Publications (15)52.25 Total impact
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Article: Central nervous system immune activation characterizes primary human immunodeficiency virus 1 infection even in participants with minimal cerebrospinal fluid viral burden.
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ABSTRACT: Central nervous system (CNS) human immunodeficiency virus (HIV) infection and immune activation lead to brain injury and neurological impairment. Although HIV enters the nervous system soon after transmission, the magnitude of infection and immunoactivation within the CNS during primary HIV infection (PHI) has not been characterized. This cross-sectional study analyzed cerebrospinal fluid (CSF) and blood from 96 participants with PHI and compared them with samples from neuroasymptomatic participants with chronic infection and ≥ 200 or < 200 blood CD4 T cells/μL, and with samples from HIV-seronegative participants with respect to CSF and plasma HIV RNA, CSF to serum albumin ratio, and CSF white blood cell counts (WBC), neopterin levels, and concentrations of chemokines CXCL10 and CCL2. The PHI participants (median 77 days post transmission) had CSF HIV RNA, WBC, neopterin, and CXCL10 concentrations similar to the chronic infection participants but uniquely high albumin ratios. 18 participants had ≤ 100 copies/mL CSF HIV RNA, which was associated with low CSF to plasma HIV ratios and levels of CSF inflammation lower than in other PHI participants but higher than in HIV-seronegative controls. Prominent CNS infection and immune activation is evident during the first months after HIV transmission, though a proportion of PHI patients demonstrate relatively reduced CSF HIV RNA and inflammation during this early period.The Journal of Infectious Diseases 09/2011; 204(5):753-60. · 6.41 Impact Factor -
Article: HIV-1 infection and cognitive impairment in the cART era: a review.
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ABSTRACT: With the introduction of combination antiretroviral therapy AIDS dementia complex or HIV-associated dementia, as it was termed later, largely disappeared in clinical practice. However, in the past few years, patients, long-term infected and treated, including those with systemically well controlled infection, started to complain about milder memory problems and slowness, difficulties in concentration, planning, and multitasking. Neuropsychological studies have confirmed that cognitive impairment occurs in a substantial (15-50%) proportion of patients. Among HIV-1-infected patients cognitive impairment was and is one of the most feared complications of HIV-1 infection. In addition, neurocognitive impairment may affect adherence to treatment and ultimately result in increased morbidity for systemic disease. So what may be going on in the CNS after so many years of apparently controlled HIV-1 infection is an urgent and important challenge in the field of HIV medicine. In this review we summarize the key currently available data. We describe the clinical neurological and neuropsychological findings, the preferred diagnostic approach with new imaging techniques and cerebrospinal fluid analysis. We try to integrate data on pathogenesis and finally discuss possible therapeutic interventions.AIDS (London, England) 12/2010; 25(5):561-75. · 4.91 Impact Factor -
Article: Cerebrospinal fluid neopterin: an informative biomarker of central nervous system immune activation in HIV-1 infection.
