Translational spatial task and its relationship to HIV-associated neurocognitive disorders and apolipoprotein E in HIV-seropositive women.

HIV-associated neurocognitive disorders (HAND) continue to be a neurological complication of HIV infection in the era of combined antiretroviral therapy. Hippocampal neurodegeneration and dysfunction occurs as a result of HIV infection, but few studies to date have assesses spatial learning and memory function in patients with HAND. We used the Memory Island (MI) test to study the effects of HIV infection, apolipoprotein E (ApoE) allele status, and cerebral spinal fluid (CSF) ApoE protein levels on spatial learning and memory in our cohort of Hispanic women. The MI test is a virtual reality-based computer program that tests spatial learning and memory and was designed to resemble the Morris Water Maze test of hippocampal function widely used in rodent studies. In the current study, HIV-seropositive women (n = 20) and controls (n = 16) were evaluated with neuropsychological (NP) tests, the MI test, ApoE, and CSF ApoE assays. On the MI, the HIV-seropositive group showed significant reduced learning and delayed memory performance compared with HIV-seronegative controls. When stratified by cognitive performance on NP tests, the HIV-seropositive, cognitively impaired group performed worse than HIV-seronegative controls in ability to learn and in the delayed memory trial. Interestingly, differences were observed in the results obtained by the NP tests and the MI test for ε4 carriers and noncarriers: NP tests showed effects of the ε4 allele in HIV-seronegative women but not HIV-seropositive ones, whereas the converse was true for the MI test. Our findings suggest that the MI test is sensitive in detecting spatial deficits in HIV-seropositive women and that these deficits may arise relatively early in the course of HAND.

Cerebrospinal fluid examination may be useful in diagnosing neurosyphilis in asymptomatic HIV+ patients with syphilis.

Lumbar puncture in neurologically asymptomatic HIV+ patients is still under debate. There are different criteria for detecting neurosyphilis through cerebrospinal fluid (CSF), especially in cases that are negative through the Venereal Disease Research Laboratory (VDRL), regarding cellularity and protein content. However, a diagnosis of neurosyphilis can still exist despite negative VDRL. Treponema pallidum hemagglutination assay (TPHA) titers and application of the TPHA index in albumin and IgG improve the sensitivity, with a high degree of specificity. Thirty-two patients were selected for this study. VDRL was positive in five of them. The number of diagnoses reached 14 when the other techniques were added. It was not determined whether cellularity and increased protein levels were auxiliary tools in the diagnosis. According to our investigation, CSF analysis using the abovementioned techniques may be useful in diagnosing neurosyphilis in these patients.

Cerebrospinal fluid and human immunodeficiency virus. Findings in healthy, asymptomatic, seropositive men.

Involvement of the central nervous system by human immunodeficiency virus is an important cause of morbidity and mortality. We have undertaken a longitudinal study of asymptomatic individuals found to be human immunodeficiency virus seropositive to identify and characterize cerebrospinal fluid abnormalities early in the disease process. Our findings in 25 individuals have been notable for a frequent incidence of cerebrospinal fluid abnormalities. Pleocytosis or elevated cerebrospinal fluid protein was found in 12 (48%) of 15 patients studied. Oligoclonal banding was present in 6 (26%) of 23 patients. Human immunodeficiency virus was isolated by culture in 4 asymptomatic patients. The cerebrospinal fluid abnormalities we observed indicate an active process occurring in the central nervous system, even in early human immunodeficiency virus infection in asymptomatic patients. Serial observation of these patients for development of neuropsychiatric findings may provide answers to the significance of cerebrospinal fluid abnormalities identified in these patients.

Expression of HIV-1 in the cerebrospinal fluid detected by the polymerase chain reaction and its correlation with central nervous system disease.

The polymerase chain reaction (PCR) was used to detect HIV-1 sequences (gag, pol, and env) in the cerebrospinal fluid (CSF) and serum samples from 53 HIV-1-positive patients and the results correlated with clinical evidence of neurological disease. Twenty-three out of 24 patients with neurological disease had HIV-1-specific sequences in CSF compared with four out of 20 asymptomatic patients who had no evidence of neurological involvement. The detection of HIV RNA sequences by PCR in the CSF of HIV-positive patients may provide early, rapid and direct evidence of neurological involvement in asymptomatic subjects.

