Lionel Resnick

Multiple sclerosis-like illness occurring with human immunodeficiency virus infection.

We describe seven men with a neurologic disease clinically indistinguishable from multiple sclerosis occurring in association with seropositivity for the human immunodeficiency virus, type 1 (HIV-1). Histopathology of the CNS obtained in three patients (2 by brain biopsy, 1 at autopsy) was consistent with MS. The neurologic symptoms preceded the onset of clinically evident immunosuppression in all patients. In three men, HIV-1 seropositivity was demonstrated concomitantly or within 3 months of the onset of their neurologic disease. In the others, features of MS preceded the demonstration of HIV-1 seropositivity by 41 months, 59 months, 11 years, and 18 years, respectively. Despite the superimposition of varying degrees of cellular immunodeficiency associated with HIV-1 infection, six of these men continued to experience relapsing neurologic symptoms.

A phase I study of recombinant human interferon-alpha 2a or human lymphoblastoid interferon-alpha n1 and concomitant zidovudine in patients with AIDS-related Kaposi's sarcoma.

To determine the safety, maximum tolerated dose, and preliminary efficacy of concomitant interferon-alpha and zidovudine therapy in AIDS-related Kaposis sarcoma (KS), 56 patients with biopsy-proven KS and documented human immunodeficiency virus type 1 (HIV) infection were enrolled into a phase I study. Interferon-alpha was given intramuscularly at a dose of 9, 18, or 27 mu once a day and zidovudine was administered as 100 or 200 mg every 4 h for 8 weeks followed by a 48-week maintenance period. The major toxicities were anemia, neutropenia, and hepatotoxicity. Neutropenia was dose limiting with 1,200 mg of zidovudine/day and the lowest dose of interferon-alpha (9 mu/day). Hepatotoxicity was dose limiting with 27 mu of interferon and 600 mg of zidovudine/day. Cumulative dose-related anemia or neutropenia was not seen during long-term follow-up. The maximum tolerated doses for the combination were defined as 18 mu daily for interferon-alpha and 600 mg daily for zidovudine. Variable changes in CD4 lymphocytes occurred during the first 8 weeks of therapy. At higher doses of the combination, sustained increases in median CD4 lymphocyte numbers were noted (p less than 0.001). In HIV antigenemic patients, progressive antigen suppression was seen with increasing doses of the combination (p less than 0.005). The overall antitumor response rate was 47%. Tumor regression was associated with better survival benefits (p less than 0.001) and a pretreatment CD4 cell count greater than or equal to 200 cells/mm3 (p = 0.01). In conclusion, intermediate doses of interferon-alpha and lower doses of zidovudine appear to be relatively well tolerated and associated with disease improvement, including survival benefits.

The benzylthio-pyrimidine U-31,355, a potent inhibitor of HIV-1 reverse transcriptase

U-31,355, or 4-amino-2-(benzylthio)-6-chloropyrimidine is an inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) and possesses anti-HIV activity in HIV-1-infected lymphocytes grown in tissue culture. The compound acts as a specific inhibitor of the RNA-directed DNA polymerase function of HIV-1RT and does not impair the functions of the DNA-catalyzed DNA polymerase or the Rnase H of the enzyme. Kinetic studies were carried out to elucidate the mechanism of RT inhibition by U-31,355. The data were analyzed using Briggs-Haldane kinetics, assuming that the reaction is ordered in that the template:primer binds to the enzyme first, followed by the addition of dNTP, and that the polymerase is a processive enzyme. Based on these assumptions, a velocity equation was derived that allows the calculation of all the essential forward and backward rate constants for the reactions occurring between the enzyme, its substrates, and the inhibitor. The results obtained indicate that U-31,355 acts as a mixed inhibitor with respect to the template:primer and dNTP binding sites associated with the RNA-directed DNA polymerase domain of the enzyme. The inhibitor possessed a significantly higher binding affinity for the enzyme-substrate complexes, than for the free enzyme and consequently did not directly affect the functions of the substrate binding sites. Therefore, U-31,355 appears to impair an event occurring after the formation of the enzyme-substrate complexes, which involves either inhibition of the phosphoester bond formation or translocation of the enzyme relative to its template:primer following the formation of the ester bond. Moreover, the potency of U-31,355 depends on the base composition of the template:primer in that the inhibitor showed a much higher binding affinity for the enzyme-poly (rC):(dG)10 complexes than for the poly (rA):(dT)10 complexes.