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ABSTRACT: HIV-1 invades the central nervous system (CNS) in the context of acute infection, persists thereafter in the absence of treatment, and leads to chronic intrathecal immunoactivation that can be measured by the macrophage activation marker, neopterin, in cerebrospinal fluid (CSF). In this review we describe our experience with CSF neopterin measurements in 382 untreated HIV-infected patients across the spectrum of immunosuppression and HIV-related neurological diseases, in 73 untreated AIDS patients with opportunistic CNS infections, and in 233 treated patients.In untreated patients, CSF neopterin concentrations are almost always elevated and increase progressively as immunosuppression worsens and blood CD4 cell counts fall. However, patients with HIV dementia exhibit particularly high CSF neopterin concentrations, above those of patients without neurological disease, though patients with CNS opportunistic infections, including CMV encephalitis and cryptococcal meningitis, also exhibit high levels of CSF neopterin. Combination antiretroviral therapy, with its potent effect on CNS HIV infection and CSF HIV RNA, mitigates both intrathecal immunoactivation and lowers CSF neopterin. However, despite suppression of plasma and CSF HIV RNA to below the detection limits of clinical assays (<50 copies HIV RNA/mL), CSF neopterin often remains mildly elevated, indicating persistent low-level intrathecal immune activation and raising the important questions of whether this elevation is driven by continued CNS infection and whether it causes continued indolent CNS injury.Although nonspecific, CSF neopterin can serve as a useful biomarker in the diagnosis of HIV dementia in the setting of confounding conditions, in monitoring the CNS inflammatory effects of antiretroviral treatment, and give valuable information to the cause of ongoing brain injury.AIDS Research and Therapy 01/2010; 7:15. · 2.54 Impact Factor -
Article: Cerebrospinal fluid neopterin: an informative biomarker of central nervous system immune activation in HIV-1 infection
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ABSTRACT: Abstract HIV-1 invades the central nervous system (CNS) in the context of acute infection, persists thereafter in the absence of treatment, and leads to chronic intrathecal immunoactivation that can be measured by the macrophage activation marker, neopterin, in cerebrospinal fluid (CSF). In this review we describe our experience with CSF neopterin measurements in 382 untreated HIV-infected patients across the spectrum of immunosuppression and HIV-related neurological diseases, in 73 untreated AIDS patients with opportunistic CNS infections, and in 233 treated patients. In untreated patients, CSF neopterin concentrations are almost always elevated and increase progressively as immunosuppression worsens and blood CD4 cell counts fall. However, patients with HIV dementia exhibit particularly high CSF neopterin concentrations, above those of patients without neurological disease, though patients with CNS opportunistic infections, including CMV encephalitis and cryptococcal meningitis, also exhibit high levels of CSF neopterin. Combination antiretroviral therapy, with its potent effect on CNS HIV infection and CSF HIV RNA, mitigates both intrathecal immunoactivation and lowers CSF neopterin. However, despite suppression of plasma and CSF HIV RNA to below the detection limits of clinical assays (<50 copies HIV RNA/mL), CSF neopterin often remains mildly elevated, indicating persistent low-level intrathecal immune activation and raising the important questions of whether this elevation is driven by continued CNS infection and whether it causes continued indolent CNS injury. Although nonspecific, CSF neopterin can serve as a useful biomarker in the diagnosis of HIV dementia in the setting of confounding conditions, in monitoring the CNS inflammatory effects of antiretroviral treatment, and give valuable information to the cause of ongoing brain injury.AIDS Research and Therapy. 01/2010; -
Article: Amyloid and tau cerebrospinal fluid biomarkers in HIV infection.
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ABSTRACT: Because of the emerging intersections of HIV infection and Alzheimer's disease, we examined cerebrospinal fluid (CSF) biomarkers related of amyloid and tau metabolism in HIV-infected patients. In this cross-sectional study we measured soluble amyloid precursor proteins alpha and beta (sAPPalpha and sAPPbeta), amyloid beta fragment 1-42 (Abeta1-42), and total and hyperphosphorylated tau (t-tau and p-tau) in CSF of 86 HIV-infected (HIV+) subjects, including 21 with AIDS dementia complex (ADC), 25 with central nervous system (CNS) opportunistic infections and 40 without neurological symptoms and signs. We also measured these CSF biomarkers in 64 uninfected (HIV-) subjects, including 21 with Alzheimer's disease, and both younger and older controls without neurological disease. CSF sAPPalpha and sAPPbeta concentrations were highly correlated and reduced in patients with ADC and opportunistic infections compared to the other groups. The opportunistic infection group but not the ADC patients had lower CSF Abeta1-42 in comparison to the other HIV+ subjects. CSF t-tau levels were high in some ADC patients, but did not differ significantly from the HIV+ neuroasymptomatic group, while CSF p-tau was not increased in any of the HIV+ groups. Together, CSF amyloid and tau markers segregated the ADC patients from both HIV+ and HIV- neuroasymptomatics and from Alzheimer's disease patients, but not from those with opportunistic infections. Parallel reductions of CSF sAPPalpha and sAPPbeta in ADC and CNS opportunistic infections suggest an effect of CNS immune activation or inflammation on neuronal amyloid synthesis or processing. Elevation of CSF t-tau in some ADC and CNS infection patients without concomitant increase in p-tau indicates neural injury without preferential accumulation of hyperphosphorylated tau as found in Alzheimer's disease. These biomarker changes define pathogenetic pathways to brain injury in ADC that differ from those of Alzheimer's disease.BMC Neurology 12/2009; 9:63. · 2.17 Impact Factor -
Article: Treatment of HIV infection: Swedish recommendations 2009.