HIV isolation from cerebrospinal fluid in relation to immunological deficiency and neurological symptoms.

Human immunodeficiency virus (HIV) could be isolated from the cerebrospinal fluid (CSF) of the majority (62%) of 72 patients in various stages of HIV infection. This high rate of successful virus isolation was achieved only when the time from lumbar puncture to initiation of the cell cultures was short, i.e. not exceeding 5 h. The HIV isolation rates were equally high in patients with persistent generalized lymphadenopathy (PGL), AIDS-related complex (ARC) and AIDS. Although the HIV recovery rate was low in patients with normal immunological parameters it was not correlated with the degree of severity of the immunodeficiency in the other patients. Furthermore, the recovery rates were not significantly correlated to the duration of the infection. HIV was recovered as often from patients with neurological symptoms as from patients without such symptoms. These findings suggest that in the majority of patients there is central nervous system (CNS) involvement early in the course of HIV infection and that HIV replication in the CNS may occur in the absence of a pronounced systemic cellular immunodeficiency and frequently without causing overt neurological symptoms.

Magnetic resonance imaging morphometric analysis of cerebral volume loss in human immunodeficiency virus infection. The HNRC Group.

Magnetic resonance imaging was used to compare male subjects seropositive for antibody to human immunodeficiency virus type 1 (HIV positive), with and without medical symptoms, with two groups of men who were seronegative (HIV negative). The control subjects included men at high risk for exposure to HIV-1 and those at low risk. None of the HIV-positive subjects met criteria for HIV-associated dementia or had detectable opportunistic brain disease. Quantitative image-analytic techniques were used to estimate volumes of ventricular and cortical cerebrospinal fluid, cerebral white matter, and cortical and subcortical gray matter structures. Relative to low-risk group control subjects and asymptomatic HIV-positive subjects, nondemented but medically symptomatic HIV-positive subjects showed significant increases in cerebrospinal fluid, reduced volume of cerebral white matter, and reduced cerebral gray matter volumes. Unexpectedly, however, some cerebrospinal fluid increases and gray matter volume decreases were present in the seronegative high-risk control subjects as well.

Neuropsychological and neurological function of human immunodeficiency virus seropositive asymptomatic individuals.

Although individuals with acquired immunodeficiency syndrome (AIDS) are often impaired on a variety of neuropsychological tasks, questions remain as to when neuropsychological decline can be reliably detected during the course of human immunodeficiency virus (HIV) infection. Detailed neuropsychological testing was accomplished on a cohort of 83 immunologically and neurologically intact asymptomatic HIV-infected individuals drawn from a larger pool of 649 US Air Force personnel with HIV antibodies. These asymptomatic subjects were compared with a group of HIV-negative subjects, and no significant differences in neuropsychological functioning were found. No significant neuropsychological differences were found as a function of cerebrospinal fluid abnormalities in these asymptomatic subjects. When data from 13 subjects with immune compromise were included in the analyses, those with abnormal cerebrospinal fluid values performed significantly poorer on a task of verbal memory, suggesting that cognitive dysfunction is antedated by immunological decline. Methodological problems that inhibit specification of the incidence, prevalence, and natural history of HIV-related cognitive impairment are discussed, as are data suggesting that previously published high estimates of the frequency of HIV-related dementia may not be representative of all HIV-infected populations.

Spectrum of cerebrospinal fluid findings in various stages of human immunodeficiency virus infection.

This report summarizes the results of neurologic and cerebrospinal fluid (CSF) study findings in over 400 of the 649 human immunodeficiency virus-infected US Air Force personnel, evaluated as of Dec 31, 1987. Eighty percent of these patients were entirely asymptomatic and immunologically normal, 13% had low T-helper lymphocyte counts and/or cutaneous anergy, and only 7% had opportunistic infection. Sixty-three percent of all patients had some CSF abnormality. Sixty percent of the asymptomatic group had at least one abnormal result, over 25% had three or four CSF abnormalities, and over 7% had five or six abnormal values. When patients with evidence of blood-brain barrier leak were excluded, significant differences were seen between disease groups with regard to CSF glucose, CSF IgG levels, and CSF IgG synthesis. No human immunodeficiency virus-related central nervous system abnormalities were found on neurologic examination in immunologically intact asymptomatic patients regardless of CSF findings. No clear-cut predictor of impending central nervous system complications has, as yet, been identified from the CSF parameters studied.

