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Michael J Peluso,
Dieter J Meyerhoff,
Richard W Price,
Julia Peterson, Evelyn Lee,
Andrew C Young,
Rudy Walter,
Dietmar Fuchs,
Bruce J Brew,
Paola Cinque,
Kevin Robertson,
Lars Hagberg,
Henrik Zetterberg,
Magnus Gisslén,
Serena Spudich
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ABSTRACT: Background. Cerebrospinal fluid (CSF) and neuroimaging abnormalities demonstrate neuronal injury during chronic AIDS, but data on these biomarkers during primary HIV infection is limited.Methods. We compared CSF concentrations of neurofilament light chain, t-tau, p-tau, amyloid precursor proteins, and amyloid-beta 42 in 92 subjects with primary HIV infection and 25 controls. We examined relationships with disease progression and neuroinflammation, neuropsychological testing, and proton-magnetic resonance spectroscopy (MRS)-based metabolites.Results. Neurofilament light chain was elevated in primary HIV infection compared with controls (p=0.0004) and correlated with CSF neopterin (r=0.38, p=0.0005), IP-10 (r=0.39, p=0.002), WBCs (r=0.32, p=0.004), protein (r=0.59, p<0.0001), and CSF:plasma albumin ratio (r=0.60, p<0.0001). Neurofilament light chain correlated with decreased N-acteylaspartate/creatine and glutamate/creatine in the anterior cingulate (r=-0.35, p=0.02; r=-0.40, p=0.009, respectively), frontal white matter (r=-0.43, p=0.003; r=-0.30, p=0.048), and parietal gray matter (r=-0.43, p=0.003; r=-0.47, p=0.001). Beta-amyloid was elevated in the primary infection group (p=0.0005) and correlated with time infected (r=0.34, p=0.003). Neither marker correlated with neuropsychological abnormalities. T-tau and soluble amyloid precursor proteins did not differ between groups.Conclusions. Elevated neurofilament light chain and its correlation with MRS-based metabolites suggest early neuronal injury in a subset of participants with primary HIV infection through mechanisms involving central nervous system inflammation.
The Journal of Infectious Diseases 03/2013; · 6.41 Impact Factor
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ABSTRACT: OBJECTIVE:: Elite controllers (ECs) are a rare subset of HIV-1 infected individuals who maintain HIV-1 RNA concentrations in plasma below the lower limit of quantification of clinical assays (<20-50 copies/mL) in the absence of antiretroviral therapy. Here we examine to what extent ECs also control infection of the central nervous system (CNS). DESIGN:: We analyzed paired cerebrospinal fluid (CSF) and plasma samples using a highly sensitive assay for HIV-1 RNA quantification. METHODS:: We analyzed 28 CSF samples and 27 concurrent plasma samples from 14 ECs with the highly sensitive single-copy assay (SCA) that allows for HIV-1 RNA quantification down to less than 1 copy of HIV-1 RNA/mL. RESULTS:: Three samples were excluded because of internal standard failure. HIV-1 RNA was detected in only 5/26 CSF samples compared to 14/26 plasma samples (P = 0.02), with a median of 0.2 (range 0.1-6) copies/mL in CSF compared to 0.8 (range 0.1-189) in plasma (P < 0.0001). CONCLUSIONS:: HIV-1 RNA could not be detected in CSF in most ECs using the highly sensitive SCA, and when detected it was at significantly lower frequencies and concentrations than in plasma. ECs thus control HIV-1 in the CNS very well. Whether the infrequent and small amounts of HIV-1 RNA in the CSF reflect production from a local reservoir or virion exchange between the blood and the CSF is uncertain.
AIDS (London, England) 12/2012; · 4.91 Impact Factor
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Michael J Peluso,
Francesca Ferretti,
Julia Peterson, Evelyn Lee,
Dietmar Fuchs,
Antonio Boschini,
Magnus Gisslén,
Nancy Angoff,
Richard W Price,
Paola Cinque,
Serena Spudich
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ABSTRACT: : To characterize HIV-infected patients with neurosymptomatic cerebrospinal fluid (CSF) 'escape', defined as detectable CSF HIV RNA in the setting of treatment-suppressed plasma levels or CSF RNA more than 1-log higher than plasma RNA.
: Retrospective case series.
: Four urban medical centers in the United States and Europe.
: Virologically controlled HIV-infected patients on antiretroviral therapy (ART) with progressive neurologic abnormalities who were determined to have CSF 'escape'.
: Optimization of ART based upon drug susceptibility and presumed central nervous system exposure.
: Levels of CSF HIV RNA and inflammatory markers, clinical signs and symptoms, and MRI findings.
: Ten patients presented with new neurologic abnormalities, which included sensory, motor, and cognitive manifestations. Median CSF HIV RNA was 3900 copies/ml (range 134-9056), whereas median plasma HIV RNA was 62 copies/ml (range <50 to 380). Median CD4 T-cell count was 482 cells/μl (range 290-660). All patients had been controlled to less than 500 copies/ml for median 27.5 months (range 2-96) and five of 10 had been suppressed to less than 50 copies/ml for median 19.5 months (range 2-96). Patients had documentation of a stable ART regimen for median 21 months (range 9-60). All had CSF pleocytosis or elevated CSF protein; seven of eight had abnormalities on MRI; and six of seven harbored CSF resistance mutations. Following optimization of ART, eight of nine patients improved clinically.
: The development of neurologic symptoms in patients on ART with low or undetectable plasma HIV levels may be an indication of CSF 'escape'. This study adds to a growing body of literature regarding this rare condition in well controlled HIV infection.