Association of ‘(tropical) ataxic neuropathy’ with HTLV-II

Jamaican Neuropathy of the ataxic type (tropical ataxic neuropathy [TAN] and spastic type (tropical spastic paraparesis [TSP]) have been recognized for over a century in Jamaica. The recent association of TSP with HTLV-I (TSP/HAM) is now well established. We now present evidence for a possible association between a TAN-like illness with HTLV-II in four females aged 34-49. All presented with ataxic gait and all four have prominent mental changes. Three of the four also have minor motor deficits with urinary frequency and two have nocturnal leg cramps. All have serum antibody and all had PCR evidence of HTLV-II infection. Antibody to HTLV-II is present in CSF from two subjects. The distinctive picture of prominent ataxia and altered mental status in these subjects contrasts with a predominantly myelopathic picture seen in TSP/HAM.

The role of HTLV in HIV‐1 neurologic disease

We performed a serologic survey for antibodies to HTLV-I/II in the course of a longitudinal study of the neurologic complications of HIV-1 infection. Nine (3.7%) of 242 HIV-1 seropositive subjects and none of 60 HIV-1 seronegative control subjects had antibodies to HTLV-I/II by ELISA. Western blot and polymerase chain reaction confirmed the presence of HTLV-I in 2 subjects and HTLV-II infection in 2 others. Both HIV-l/HTLV-I coinfected subjects and 1 HIV-l/HTLV-II coinfected subject had a slowly progressive myelopathy clinically identical to tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM). The presence of a myelopathy resembling TSP/HAM in the coinfected subjects suggests that HIV-1 may enhance the expression of neurologic disease caused by HTLV. Patients with a progressive myelopathy occurring in association with HIV-1 infection should be serologically tested for the presence of HTLV. Establishing dual infection has therapeutic and prognostic import as 1 of the HIV-l/HTLV-I subjects substantially improved with corticosteroids and the HIV-l/HTLV-II subject with myelopathy had a marked improvement in the absence of therapeutic intervention.

HIV-induced syncytium formation requires the formation of conjugates between virus-infected and uninfected T-cells in vitro

The transmission of HIV requires the interaction of the cell-surface CD4 receptor and the viral envelope glycoprotein. Experiments were performed to determine the role of other cell-surface molecules in the development of HIV-induced syncytia. Although CEM and MT-2 cells had similar cell-surface CD4 receptor densities, less than 1% of CEM cells and greater than 95% of MT-2 cells formed syncytia with H9 cells chronically infected with HIV-1 (H9-IIIB). When compared with CEM cells, MT-2 cells exhibited a 10-fold and threefold greater capacity to form homotypic and heterotypic conjugates with H9 cells, respectively. Increasing the conjugate formation capacity of CEM cells with the lectin wheat germ agglutinin led to a greater than 30-fold increase in the formation of syncytia with H9/IIIB cells. The formation of syncytia between MT-2 and H9/IIIB cells was magnesium-, energy-, temperature-, and actin-cytoskeleton-dependent, and could be inhibited (65%) by an anti-LFA-1 monoclonal antibody. The combination of anti-leukocyte function-associated antigen-1 (LFA-1) and anti-CD2 monoclonal antibodies resulted in a synergistic inhibition (89%) of syncytium formation. These results indicate that integrins and other cell-surface adhesion molecules regulate HIV-induced syncytium formation.

Concentration-targeted phase I trials of atevirdine mesylate in patients with HIV infection: dosage requirements and pharmacokinetic studies