Progressive cerebral volume loss in human immunodeficiency virus infection: a longitudinal volumetric magnetic resonance imaging study. HIV Neurobehavioral Research Center Group.

OBJECTIVE: To compare rates and anatomical patterns of brain atrophy during 3 stages of human immunodeficiency virus (HIV) disease. DESIGN: Comparisons of multiple serial brain magnetic resonance images in men without HIV infection and HIV-infected men in Centers for Disease Control and Prevention (CDC, Atlanta, Ga) stages A, B, and C. SETTING: Longitudinal cohort study of the San Diego HIV Neurobehavioral Research Center, San Diego, Calif. PARTICIPANTS: Eighty-six HIV-1-positive (HIV-positive) and 23 HIV-negative men who were similar in age and risk group. The number of HIV-positive men in each CDC stage was as follows: A, 33; B, 19; C, 34. All HIV-positive men were free of clinically detectable opportunistic neurologic illness. MAIN OUTCOME MEASURES: Regional volumes of serial magnetic resonance images converted to standardized slope estimates of change in regional volumes of interest. RESULTS: Medically asymptomatic men (CDC stage A) and medically symptomatic men (CDC stage C) had more rapid loss of cortical tissues than did HIV-negative men as manifested by higher slopes (Tukey honestly significant difference test, P=.02 and P=.001, respectively) for cortical fluid volume. Accelerated ventricular volume enlargement occurred only in men with CDC stage C disease. Reduction in the volume of white matter was accelerated in participants with CDC stage C disease compared with participants with CDC stage A disease. Of the gray matter regions, only the caudate nucleus sustained accelerated volume loss during CDC stage C disease. Participants whose systemic disease progressed to a higher CDC stage had significantly accelerated ventricular volume increases and caudate atrophy. Rates of cortical and subcortical fluid volume increases and reductions in the volumes of white matter and the caudate nucleus were significantly related to the rate of decline in the CD4+ lymphocyte count. CONCLUSIONS: In the absence of cerebral opportunistic disease, HIV infection causes progressive atrophy within the gray and white matter in the brain. These changes were most severe in the most advanced stage of disease but were evident even in medically asymptomatic HIV-positive persons. Within the gray matter, the caudate nucleus exhibited progressive volume loss linked to disease stage and the rate of decline of the CD4+ cell count. Structural brain changes can begin in the early stages of HIV infection and accelerate during advanced illness.

Intrathecal IgG synthesis and albumin leakage are increased in subjects with HIV-1 neurologic disease.

We analyzed matched cerebrospinal fluid and blood samples from 139 subjects enrolled in a study of the effects of human immunodeficiency virus type 1 (HIV-1) on the nervous system. Mean total intrathecal IgG synthesis rate was significantly higher in subjects with HIV-1-related neurologic disease (NeuroPos) than in HIV-1-seropositive (HIV+) subjects without neurologic disease (NeuroNeg) or at-risk seronegative controls (SNC). Mean trans-blood-brain barrier (BBB) albumin leakage (AL) rate increased significantly across groups (SNC < NeuroNeg < NeuroPos). AL was significantly higher in subjects with absolute CD4 counts < 100/mm3 versus those with > or = 100 cells/mm3 and significantly higher in AIDS compared with asymptomatic HIV+. Elevated total intrathecal IgG synthesis rate could not be accounted for solely by the presence of a damaged BBB, because 79% of subjects with elevated IgG synthesis rates had a normal BBB as assessed by the AL formula. Furthermore, the Tourtellotte formula inherently corrects for BBB leakage. We confirmed, using state-of-the-art albumin and IgG determinations, that intrathecal IgG synthesis is prevalent in all stages of HIV-1 disease. In the absence of a CNS opportunistic infection or tumor, mean total intrathecal IgG synthesis rate and trans-BBB AL are significantly higher in subjects with clinical HIV-1 CNS disease than in neurologically normally HIV+ subjects.

