Progressive increase in central nervous system immune activation in untreated primary HIV-1 infection

Suh, Joome; Sinclair, Elizabeth; Peterson, Julia; Lee, Evelyn; Kyriakides, Tassos C.; Li, Fangyong; Hagberg, Lars; Fuchs, Dietmar; Price, Richard W.; Gisslén, Magnus; Spudich, Serena

doi:10.1186/s12974-014-0199-y

Cited by 35 publications

(26 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Studies have linked untreated HIV infection with increasing amounts of neuroinflammation in the early parts of the disease process (Suh, Sinclair et al 2014), which is believed to be a major contributor of HIV-related cognitive effects (Hong and Banks 2014). In addition, the presence of HIV-related proteins in model animals, without viral infectivity, can cause depressive-like and anxiety-like behaviors in adolescent female rats (Nemeth, Glasper et al 2014), produce changes in the medial PFC of male rats (Wayman, Dodiya et al 2012), and increase oxidative stress driven apoptosis in the rat hippocampus (Kruman, Nath et al 1998).…”

Section: ) Introductionmentioning

confidence: 99%

HIV-1 proteins accelerate HPA axis habituation in female rats

Panagiotakopoulos

Kelly

Neigh

2015

Physiology & Behavior

View full text Add to dashboard Cite

Congenital infection by the Human Immunodeficiency Virus (HIV) has been shown to lead to multiple co-morbidities, and people living with HIV have a higher incidence of affective and anxiety disorders. A marked increase in mood disorders is evident during the sensitive phase of adolescence and this is further pronounced in females. Depression has been linked to dysfunction of the intracellular response system to corticosteroids at the level of the hippocampus (HC) and prefrontal cortex (PFC) with a notable role of the glucocorticoid receptor (GR) and its co-chaperones (FKBP5 and FKBP4). The current study examined the extent to which HIV protein expression in adolescent female rats altered the stress response at both the level of corticosterone output and molecular regulation of the glucocorticoid receptor in the brain. WT and HIV-1 genotype female rats were randomly allocated in control, acute stress and repeat stress groups. Corticosterone plasma levels and expression of GR, FKBP4, and FKBP5 in the HC and PFC were measured. The presence of HIV-1 proteins facilitate habituation of the corticosterone response to repeated stressors, such that HIV-1 TG rats habituated to repeated restraint and WT rats did not. This was reflected by interactions between stress exposure and HIV-1 protein expression at the level of GR co-chaperones. Although expression of the GR was similarly reduced after acute and repeat stress in both genotypes, expression of FKBP5 and FKBP4 was altered in a brain-region specific manner depending on the duration of the stress exposure and the presence or absence of HIV-1 proteins. Collectively, the data presented demonstrate that HIV-1 proteins accelerate habituation to repeated stressors and modify the influence of acute and repeat stressors on GR co-chaperones in a brain region-specific manner.

show abstract

Section: ) Introductionmentioning

confidence: 99%

HIV-1 proteins accelerate HPA axis habituation in female rats

Panagiotakopoulos

Kelly

Neigh

2015

Physiology & Behavior

View full text Add to dashboard Cite

show abstract

“…HIV infiltrates the CNS during PHI [6][7][8], as indicated by the presence of HIV RNA in the cerebrospinal fluid (CSF) compartment, even in the absence of neurological symptoms [1,[8][9][10][11]. CNS immune activation accompanies this viral invasion, as reflected by elevations in the CSF white blood cell count and the soluble CSF biomarkers neopterin (reflecting macrophage activation) and CXCL-10/IP-10 (a lymphocyte chemokine) and by T-lymphocyte activation in CSF [1,[12][13][14][15]. Furthermore, markers of immune activation may reflect the degree of viral load and neurocognitive impairment [16].…”

mentioning

confidence: 99%

Blood-Brain Barrier Disruption Is Initiated During Primary HIV Infection and Not Rapidly Altered by Antiretroviral Therapy