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ABSTRACT: On 4 previous occasions, in 2002, 2003, 2005 and 2007, the Swedish Medical Products Agency (Lakemedelsverket) and the Swedish Reference Group for Antiviral Therapy (RAV) have jointly published recommendations for the treatment of HIV infection. In November 2008, an expert group under the guidance of RAV once more revised the guidelines, of which this is a translation into English. The most important updates in the present guidelines include the following: (a) treatment initiation is now recommended at a CD4 cell count of approximately 350/microl; (b) new recommendations for first-line therapy: abacavir/lamivudine or tenofovir/emtricitabine in combination with efavirenz or a boosted protease inhibitor (PI/r); (c) an increased focus on reducing the use of antiretroviral drugs that may cause lipoatrophy; (d) an emphasis on quality assurance of HIV care through the use of InfCare HIV; (e) considerably altered recommendations for the initiation of antiretroviral therapy in children. All infants (<1 y) should start antiretroviral therapy, regardless of immune status. Also, absolute CD4+ cell counts, rather than percentage, may be used to guide treatment initiation in children above the age of 5 y.Scandinavian Journal of Infectious Diseases 09/2009; · 1.72 Impact Factor -
Article: Reduction of the HIV-1 reservoir in resting CD4+ T-lymphocytes by high dosage intravenous immunoglobulin treatment: a proof-of-concept study.
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ABSTRACT: The latency of HIV-1 in resting CD4+ T-lymphocytes constitutes a major obstacle for the eradication of virus in patients on antiretroviral therapy (ART). As yet, no approach to reduce this viral reservoir has proven effective. Nine subjects on effective ART were included in the study and treated with high dosage intravenous immunoglobulin (IVIG) for five consecutive days. Seven of those had detectable levels of replication-competent virus in the latent reservoir and were thus possible to evaluate. Highly purified resting memory CD4+ T-cells were activated and cells containing replication-competent HIV-1 were quantified. HIV-1 from plasma and activated memory CD4+ T-cells were compared with single genome sequencing (SGS) of the gag region. T-lymphocyte activation markers and serum interleukins were measured. The latent HIV-1 pool decreased with in median 68% after IVIG was added to effective ART. The reservoir decreased in five, whereas no decrease was found in two subjects with detectable virus. Plasma HIV-1 RNA >or= 2 copies/mL was detected in five of seven subjects at baseline, but in only one at follow-up after 8-12 weeks. The decrease of the latent HIV-1 pool and the residual plasma viremia was preceded by a transitory low-level increase in plasma HIV-1 RNA and serum interleukin 7 (IL-7) levels, and followed by an expansion of T regulatory cells. The magnitude of the viral increase in plasma correlated to the size of the latent HIV-1 pool and SGS of the gag region showed that viral clones from plasma clustered together with virus from activated memory T-cells, pointing to the latent reservoir as the source of HIV-1 RNA in plasma. The findings from this uncontrolled proof-of-concept study suggest that the reservoir became accessible by IVIG treatment through activation of HIV-1 gene expression in latently-infected resting CD4+ T-cells. We propose that IVIG should be further evaluated as an adjuvant to effective ART.AIDS Research and Therapy 08/2009; 6:15. · 2.54 Impact Factor -
Article: Prophylaxis and treatment of HIV-1 infection in pregnancy: Swedish Recommendations 2007.
