Treatment of human immunodeficiency virus infections.
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Biomedical subjects
Publications and source records attributed to M S Hirsch.
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The detection of human immunodeficiency virus (HIV)-associated antigens was simplified by the application of dot immunobinding on a nitrocellulose matrix. Antigens were detected by applying the polyethylene glycol-precipitated supernatants of experimentally infected cultures directly onto nitrocellulose strips and sequentially incubating the strips with an anti-HIV antiserum and an alkaline phosphatase-conjugated, species-specific antiserum. The immune reaction was developed by adding the precipitable substrate indoyl phosphate. The dot immunobinding assay was nearly as sensitive as the reverse transcriptase assay in detecting HIV antigens in experimentally infected peripheral blood mononuclear cells, as well as in a T-cell line. The technique was also useful in the in vitro evaluation of antiviral agents. The dot immunobinding assay is a simple and sensitive technique that is useful in the detection of HIV antigens in studies of viral pathogenesis.
Serum neutralizing antibodies against the human immunodeficiency virus were frequently detected in infected individuals, and low or absent serum neutralizing titers correlated with poor prognosis. Multiple diverse human immunodeficiency virus isolates were found to exhibit similar susceptibility to neutralization by a panel of human seropositive sera, suggesting that neutralizing antibodies are largely directed against conserved viral domains. Furthermore, utilizing antisera raised against a library of synthetic env peptides, four regions which are important in the neutralization process have been identified within both human immunodeficiency virus envelope glycoproteins (gp41 and gp120). Three of these are in conserved domains and should be considered for inclusion in a candidate vaccine.
Subacute encephalitis, characterized by demyelination, gliosis of the gray and white matter, focal necrosis, microglial nodules, atypical oligodendrocyte nuclei, and multinucleation of cells, was present in 27 of 30 (90%) autopsied patients with acquired immune deficiency syndrome (AIDS) or AIDS-related complex. Subacute encephalitis was mainly distributed in the frontal (58%) and temporal (69%) lobes, basal ganglia (77%), amygdala (80%), and hippocampus (64%). Ten (37%) with moderate or severe subacute encephalitis were demented; 82% with mild subacute encephalitis had no recognized neurologic disorder. Human T-lymphotropic virus type III (HTLV-III) was isolated from neural tissue or CSF in 11 of 13 patients, 10 with subacute encephalitis, and 1 without CNS lesions. We conclude that subacute encephalitis is common in AIDS patients and is most likely caused by CNS infection with HTLV-III.
Human immunodeficiency virus (HIV) has been isolated from both male and female genital secretions. We evaluated the pattern of female genital carriage during the menstrual cycle, and its relationship to HIV viremia. Seven menstruating seropositive women and one seronegative control had cervical secretions and venous blood samples cultured at weekly intervals during a single menstrual cycle. The virus was isolated from cervical secretions in four of seven women. No specific cycle pattern was seen, and positivity for HIV at one site (blood or cervical) did not correlate with positivity at another site. Blood cultures generally, but not always, became positive earlier than cultures from cervical specimens, suggesting higher titers of virus in blood. Thus, HIV secretion may be intermittent. These findings, together with earlier reports, suggest that seropositive women may transmit HIV at any time during the menstrual cycle.
Subacute encephalitis caused by infection of the central nervous system by the human immunodeficiency virus (HIV) is the most frequent cause of neurologic dysfunction in patients with the acquired immunodeficiency syndrome (AIDS). This disorder results in progressive cognitive, motor, and behavioral abnormalities in at least two thirds of patients with AIDS. Pathologic evidence of subacute encephalitis is found in 90% of these patients at autopsy. Human immunodeficiency virus is also the etiologic agent of aseptic meningitis, a disease that can occur at the time of seroconversion. Other neurologic disorders frequently associated with HIV include peripheral neuropathies and vacuolar myelopathy. Thus, HIV is neurotropic and may enter the central nervous system early in the course of infection. Neurologic disease may be the only clinical manifestation of HIV infection. Although mechanisms of pathogenesis are unclear, cells of monocyte-macrophage lineage may be important in viral spread to and within the central nervous system. Effective antiviral therapy will probably require penetration of drugs across the blood-brain barrier.
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Effective antiviral drugs are urgently needed to treat individuals who are infected with the human immunodeficiency virus (HIV). Several compounds, such as nucleoside analogs (AZT, ddCyd), phosphonoformate, and HPA-23 inhibit reverse transcriptase. The mode of action of ribavirin and interferon alpha A is less clear. A number of compounds have been tested in early clinical trials, and AZT so far looks the most promising. New drugs should undergo rapid but thorough in vitro and animal testing. Promising compounds should be made available as soon as possible for phase I trials.
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Cervical secretions from 14 women seropositive for HTLV-III/LAV were obtained between days 7 and 21 of the menstrual cycle and cultured for virus. HTLV-III/LAV was isolated from cervical secretions in 4 of 14 women, as well as from blood of 7 of 13 women tested. Female genital secretions may therefore be a source for sexual transmission of the virus to men.