Rahimy¹,

Hagberg³

et al. 2017

The Journal of Infectious Diseases

Self Cite

View full text Add to dashboard Cite

Background. We explored the establishment of abnormal blood-brain barrier (BBB) permeability and its relationship to neuropathogenesis during primary human immunodeficiency virus (HIV) infection by evaluating the cerebrospinal fluid (CSF) to serum albumin quotient (Q Alb ) in patients with primary HIV infection. We also analyzed effects of initiating combination antiretroviral therapy (cART).Methods. The Q Alb was measured in longitudinal observational studies of primary HIV infection. We analyzed trajectories of the Q Alb before and after cART initiation, using mixed-effects models, and associations between the Q Alb and the CSF level of neurofilament light chain (NFL), the ratio of N-acetylaspartate to creatinine levels (a magnetic resonance spectroscopy neuronal integrity biomarker), and neuropsychological performance.Results. The baseline age-adjusted Q Alb was elevated in 106 patients with primary HIV infection (median time of measurement, 91 days after infection), compared with that in 64 controls (P = .02). Before cART initiation, the Q Alb increased over time in 84 participants with a normal baseline Q Alb (P = .006) and decreased in 22 with a high baseline Q Alb (P = .011). The Q Alb did not change after a median cART duration of 398 days, initiated at a median interval of 225 days after infection (P = .174). The Q Alb correlated with the NFL level at baseline (r = 0.497 and P < .001) and longitudinally (r = 0.555 and P < .001) and with the ratio of N-acetylaspartate to creatinine levels in parietal gray matter (r = −0.352 and P < .001 at baseline and r = −0.387 and P = .008 longitudinally) but not with neuropsychological performance.Conclusion. The Q Alb rises during primary HIV infection, associates with neuronal injury, and does not significantly improve over a year of treatment. BBB-associated neuropathogenesis in HIV-infected patients may initiate during primary infection.

show abstract

“…16 Virus appears in the CNS weeks after HIV infection and coincides with the appearance of inflammatory molecules in the cerebrospinal fluid. 17 Virus then resides in the perivascular monocytes/macrophages that are infected in the periphery. 4 Before introduction of ART, an uncontrolled infection in the brain leads to HIV-1 encephalitis, which occurs in immunosuppressed patients because of the depletion of CD4 þ T lymphocytes, thereby resulting in inadequate immune control over HIV-1 replication in the CNS and other organs.…”

Section: Future Directionsmentioning

confidence: 99%

Insights into End-Organ Injury in HIV Infection

Persidsky

2015

The American Journal of Pathology

View full text Add to dashboard Cite

Neurocognitive impairment (collectively named as HIV1eassociated neurocognitive disorders or HAND) is highly prevalent in HIV-1einfected patients, including those receiving antiretroviral therapy (ART).1 Monocyte and macrophage infiltration in the brain is associated with HAND development 2 ; however, precise timing and dynamics of this infiltration remain debatable. Researchers recapitulate HIV infection in nonhuman primates (macaque model) by infecting with SIV. For the first time, by using SIV-infected animals that developed SIV encephalitis (SIVE), Nowlin et al 3 studied monocyte-to-macrophage turnover in the central nervous system (CNS) under physiological conditions. 4 Study DesignNeuropathologic features of SIVE recapitulate signs of HIV encephalitis, 4 a morphological correlate of cognitive decline. Nowlin et al 3 used straightforward multilabel immunohistochemical approaches to assess macrophage populations and their turnover in the choroid plexus, meninges, perivascular space, and parenchymal lesions (when present in animals with SIVE). The method also allowed comparison of the rates of turnover in early acute inflammation and in the later inflammation as the animals developed AIDS and CNS lesions. They used a cuttingedge combination of bromodeoxyuridine (BrdU)elabeled macrophage precursors in bone marrow (that can potentially traffic to the brain) to detect macrophage populations and the serial injection of dextran dyes intercisternally to determine the macrophage populations (early or late) contributing to lesion formation as well as to identify the infected cells in the CNS. Study OutcomeThe findings of Nowlin et al 3 are of great interest to CNS macrophage biologists as well as immunologists studying acute and chronic inflammation. Early during SIV infection, Nowlin et al 3 reported most cells to be MAC387 þ recently recruited monocytes/macrophages. As expected, most of these cells were detected in the meninges and the choroid plexus (which appeared to have trafficking kinetics similar to the blood than to the CNS compartments). Consistent with the observations from the bone marrow during inflammation, most BrdU þ cells were also MAC387 þ . During the late stages of inflammation, Nowlin et al 3 found macrophage accumulation primarily in the perivascular space and in SIVE lesions, not in the meninges and choroid plexus. It is likely that the meninges and choroid plexus have cells trafficking through them in late stages of inflammation, thereby decreasing accumulation. Interestingly, most cells in the SIVE lesion (>80%) were present in the CNS before lesion development, suggesting Supported by NIH research grants AA015913 and MH65151.

show abstract

Progressive increase in central nervous system immune activation in untreated primary HIV-1 infection

Cited by 35 publications

References 37 publications

HIV-1 proteins accelerate HPA axis habituation in female rats

HIV-1 proteins accelerate HPA axis habituation in female rats

Blood-Brain Barrier Disruption Is Initiated During Primary HIV Infection and Not Rapidly Altered by Antiretroviral Therapy

Insights into End-Organ Injury in HIV Infection

Contact Info

Product

Resources

About