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ABSTRACT: Prophylaxis and treatment with antiretroviral drugs, a consequent low viral load, and the use of elective Caesarean section, are factors that radically decrease the risk of HIV transmission from mother to child during pregnancy and delivery. The availability of new antiretroviral drugs, updated general treatment guidelines and increasing knowledge of the importance of drug resistance, have necessitated recurrent revisions of the recommendations for 'Prophylaxis and treatment of HIV-1 infection in pregnancy'. For these reasons, The Swedish Reference Group for Antiviral Therapy (RAV) has, at an expert meeting on May 4, 2007, once more updated the treatment recommendations of 1999, 2002 and 2005, which were defined in cooperation with the Swedish Medical Products Agency (Läkemedelsverket). This new text takes the recently updated general HIV treatment recommendations into account. Furthermore, the very low risk of HIV transmission when the mother is treated with combination antiretroviral therapy, has undetectable levels of viraemia and no obstetric risk factors, has been considered in the recommendations concerning the mode of delivery. Finally, the recommendations for monitoring of infants born to HIV-infected mothers have been modified. The recommendations are evidence graded in accordance with the Oxford Centre for Evidence Based Medicine, 2001 (see http://www.cebm.net/levels_of_evidence.asp#levels).Scandinavian Journal of Infectious Diseases 02/2008; 40(6-7):451-61. · 1.72 Impact Factor -
Article: Elevated cerebrospinal fluid neurofilament light protein concentrations predict the development of AIDS dementia complex.
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ABSTRACT: The light subunit of neurofilament protein (NFL) is a sensitive indicator of central nervous system axonal injury. We retrospectively identified 9 subjects participating in a longitudinal cohort study who developed acquired immunodeficiency syndrome dementia complex (ADC) and who had had a lumbar puncture performed within 2 years before presentation. Elevated cerebrospinal fluid (CSF) NFL concentrations were found in 7 (78%) of the 9 case patients who later developed ADC, compared with 9 (33%) of 27 CD4 cell count-matched HIV-1-infected control subjects. By contrast, no differences were found in CSF HIV-1 RNA or neopterin concentrations between the 2 groups. CSF NFL may prove to be a useful predictive marker for ADC.The Journal of Infectious Diseases 07/2007; 195(12):1774-8. · 6.41 Impact Factor -
Article: Defining and evaluating HIV-related neurodegenerative disease and its treatment targets: a combinatorial approach to use of cerebrospinal fluid molecular biomarkers.
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ABSTRACT: There are a number of reasons that the accomplishments of clinical trials related to HIV-related neurodegenerative disease (HRND) and the AIDS dementia complex (ADC) have had such limited impact on clinical practice. These include: rapid evolution and progress in the treatment of systemic HIV infection that has quickly outpaced neurological efforts and has markedly reduced disease incidence; ethical constraints that (rightly) demand neurologically compromised patients receive the best available treatment before experimental therapeutics; complicated backgrounds and comorbidities of patients now most susceptible to HRND; and reluctance of general AIDS clinicians and drug companies to look beyond systemic or pivotal outcomes. However, the field has also been slow to adopt methods that better exploit advances in understanding of the pathogenesis of central nervous system (CNS) infection and brain injury, and that might circumvent some of these constraints. Using a simple model of pathogenesis, we propose an approach to characterizing patients, selecting treatment targets, and evaluating outcomes that emphasize a combination of cerebrospinal fluid (CSF) markers. This model begins by using three markers related to cardinal components of HRND: CNS HIV infection (measurement of CSF HIV RNA), intrathecal immunoactivation (CSF neopterin), and brain injury [CSF light chain neurofilament (NFL)]. Careful analysis of this and other marker combinations promises more rational trial design and more rapid progress in managing CNS HIV infection and HRND using both antiviral and adjuvant treatment approaches.Journal of Neuroimmune Pharmacology 04/2007; 2(1):112-9. · 4.57 Impact Factor -
Article: Cerebrospinal fluid markers in central nervous system HIV infection and AIDS dementia complex.