RATIONALE To determine the dosage requirements and pharmacokinetics of atevirdine, a non-nucleoside reverse transcriptase inhibitor and its N-dealkylated metabolite (N-ATV) during phase I studies in patients receiving atevirdine alone or in combination with zidovudine. DESIGN Two open label, phase I studies conducted by the adult AIDS Clinical Trials Group (ACTG) in which atevirdine was administered every 8 h with weekly dosage adjustments to attain targeted trough plasma atevirdine concentrations. SETTING Five Adult AIDS Clinical Trials Units. PATIENTS Fifty patients (ACTG 199; n = 20 and ACTG 187; n = 30) with HIV-1 infection and < or =500 CD4+ lymphocytes/mm3. INTERVENTION ACTG 199; 12 weeks of therapy with atevirdine (dose-adjusted to achieve plasma trough atevirdine concentrations of 5-10 microM) and zidovudine (200 mg every 8 h). ACTG 187: 12 weeks of atevirdine monotherapy with atevirdine doses adjusted to achieve escalating, targeted trough plasma concentration ranges (5-13, 14-22, and 23-31 microM). MEASUREMENTS ACTG 199: atevirdine, N-ATV and zidovudine trough determinations weekly (all patients) and intensive pharmacokinetics (selected patients) prior to and at 6 and 12 weeks during combination therapy. ACTG 187: atevirdine and N-ATV trough concentrations over a 12 week period. Intensive pharmacokinetic studies were conducted prior to and at 4 and/or 8 weeks during atevirdine monotherapy in female patients. RESULTS Atevirdine plasma concentrations demonstrated considerable interpatient variability which was minimized by the adjustment of maintenance doses (range: 600-3900 mg/day) to achieve the desired trough concentrations. In ACTG 187, the mean number of weeks to attain the target value, and the percentage of patients who attained the target, was group I (5-11 microM): 2.7+/-2.4 weeks (92%); group II (12-21 microM): 2.6+/-1.8 (64%); and group III (22-31 microM): 7.0+/-5.6 weeks (27%). In ACTG 199 it was 3.2+/-5.2 weeks (95%) to achieve a 5-10 microM trough. Atevirdine demonstrated a mono- or bi-exponential decline among most of the patients studied after the first dose. During multiple-dosing a number of patterns of atevirdine disposition were observed including; rapid absorption with Cmax at 0.5-1 h, delayed absorption with Cmax at 3-4 h; minimal Cmax to Cmin fluctuation and Cmax to Cmin ratios of > 4. N-ATV (an inactive metabolite) patterns were characterized on day one by rapid appearance of the metabolite which peaked at 2-3 h after the dose and declined in a mono- or bi-exponential manner. At steady-state N-ATV patterns demonstrated minimal Cmax to Cmin fluctuations with some of the patients having more stable plasma N-ATV concentrations, while others had greater fluctuations week to week. CONCLUSIONS Considerable interpatient variability was noted in the pharmacokinetics of atevirdine. The variation in drug disposition was reflected in the range of daily doses required to attain the targeted trough concentrations. Atevirdine metabolism did not appear to reach saturation during chronic dosing in many of our patients, as reflected by the pattern of N-ATV/ATV ratios in plasma and saturation was not an explanation for the variation in dosing requirements. No apparent differences were noted between males and females, and atevirdine did not appear to influence zidovudine disposition.

Phase I study of atevirdine mesylate (U-87201E) monotherapy in HIV-1-infected patients.

The safety, tolerability, and antiviral activity of atevirdine (ATV), a nonnucleoside reverse transcriptase inhibitor, were studied in a phase I/II clinical trial (ACTG 187) of patients with CD4 counts < or =500/mm3. In all, 34 HIV-1-infected patients were randomized to receive ATV for 12 weeks in doses chosen to achieve one of three serum trough levels: 5 to 13 microM, 14 to 22 microM, or 23 to 31 microM. Rash was the most common adverse event, with a grade 3 or 4 rash occurring in 4 patients. No significant change from baseline in HIV-1 plasma RNA mean copy number was detected at week 4 (+0.09 log10 copies/ml; p = .30). However, some evidence indicated moderate antiviral activity at week 4, based on median changes in CD4 count (+23/mm3; p = .05), and viral peripheral blood mononuclear cell (PBMC) titer (-0.68 log10) copies/ml; p = .03). In addition, 2 of 4 patients with detectable baseline serum p24 antigen showed declines of >50%. HIV-1 resistance to ATV was detected in 41% of patients and was most commonly associated with RT mutations K103N and Y181C. In contrast, the Y181C mutation was not detected in ATV-resistant isolates obtained from patients enrolled in ACTG 199, a study of ATV given in combination with zidovudine. Under the conditions of this study, ATV failed to demonstrate significant antiretroviral activity. However, transient in vivo activity might have been obscured by rapid development of resistance coupled with inadequate sampling at early time points following initiation of ATV therapy.

Development of an assay that detects transcriptionally competent human immunodeficiency virus type one particles

To study the functional properties of HIV-1 reverse transcriptase (RT) from intact viral particles without the requirement for tissue culture expansion, a method that couples HIV-1 reverse transcription utilizing its endogenous RT (ERT) with polymerase chain reaction amplification (PCR) was developed. Detection of endogenous reverse transcripts from HIV particles by ERT-PCR was compared to HIV RNA PCR detection using avian myeloblastosis virus (AMV) RT from plasma samples from 45 HIV-1 infected patients. The HIV ERT-PCR method was capable of detecting plasma viremia with the same efficiency (29/29 patients) as the AMV RT HIV RNA PCR in patients with CD4 cell counts of less than 500/mm3. The determination of HIV-RT drug sensitivities using four well-characterized HIV-1 lab strains was assessed. The ERT-PCR method detected reduced sensitivity to TIBO R82150 (10 microM) in a TIBO resistant strain but not in the TIBO sensitive HTLV-IIIB viral mixture or an HTLV-IIIB clone. In summary, the HIV ERT-PCR method provides a useful approach for the detection of HIV and the characterization of RT sensitivities among HIV-1 strains.