Measurement of cerebrospinal fluid antibody to the HIV-1 principal neutralizing determinant (V3 loop).

Antibody to the human immunodeficiency virus (HIV)-1 principal neutralizing determinant (V3 loop) was measured by peptide enzyme-linked immunosorbent assay (ELISA) in cerebrospinal fluid (CSF) and paired serum samples of 21 HIV-seropositive patients. These patients had normal neurologic examinations and were without neurologic symptoms. Peptide ELISA demonstrated intrathecal antibody synthesis against the V3 loop of HIVMN, the V3 loop of HIVNY5, the V3 loop of HIVLAI, and the entire recombinant HIV-1MN gp120 in 21 of 21, 10 of 21, one of 21, and 12 of 21 patients, respectively. Biospecific interaction analysis (BIAcore), which requires only small amounts of CSF, was also used to detect anti-V3 CSF antibody. Fine mapping of linear epitopes within the V3 region was successful in three of five patients by Geysen PIN (PEPSCAN) ELISA and discordance between epitope specificity of CSF and serum antibody was found. While detection of CSF antibody against the V3 loop of HIVMN by peptide ELISA has been recently reported, we add to this finding using the peptide ELISA, PEPSCAN and BIAcore methodologies as well as measuring intrathecal antibody synthesis against V3 loops from HIV strains. Application of these techniques to future studies of anti-V3 antibody in CSF from persons receiving anti-HIV-1 immunizations may provide insight into the immunoregulation of the virus in the nervous system.

Effect of antiretroviral therapy on the cerebrospinal fluid of patients seropositive for the human immunodeficiency virus.

Elevated levels of beta 2-microglobulin and neopterin in cerebrospinal fluid (CSF) have been associated with neurologic complications of infection with the human immunodeficiency virus (HIV). The effect of zidovudine (ZDV) on these markers was assessed by studying the effect of ZDV treatment duration on CSF levels in a cohort of 145 HIV-positive men who were receiving ZDV. CSF beta 2-microglobulin and neopterin levels were significantly lower in those who had been taking ZDV for an intermediate period of time (46-365 days) than in those who had received ZDV either long term (> 365 days) or short term (1-45 days). CSF quinolinic acid levels were independent of duration of ZDV administration. A second CSF evaluation was available after 1 year for 54 HIV-positive men (19 of whom were also in the first cohort) and 11 HIV-negative controls. Patients who had started ZDV between lumbar punctures showed a significant decrease in CSF beta 2-microglobulin, but in those who had been receiving ZDV for > 1 year beta 2-microglobulin increased (p = 0.001). The effect was not observed with neopterin (p = 0.14). (Quinolinic acid levels were not studied longitudinally.) Finally, we observed that CSF levels of beta 2-microglobulin, neopterin, and quinolinic acid correlated strongly with each other in HIV-positive individuals (r = 0.7, p < 0.0001), even though ZDV might have different effects on these markers. In conclusion, we report that initiation of ZDV therapy is associated with a transient decrease in CSF levels of beta 2-microglobulin and neopterin.(ABSTRACT TRUNCATED AT 250 WORDS)

Neopterin and interferon-gamma in serum and cerebrospinal fluid of patients with HIV-associated neurologic disease.