AIDS (London, England) 05/2012; 26(14):1765-74. · 4.91 Impact Factor
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ABSTRACT: Despite suppression of plasma human immunodeficiency virus type 1 (HIV-1) RNA by antiretroviral therapy to levels below clinical assay detection, infection and immune activation may persist within the central nervous system and possibly lead to continued brain injury. We hypothesized that intensifying therapy would decrease cerebrospinal fluid (CSF) infection and immune activation.
This was a 12-week, randomized, open-label pilot study comparing addition of the integrase inhibitor raltegravir to no treatment augmentation, with an option for rollover to raltegravir. CSF and plasma were analyzed for HIV-1 RNA using a single-copy assay. CSF and blood immune activation was assessed by neopterin concentrations and CD4(+) and CD8(+) T-cell surface antigen expression.
Primary analysis compared 14 intensified (including rollovers) to 9 nonintensified subject experiences. Median HIV-1 RNA levels in all samples were lower in CSF (<.3 copies/mL) than in plasma (<.9 copies/mL; P < .0001), and raltegravir did not reduce HIV-1 RNA, CSF neopterin, or CD4(+) and CD8(+) T-cell activation.
Raltegravir intensification did not reduce intrathecal immunoactivation or alter CSF HIV-1 RNA levels in subjects with baseline viral suppression. With and without raltegravir intensification, HIV RNA levels in CSF were very low in the enrolled subjects. Clinical Trials Registration. NCT00672932.
The Journal of Infectious Diseases 12/2011; 204(12):1936-45. · 6.41 Impact Factor
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Serena Spudich,
Magnus Gisslen,
Lars Hagberg, Evelyn Lee,
Teri Liegler,
Bruce Brew,
Dietmar Fuchs,
Giuseppe Tambussi,
Paola Cinque,
Frederick M Hecht,
Richard W Price
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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
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ABSTRACT: Minocycline is a tetracycline antibiotic that has been shown to attenuate central nervous system (CNS) lentivirus infection, immune activation, and brain injury in model systems. To initiate assessment of minocycline as an adjuvant therapy in human CNS HIV infection, we conducted an open-labelled pilot study of its effects on cerebrospinal fluid (CSF) and blood biomarkers of infection and immune responses in 7 viremic subjects not taking antiretroviral therapy.
There were no discernable effects of minocycline on CSF or blood HIV-1 RNA, or biomarkers of immune activation and inflammation including: CSF and blood neopterin, CSF CCL2, CSF white blood cell count, and expression of cell-surface activation markers on CSF and blood T lymphocytes and monocytes.
This pilot study of biological responses to minocycline suggests little potential for its use as adjunctive antiviral or immunomodulating therapy in chronic untreated HIV infection.
AIDS Research and Therapy 01/2011; 8:17. · 2.54 Impact Factor
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ABSTRACT: A subset of HIV-infected patients, termed 'elite' viral controllers, maintain undetectable plasma HIV RNA levels in the absence of therapy. In this group, host-mediated viral control may be accompanied by chronic systemic inflammation. It is unknown whether either infection or chronic inflammation is present within the central nervous system of these individuals.
Cross-sectional analysis compared cerebrospinal fluid (CSF) HIV RNA and biomarkers of intrathecal inflammation in eight controllers (plasma HIV RNA levels <50 copies/ml) with 26 HIV-uninfected individuals, 25 untreated individuals HIV-infected, viremic individuals, and 23 HIV-infected individuals with treatment-mediated viral suppression (plasma HIV RNA levels <50 copies/ml).
All controllers had CSF HIV RNA levels below 2.5 copies/ml. CSF white blood cell (WBC) counts and CSF: plasma albumin ratios in the controllers were similar to those in both HIV-uninfected individuals and antiretroviral therapy-suppressed HIV-infected individuals. CSF neopterin, MCP-1, and IP-10 concentrations were also not different in the controllers from either HIV-uninfected or treated HIV-infected individuals.
The character of CSF HIV infection and degree of immunoactivation in controllers is comparable to that of HIV-uninfected and antiretroviral therapy-suppressed HIV-infected individuals, but distinct from that of untreated, viremic HIV-infected individuals.
AIDS (London, England) 03/2010; 24(7):1001-5. · 4.91 Impact Factor
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ABSTRACT: Raltegravir is an HIV-1 integrase inhibitor currently used in treatment-experienced HIV-1-infected patients resistant to other drug classes. In order to assess its central nervous system penetration, we measured raltegravir concentrations in cerebrospinal fluid (CSF) and plasma in subjects receiving antiretroviral treatment regimens containing this drug.
Raltegravir concentrations were determined by liquid chromatography tandem mass spectrometry in 25 paired CSF and plasma samples from 16 HIV-1-infected individuals. The lower limit of quantitation was 2.0 ng/ml for CSF and 10 ng/ml for plasma.
Twenty-four of the 25 CSF samples had detectable raltegravir concentrations with a median raltegravir concentration of 18.4 ng/ml (range, <2.0-126.0). The median plasma raltegravir concentration was 448 ng/ml (range, 37-5180). CSF raltegravir concentrations correlated with CSF:plasma albumin ratios and CSF albumin concentrations.
Approximately 50% of the CSF specimens exceeded the IC(95) levels reported to inhibit HIV-1 strains without resistance to integrase inhibitors. In addition to contributing to control of systemic HIV-1 infection, raltegravir achieves local inhibitory concentrations in CSF in most, but not all, patients. Blood-brain and blood-CSF barriers likely restrict drug entry, while enhanced permeability of these barriers enhances drug entry.
PLoS ONE 01/2009; 4(9):e6877. · 4.09 Impact Factor