We randomly assigned 208 patients who underwent brain biopsy for presumptive herpes simplex encephalitis to receive either vidarabine (15 mg per kilogram of body weight per day) or acyclovir (30 mg per kilogram per day) for 10 days. Sixty-nine patients (33 percent) had biopsy-proved disease; 37 received vidarabine, and 32 acyclovir. The mortality in the vidarabine recipients was 54 percent, as compared with 28 percent in the acyclovir recipients (P = 0.008). Six-month mortality varied according to the Glasgow coma score at the onset of therapy. For scores of greater than 10, 7 to 10, and less than or equal to 6, mortality was 42, 46, and 67 percent in the patients treated with vidarabine, as compared with 0, 25, and 25 percent in those treated with acyclovir. A six-month morbidity assessment using an adapted scoring system revealed that 5 of 37 patients receiving vidarabine (14 percent) as compared with 12 of 32 receiving acyclovir (38 percent) were functioning normally (P = 0.021). Eight vidarabine-treated patients (22 percent) and three acyclovir-treated patients (9 percent) had moderate debility. Patients under 30 years of age and with a Glasgow coma score above 10 had the best outcome with acyclovir treatment. We conclude that acyclovir is currently the treatment of choice for biopsy-proved herpes simplex encephalitis.
Recent reports have suggested a role for BW-B759U in the treatment of cytomegalovirus retinitis. The present study presents the ophthalmoscopic features in three treated patients, and examines the microscopic findings in the eyes of the first patient ever treated with BW-B759U for cytomegalovirus retinitis. Ophthalmoscopic findings of improvement on drug therapy included remission of perivascular infiltration, stabilization of the extent of the retinal area involved, and development of a pigmented chorioretinal scar in the involved area. Relapses occurred with cessation of therapy, and repeated courses of therapy were required. One patient developed a rhegmatogenous detachment with retinal breaks in an atrophic area of treated retinitis. Electron microscopic examination of the eyes of one patient disclosed the persistence of cytomegalovirus inclusions in retinal cells despite previous drug therapy. These findings suggest a virostatic action for BW-B759U.
Human T-cell lymphotropic virus type III (HTLV-III) has been isolated from neural tissues and cerebrospinal fluid (CSF) of patients with neurological syndromes associated with the acquired immune deficiency syndrome (AIDS) and the virus may be directly involved in the pathogenesis of the syndromes. To detect HTLV-III antigen in neural tissues from patients with AIDS, immunoperoxidase studies using a goat anti-HTLV-III serum were performed on frozen tissue sections of brain, spinal cord, and nerve from 13 patients with AIDS or HTLV-III-related neurological syndromes. HTLV-III was cultured from neural tissues or CSF in 11 of 13 of these patients. HTLV-III antigen was detected in the brains of 5 patients with AIDS and in none of the 13 non-AIDS control subjects. Rare positively stained cells were seen, frequently associated with capillaries and often located near microglial nodules. Morphologically, the cells resembled monocyte/macrophages and were found most frequently in the cortex of the frontal, temporal, and parietal lobes. These results provide further evidence that the subacute encephalitis of AIDS is associated with central nervous system infection by HTLV-III and that monocyte/macrophages are among the infected cell populations.
The ability of cells infected with human T lymphotropic virus type III (HTLV-III) to suppress lymphocyte responses to concanavalin A (ConA) was evaluated. Thirty homosexual men, both HTLV-III seropositive and seronegative, and 11 seronegative laboratory personnel were studied. Peripheral blood lymphocytes from all groups had lower responses to ConA in the presence of HTLV-III-infected H9 cells than in the presence of uninfected H9 cells. Among HTLV-III-seropositive males, responses to ConA in the presence of infected or uninfected H9 cells correlated with the number of T4 cells present. The studies suggest that HTLV-III-infected cells can suppress normal lymphocyte responses. Possible mechanisms of this suppression are discussed.
The human T-lymphotropic retrovirus type III (HTLV-III), the etiological agent of AIDS, has recently been detected in tears, cornea, and conjunctiva, raising the possibility of transmission of HTLV-III via contact lens trial sets used in routine fitting. We evaluated the ability of several contact lens cleaning solutions, with or without conditioning or disinfecting solutions, to disinfect contact lenses experimentally contaminated with HTLV-III. Following attempted disinfection, the lenses were cultured for residual HTLV-III on Hg cells for 28 days. Cultures without characteristic cytopathic effects, reverse transcriptase activity, and HTLV-III-specific antigen expression were considered negative. We found that all commercially available cleaning solutions tested were able to disinfect contact lenses exposed to HTLV-III.
Phosphonoformate and recombinant alpha-A interferon synergistically inhibited the replication of human T-cell lymphotropic virus type III in cultured peripheral blood lymphocytes. T-cell proliferative capability was maintained by this combination, and toxicity was minimal.