We measured the levels of interferon-gamma (IFN-gamma) and neopterin in the serum and cerebrospinal fluid of 121 human immunodeficiency virus-seropositive (HIV+) and 62-seronegative (HIV-) individuals evaluated for neurologic disease. CSF levels of IFN-gamma and serum and CSF levels of neopterin were higher in HIV+ than in HIV- individuals. Patients with HIV- related meningitis and with opportunistic CNS infections had higher serum neopterin levels than HIV+ asymptomatic individuals. CSF levels of IFN-gamma were slightly higher in CSF of HIV+ individuals in all groups (0.31 +/- 0.03 U/ml) than in HIV- individuals (0.12 +/- 0.03). CSF levels of neopterin were similar in HIV+ asymptomatic individuals (6.9 +/- 0.7 nmol/l) and HIV- individuals (5.9 +/- 1.1), but were elevated in those HIV-infected individuals with neurologic disease, particularly patients with HIV-associated meningitis (72.1 +/- 13.3 nmol/l), opportunistic CNS infections (36 +/- 9.1), and inflammatory demyelinating polyneuropathies (32.4 +/- 17.2). Levels of neopterin correlated positively with levels of soluble interleukin 2 receptor and soluble CD8, 2 additional indicators of immune activation. In the absence of neurologic disease, levels of IFN-gamma and neopterin in both serum and CSF were stable for up to 4 years after seroconversion. These data suggest that increased CSF neopterin is associated with HIV-associated neurologic disease.

Intrathecal synthesis of anti-HIV IgG: correlation with increasing duration of HIV-1 infection.

We determined intrathecal synthesis (ITS) of anti-HIV-1 immunoglobulin in 62 CSF samples from 51 HIV-1 seropositive homosexual men using an ELISA technique with paired serum and CSF samples diluted to a concentration of IgG of 10 micrograms/ml. All subjects were neurologically normal and none was taking zidovudine. We estimated duration of HIV-1 infection from semiannual serologic testing during the 3-year period before CSF analysis and detected ITS of anti-HIV-1 immunoglobulin in 2 of 12 (17%) of those with less than 18 months of HIV-1 seropositivity, in 3 of 21 (14%) with 19 to 36 months, and in 13 of 29 (45%) with greater than 36 months of HIV-1 seropositivity (p = 0.037). There was a trend toward an inverse relationship between level of ITS and the peripheral blood T-helper lymphocyte count. This study demonstrates that increasing ITS of anti-HIV-1 IgG is related to duration of HIV-1 infection and suggests an inverse correlation with systemic immune status. The detection of ITS of anti-HIV-1 immunoglobulin is not necessarily a marker of clinically overt neurologic involvement.

Intrathecal humoral immunologic response in neurologically symptomatic and asymptomatic patients with human immunodeficiency virus infection.

We analyzed the intrathecal humoral immunologic response in 42 human immunodeficiency virus (HIV)-infected patients. Eighteen patients had clinical neurologic abnormalities, while the remaining 24 patients were neurologically symptom-free. Nine of the neurologically symptomatic patients at early infection had slight neurologic dysfunction; in nine other subjects at late infection, the neurologic impairment was moderate or severe. When compared with symptom-free patients, neurologically symptomatic patients had increased intra-blood-brain barrier (BBB) HIV-specific IgG (p less than 0.001) and total IgG synthesis (p less than 0.01) with oligoclonal bands (OCBs) in the CSF and/or serum (11/18 versus 3/24). At early stages of the infection, neurologically symptomatic patients showed increased total intrathecal IgG synthesis (9/9) coincident with OCBs in the CSF and serum (7/9) and slight mononuclear pleocytosis (7/9), but less frequent HIV-specific IgG production within the CNS (6/9). In advanced infection, the number of neurologically symptomatic patients with intrathecal HIV-specific IgG synthesis (8/9) was higher, while the number of those with increased total intra-BBB IgG synthesis (5/9; p less than 0.01), OCBs (4/9), and increased CSF leukocyte count (1/9; p less than 0.001) was lower than at early infection. Our data suggest humoral intra-BBB immunoactivation at early stages of HIV infection followed by declining B cell response within the CNS at advanced infection.

Mediator release in cerebrospinal fluid of human immunodeficiency virus-positive patients with central nervous system involvement.

