocognitive Disorders among individuals starting antiretroviral therapy in South AfricaAIDS Behav2011 11611971203
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161.
Lawler K Mosepele M Ratcliffe S Seloilwe E Steele K Nthobatsang R Steenhoff A Neurocognitive impairment among HIV-positive individuals in Botswana: a pilot studyJ Int AIDS Soc2010 1115
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Modi G Hari K Modi M Mochan A The frequency and profile of neurology in black South African HIV infected (clade C) patients - a hospital-based prospective auditJ Neurol Sci2007 111–26064
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163.
Bachu M Yalla S Asokan M Verma A Neogi U Sharma S Murali RV Mukthey AB Bhatt R Chatterjee S Rajan RE Cheedarla N Yadavalli VS Mahadevan A Shankar SK Rajagopalan N Shet A Saravanan S Balakrishnan P Solomon S Vajpayee M Satish KS Kundu TK Jeang KT Ranga U Multiple NF-kappaB sites in HIV-1 subtype C long terminal repeat confer superior magnitude of transcription and thereby the enhanced viral predominanceJ Biol Chem2012 11534471444735
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164.
Shankarappa R Chatterjee R Learn GH Neogi D Ding M Roy P Ghosh A Kingsley L Harrison L Mullins JI Gupta P Human immunodeficiency virus type 1 env sequences from Calcutta in eastern India: identification of features that distinguish subtype C sequences in India from other subtype C sequencesJ Virol2001 11211047910487
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Dore GJ McDonald A Li Y Kaldor JM Brew BJ National HIVSC Marked improvement in survival following AIDS dementia complex in the era of highly active antiretroviral therapyAids2003 111015391545
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166.
Alkali NH Bwala SA Nyandaiti YW Danesi MA NeuroAIDS in sub-Saharan Africa: a clinical reviewAnn Afr Med2013 111110
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167.
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