Handbook of Clinical Neurology 02/2007; 85:261-300. -
Article: Cerebrospinal fluid interferon-gamma-inducible protein 10 (IP-10, CXCL10) in HIV-1 infection.
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ABSTRACT: Interferon-gamma-inducible protein (IP-10 or CXCL10) is a potent chemoattractant and has been suggested to enhance retrovirus infection and mediate neuronal injury. In order to assess this chemokine in central nervous system (CNS) HIV infection, we measured the cerebrospinal fluid (CSF) and plasma concentrations of CXCL10 by immunoassay in samples derived from 97 HIV-infected subjects across a spectrum of immunological progression and CNS complications and from 16 HIV seronegative control subjects studied at three clinical centers between 1994 and 2001. We also examined changes in the CSF and plasma CXCL10 concentrations in 30 subjects starting and three stopping antiretroviral therapy. CSF CXCL10 concentrations: (1) correlated with CSF HIV RNA and white blood cell (WBC) counts, but not with blood CXCL10, HIV RNA, or CD4 counts; (2) were increased in subjects with primary and asymptomatic HIV infections and AIDS dementia complex, but less frequently in those with more advanced infection, with or without CNS opportunistic diseases except cytomegalovirus encephalitis; (3) decreased in subjects starting antiretroviral in association with decreases in CSF and plasma HIV RNA and CSF WBCs; and (4) conversely, increased in subjects stopping treatment in parallel with CSF HIV RNA and WBCs. These results confirm that CSF CXCL10 associates closely with both CSF HIV and WBCs and suggest that this chemokine may be both a response to and contributing determinant of local infection. High CSF levels may be useful in the diagnosis of ADC in subjects with advanced immunosuppression in whom CMV encephalitis has been ruled out, though this issue requires further study.Journal of Neuroimmunology 12/2005; 168(1-2):154-63. · 2.96 Impact Factor -
Article: Expression of the urokinase plasminogen activator and its receptor in HIV-1-associated central nervous system disease.
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ABSTRACT: The urokinase plasminogen activator (uPA) and its receptor (uPAR) play important physiological functions in extracellular proteolysis, as well as cell adhesion and migration. Through dysregulation of these functions, the uPA/uPAR system might be involved in the pathogenesis of AIDS dementia complex (ADC), and, in fact, uPAR has been found to be overexpressed in the cerebrospinal fluid (CSF) and brain tissues of patients with ADC. On the other hand, its ligand uPA has been shown to down-regulate HIV replication in vitro. In this study, we examined uPAR and uPA expression in the brain of HIV-related lesions, as well as CSF levels of soluble uPAR (suPAR), uPA, and complexes between these two molecules (suPAR/uPA) in patients with HIV infection with or without ADC. uPAR was highly expressed by macrophages in both HIV encephalitis (HIV-E) or leukoencephalopathy (HIV-LE), with a distribution exceeding that of HIV p24 antigen. In contrast, uPA was detected only on rare cells in most of the cases. Both uPA and suPAR/uPA complex concentrations were significantly correlated with CSF suPAR levels, and CSF concentrations of both markers were higher in ADC patients than controls. However, uPA levels were substantially lower than corresponding suPAR levels. Although these findings remain correlative, they add support to the hypothesis that uPAR might be an important participant in the events leading to ADC. Additionally, these findings are consistent with a model in which overexpression of uPAR and overproduction of its soluble form may promote HIV replication via binding and removal of uPA from cell surface.Journal of Neuroimmunology 01/2005; 157(1-2):133-9. · 2.96 Impact Factor -
Article: The urokinase receptor is overexpressed in the AIDS dementia complex and other neurological manifestations.