In this study we evaluated the release of some mediators of inflammatory reactions such as histamine (H), leukotriene B4 (LTB4), leukotriene C4 (LTC4) and prostaglandin D2 (PGD2) in the cerebrospinal fluid (CSF) of 15 patients with acquired immunodeficiency syndrome (AIDS), eight with opportunistic infections of the central nervous system (CNS) and seven without HIV-related neurological pathology, and of 25 HIV-negative control subjects with other neurological diseases. The cerebrospinal LTB4 level was increased in all the AIDS patients (mean 348 pg/ml); the control group revealed normal levels of LTB4 in the CSF (mean 63.2 pg/ml). The PGD2 level in the HIV-positive (mean 264 pg/ml) patients was higher than of the control subjects (mean 50 pg/ml), while low LTC4 levels were found both in the HIV-positive and control groups. We did not find any significant concentration of H in the CSF of either the HIV-positive or the control subjects. These findings may be due to the presence of chronic HIV infection or to the opportunistic infections of the CNS that so often occur in the latest stages of the disease.

Human immunodeficiency virus (HIV)-specific antibodies, neutralizing activity and antibody-dependent cellular cytotoxicity (ADCC) in the cerebrospinal fluid of HIV-infected patients.

We assessed the capacity of cerebrospinal fluids (CSF) and sera from human immunodeficiency virus (HIV)-seropositive patients to neutralize HIV and to mediate specific antibody-dependent lysis of HIV-infected target cells. A local HIV-specific intrathecal antibody synthesis was found in all stages of HIV infection regardless of neurological manifestations. Virus-neutralizing antibodies could not be detected in the CSF of patients with primary encephalitis or polyneuropathy. Cytotoxic antibodies mediating HIV-specific antibody-dependent cellular cytotoxicity (ADCC) were demonstrable in the CSF of most patients without evidence of central nervous system (CNS) involvement, but only in 43% of cases with HIV encephalitis. In some cases, the exclusive detection of ADCC activity in either the CSF or serum compartment suggested the presence of non-identical target antigens in the CSF and serum of the same patient. Further studies are needed to clarify the significance of these findings for the manifestation of CNS involvement in HIV infection.

Increasing intrathecal lymphocytosis and immunoglobulin G production in neurologically asymptomatic HIV-1 infection.

Cerebrospinal fluid from 34 human immunodeficiency virus (HIV-1) seropositive patients, only four of whom had HIV-related neurological symptoms, was examined by cytology, protein quantification, isoelectric focusing and specific serological tests. CSF lymphocytosis and evidence of intrathecal IgG production, found in 21 and 20 respectively of the 34 patients, correlated significantly with the duration of the infection. Increasing IgG index was found in two patients with repeated CSF examinations during greater than 7 years. Intrathecal HIV antibodies were detected on Western blot in 32/34 patients. HIV antigen test positive in 5/34 sera was negative in all 34 CSF samples. Intrathecal B cell activation seems to increase during the early HIV infection.

Soluble interleukin-2 receptor and soluble CD8 in serum and cerebrospinal fluid during human immunodeficiency virus-associated neurologic disease.

We have measured levels of soluble interleukin-2 receptor (sIL-2R) and soluble CD8 (sCD8) in serum and cerebrospinal fluid (CSF) of 127 human immunodeficiency virus (HIV)-seropositive and 51 HIV-seronegative individuals. Serum levels of sIL-2R and sCD8 were higher in HIV+ than in HIV- individuals. HIV+ individuals were grouped by neurological status: asymptomatic, abnormal on neuropsychological screening, HIV-related meningitis, inflammatory demyelinating polyneuropathy, opportunistic central nervous system (CNS) infections and HIV-related dementia, myelopathy or sensory neuropathy. Serum levels of sIL-2R and sCD8 were higher in all HIV+ categories compared to HIV- individuals. Patients with HIV-related meningitis had higher levels of sIL-2R and sCD8 than asymptomatic HIV+ individuals, and inflammatory polyneuropathy patients had higher levels of sCD8. CSF levels of sCD8 were higher in all categories of HIV+ than in HIV- individuals. Patients with HIV-related meningitis, inflammatory neuropathy and opportunistic infections had higher levels than asymptomatic individuals. Examination of the time course showed that serum and CSF levels of sIL-2R and sCD8 increased to very high levels during acute HIV infections. Serum levels then declined over several months to relatively stable elevated levels. By 1-2 years after HIV infection sIL-2R was relatively low in CSF, while sCD8 remained elevated with a gradual decrease over the subsequent years of follow-up.