HIV-1 Replication in the Central Nervous System Occurs in Two Distinct Cell Types

Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, United States of America.
PLoS Pathogens (Impact Factor: 7.56). 10/2011; 7(10):e1002286. DOI: 10.1371/journal.ppat.1002286
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Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system (CNS) can lead to the development of HIV-1-associated dementia (HAD). We examined the virological characteristics of HIV-1 in the cerebrospinal fluid (CSF) of HAD subjects to explore the association between independent viral replication in the CNS and the development of overt dementia. We found that genetically compartmentalized CCR5-tropic (R5) T cell-tropic and macrophage-tropic HIV-1 populations were independently detected in the CSF of subjects diagnosed with HIV-1-associated dementia. Macrophage-tropic HIV-1 populations were genetically diverse, representing established CNS infections, while R5 T cell-tropic HIV-1 populations were clonally amplified and associated with pleocytosis. R5 T cell-tropic viruses required high levels of surface CD4 to enter cells, and their presence was correlated with rapid decay of virus in the CSF with therapy initiation (similar to virus in the blood that is replicating in activated T cells). Macrophage-tropic viruses could enter cells with low levels of CD4, and their presence was correlated with slow decay of virus in the CSF, demonstrating a separate long-lived cell as the source of the virus. These studies demonstrate two distinct virological states inferred from the CSF virus in subjects diagnosed with HAD. Finally, macrophage-tropic viruses were largely restricted to the CNS/CSF compartment and not the blood, and in one case we were able to identify the macrophage-tropic lineage as a minor variant nearly two years before its expansion in the CNS. These results suggest that HIV-1 variants in CSF can provide information about viral replication and evolution in the CNS, events that are likely to play an important role in HIV-associated neurocognitive disorders.

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Available from: Sarah Beth Joseph, Jan 27, 2014
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    • "Dr Deeks noted that in both humans and SIV primate models, HIV infects the brain during primary HIV infection and during untreated HIV/SIV infection. Dr Deeks referred to the work of Schnell et al. demonstrating that genetically distinct HIV variants exist in the CNS and plasma (Schnell et al. 2011). He also cited Dahl et al. who showed that in patients with HIVassociated dementia (HAD), genetically diverse macrophagetropic and R5 T-cell-tropic viruses are present in the CSF and evince slow and rapid decay kinetics, respectively following cART commencement (Dahl et al. 2014a). "
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    ABSTRACT: On 18 July 2014, the National Institute of Mental Health in collaboration with ViiV Health Care and Boehringer Ingelheim supported a symposium on HIV eradication and what it meant for the brain. The symposium was an affiliated event to the 20th International AIDS Conference. The meeting was held in Melbourne, Australia, and brought together investigators currently working on HIV eradication together with investigators who are working on the neurological complications of HIV. The purpose of the meeting was to bring the two fields of HIV eradication and HIV neurology together to foster dialogue and cross talk to move the eradication field forward in the context of issues relating to the brain as a potential reservoir of HIV. The outcomes of the symposium were that there was substantive but not definitive evidence for the brain as an HIV reservoir that will provide a challenge to HIV eradication. Secondly, the brain as a clinically significant reservoir for HIV is not necessarily present in all patients. Consequently, there is an urgent need for the development of biomarkers to identify and quantify the HIV reservoir in the brain. Lastly, when designing and developing eradication strategies, it is critical that approaches to target the brain reservoir be included.
    Journal of NeuroVirology 03/2015; 21(3). DOI:10.1007/s13365-015-0322-6 · 2.60 Impact Factor
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    • "In the CNS, where macrophages could be exposed to high concentrations of dopamine, R5-tropic viruses predominate [52]–[54]. However, in addition to CCR5-mediated entry, HIV can enter macrophages through alternative pathways such as the endocytic pathway or through interaction with the co-receptor CXCR4 or minor co-receptors including CCR3 [53], [55]–[60]. "
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    ABSTRACT: Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers.
    PLoS ONE 09/2014; 9(9):e108232. DOI:10.1371/journal.pone.0108232 · 3.23 Impact Factor
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    • "HIV may also enter the CNS via infected lymphocytes or as cell-free virus [18,19]. A recent study by Schnell et al. identified both T cell-tropic and macrophage-tropic HIV-1 populations genetically compartmentalized to the cerebrospinal fluid (CSF) of individuals with HAD [20]. Irrespective of the method of entry, the infection and activation of monocytes and macrophages are thought to play an important role in the pathogenesis of HIVE as well as HAD [21–23]. "
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    ABSTRACT: Background The widespread use of highly effective, combination antiretroviral therapy (cART) has led to a significant reduction in the incidence of HIV-associated dementia (HAD). Despite these advances, the prevalence of HIV-1 associated neurocognitive disorders (HANDs) has been estimated at approximately 40%-50%. In the cART era, the majority of this disease burden is represented by asymptomatic neurocognitive impairment and mild neurocognitive disorder (ANI and MND respectively). Although less severe than HAD, these diagnoses carry with them substantial morbidity.ResultsIn this cross-sectional study, single genome amplification (SGA) was used to sequence 717 full-length HIV-1 envelope (env) clade B variants from the paired cerebrospinal fluid (CSF) and blood plasma samples of fifteen chronically infected HIV-positive individuals with normal neurocognitive performance (NCN), ANI and MND. Various degrees of compartmentalization were found across disease states and history of cART utilization. In individuals with compartmentalized virus, mean HIV-1 env population diversity was lower in the CSF than plasma-derived variants. Overall, mean V1V2 loop length was shorter in CSF-derived quasispecies when compared to contemporaneous plasma populations, and this was found to correlate with a lower mean number of N-linked glycosylation sites in this region. A number of discrete amino acid positions that correlate strongly with compartmentalization in the CSF were identified in both variable and constant regions of gp120 as well as in gp41. Correlated mutation analyses further identified that a subset of amino acid residues in these compartmentalization ¿hot spot¿ positions were strongly correlated with one another, suggesting they may play an important, definable role in the adaptation of viral variants to the CSF. Analysis of these hot spots in the context of a well-supported crystal structure of HIV-1 gp120 suggests mechanisms through which amino acid differences at the identified residues might contribute to viral compartmentalization in the CSF.Conclusions The detailed analyses of SGA-derived full length HIV-1 env from subjects with both normal neurocognitive performance and the most common HAND diagnoses in the cART era allow us to identify novel and confirm previously described HIV-1 env genetic determinants of neuroadaptation and relate potential motifs to HIV-1 env structure and function.
    Retrovirology 08/2014; 11(1):65. DOI:10.1186/PREACCEPT-1509273248119831 · 4.19 Impact Factor
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