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ABSTRACT: The urokinase-type plasminogen activator (uPA) and its receptor (uPAR) play an important role in extracellular matrix degradation and cell migration in the central nervous system (CNS). To investigate the role of the uPA/uPAR system in the pathophysiology of acquired immunodeficiency syndrome dementia complex (ADC), we measured soluble uPAR (suPAR) levels in cerebrospinal fluid (CSF) and plasma from human immunodeficiency virus (HIV)-1-infected patients and controls. CSF suPAR levels were significantly higher in HIV-1-infected patients than in controls and in patients with ADC or opportunistic CNS infections (CNS-OIs) than in neurologically asymptomatic patients, irrespective of HIV-1 disease stage. The highest levels of suPAR were found in patients with ADC, and among those with CNS-OIs in patients with cytomegalovirus encephalitis or cryptococcosis. Plasma suPAR levels were higher in HIV-1-infected patients than in controls and increased with HIV-1 disease stage regardless of the presence of CNS disease. In patients with ADC or CNS-OIs, CSF suPAR levels correlated with CSF HIV-1 RNA, but not with plasma suPAR concentrations. Highly active antiretroviral therapy was associated with a significant and parallel decrease of both CSF suPAR and HIV-1 RNA. In brain tissue from patients with HIV-1 encephalitis, uPAR was highly expressed by microglial and multinucleated giant cells staining positively for HIV-1. The overexpression of uPAR in the CNS of patients with ADC suggests that the uPA/uPAR system may contribute to the tissue injury and neuronal damage in this disease.Annals of Neurology 06/2004; 55(5):687-94. · 11.09 Impact Factor -
Article: pol gene sequence variation in Swedish HIV-2 patients failing antiretroviral therapy.
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ABSTRACT: There is limited knowledge about how to treat and interpret results from genotypic resistance assays in HIV-2 infection. Here, genetic variation in HIV-2 pol gene was studied in 20 of 23 known HIV-2 cases in Sweden. Five patients with signs of virological treatment failure were longitudinally studied. Clinical, virological and immunological data were collected and the protease (PR) and first half of the reverse transcriptase (RT) was amplified and directly sequenced from plasma samples. Moderate to extensive genetic evolution was observed in four of the five patients who failed treatment. Some mutations occurred at positions known to confer resistance in HIV-1, but many occurred at other positions in PR and RT. All patients had been treated with zidovudine alone or in combination with other antiretroviral drugs, but none displayed a mutation at position 215, which is the primary zidovudine resistance site in HIV-1. Instead, a E219D mutation evolved in virus from two patients and a Q151M mutation evolved in two other patients. A M184V mutation indicative of lamivudine resistance was detected in three patients. The virus of one patient who had been treated with ritonavir, nelfinavir, and lopinavir successively acquired nine unusual mutations in the protease gene, most of which are not considered primary or secondary resistance mutations in HIV-1. Our data indicate that the evolutionary pathways that lead to antiretroviral resistance in HIV-2 and HIV-1 exhibit both similarities and differences. Genotypic HIV-2 resistance assays cannot be interpreted using algorithms developed for HIV-1, instead new algorithms specific for HIV-2 have to be developed.AIDS Research and Human Retroviruses 08/2003; 19(7):543-50. · 2.25 Impact Factor
Top co-authors
Top Journals
Institutions
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2011
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University of California, San Francisco
- Department of Neurology
San Francisco, CA, USA
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2009
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Karolinska Institutet
- Institutionen för laboratoriemedicin
Solna, Stockholm, Sweden -
University of Gothenburg
- Department of Infectious Diseases
Göteborg, Vaestra Goetaland, Sweden
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2007–2008
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Sahlgrenska University Hospital
Göteborg, Vaestra Goetaland, Sweden -
St. Vincent's Hospital Sydney
Sydney, New South Wales, Australia
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