Lysis of infected cells in vivo by antiviral cytolytic T cells demonstrated by release of cell internal viral proteins.

Immunocompetent adult mice infected with lymphocytic choriomeningitis virus (LCMV) generate a strong antiviral cytotoxic T cell response that clears virus from all organs. Although there is good evidence that immune cytotoxic T lymphocytes (CTL) kill target cells in vitro, in vivo it is debated whether antiviral activity of CD8+ T cells is mediated via direct target cell lysis or via soluble mediators. To demonstrate CD8+ T cell-mediated destruction of infected cells in vivo a specific cell-internal releasable marker was used as label, i.e. the nucleoprotein (NP) of LCMV. Since LCMV is non-cytopathic the viral NP will only be released in substantial amounts because of destruction of infected host cells by immune CTL. It is shown here that the amount of NP released from infected and 51Cr-labeled target cells in vitro correlated well with the amount of radioactivity released. Viral NP released in vivo by CTL is bound and masked by the anti-NP antibodies that are produced very early and efficiently. However, NP could readily be detected in sera of LCMV-infected CD8+ competent mice that could not generate antibodies specific for the NP because they were treated with a depleting anti-CD4 antibody. NP was also detected in the cerebrospinal fluid of mice suffering from CD8+ T cell-mediated lymphocytic choriomeningitis after intracerebral infection. NP titers in sera of anti-CD4-treated LCMV-infected mice exhibited a peak around day 7-8 when CTL activity was highest. When mice were CD8 T cell-depleted with anti-CD8 monoclonal antibody or in LCMV-carrier mice, no NP was detected in the serum. Highly activated LCMV-specific CTL adoptively transfused to LCMV-infected irradiated recipient mice also caused a time-dependent release of NP into serum. This confirms that the CD8+ population is responsible for the release of NP from infected host cells. These results represent an in vivo correlate of CTL-mediated cytolysis and evidence that antiviral cytotoxic T cells are cytolytic in vivo. They also suggest that antibody responses to internal antigens of non-cytopathic viruses may signal CD8+ T cell-mediated destruction of infected host cells.

Comparison of spinal fluid beta 2-microglobulin levels with CD4+ T cell count, in vitro T helper cell function, and spinal fluid IgG parameters in 163 neurologically normal adults infected with the human immunodeficiency virus type 1.

Beta 2-microglobulin levels were measured in the cerebrospinal fluid (CSF) and serum of 163 human immunodeficiency virus-positive (HIV+) persons with normal neurologic physical examinations. None were on antiretroviral therapy. Only 3% had a positive CSF HIV p24 antigen test. The CSF beta 2-microglobulin levels increased as the CD4+ T cell count decreased. Intrathecal production of beta 2-microglobulin was suggested by finding CSF concentrations greater than serum concentrations in 15% of patients. The CSF beta 2-microglobulin levels rose as in vitro T helper cell function deteriorated, independent of CD4+ T cell count. CSF beta 2-microglobulin levels paralleled CSF IgG, IgG index, and IgG synthesis. Higher CSF beta 2-microglobulin levels were found in persons with positive CSF oligoclonal bands. CSF beta 2-microglobulin concentration may serve as a marker for subclinical neurologic damage due to HIV. If this is established, defining the effect of anti-HIV interventions on CSF beta 2-microglobulin would be warranted.

Measles virus polypeptide-specific antibody profile in multiple sclerosis.

Elevated antibody (Ab) titers to measles virus (MV) is a frequent finding in MS. Although MV-Abs are synthesized intrathecally, it is not known whether this is due to polyclonal activation of B cells recruited from the blood, recognition of MV antigens within the CNS, or cross-reactivity with myelin antigens. This study examined these possibilities using purified MV polypeptides. We examined Ab reactivity to each polypeptide in serum and CSF from 21 MS patients, 5 with subacute sclerosing panencephalitis (SSPE), and 11 patients with other neurologic diseases (OND), and serum from 5 patients with acute MV infection and 11 normal controls. The serum of all subjects tested contained reactivity with MV and the 5 polypeptides. Of 21 MS patients, 20 had CSF reactivity with MV compared with 3/11 ONDs and 5/5 SSPE patients. Intrathecal MV-Ab synthesis was present in 11/21 MS patients, 5/5 SSPE, and in none of the ONDs. Nine of 21 MS patients had intrathecal synthesis of Ab to 2 MV polypeptides. Serum and CSF reactivity in MS patients was skewed towards the F polypeptide. The results are consistent with the concept of polyclonal B cell activation within the CNS, but the heightened response to F could also reflect cross-reactivity with a relevant antigen in MS.

Declining incidence of AIDS dementia complex after introduction of zidovudine treatment.

OBJECTIVE: To assess the incidence of the AIDS dementia complex and the presence of HIV I p24 antigen in cerebrospinal fluid in relation to zidovudine treatment. DESIGN: Retrospective study of a consecutive series of patients with AIDS from 1982 to 1988. SETTING: An academic centre for AIDS. PATIENTS: 196 Patients with AIDS and neurological symptoms examined from 1982 to 1988. INTERVENTIONS: Zidovudine treatment, which was introduced to The Netherlands on 1 May 1987 for patients with severe symptoms of HIV infection (Centers for Disease Control groups IVA, B, C, and D). MAIN OUTCOME MEASURES: Diagnosis of AIDS dementia complex and presence of HIV I p24 antigen in cerebrospinal fluid. RESULTS: The AIDS dementia complex was diagnosed in 40 of the 196 (20%) patients with AIDS. Thirty eight of 107 patients with AIDS (36%) not taking zidovudine developed the AIDS dementia complex compared with two of the 89 (2%) taking the drug (p less than 0.00001). The incidence of the AIDS dementia complex increased to 53% in the first half of 1987, after the introduction of zidovudine in May 1987, decreasing to 10% in the second half of 1987 and to 3% in 1988. Dementia was diagnosed before definition of the AIDS dementia complex (1986) according to DSM-III criteria and there was good agreement between diagnosis before and after 1986. Sixteen of 61 samples of cerebrospinal fluid (26%) from patients with AIDS (10 with the AIDS dementia complex) not taking zidovudine were positive for HIV I p24 antigen, whereas none of 37 cerebrospinal fluid samples from patients with AIDS (two with the AIDS dementia complex) taking zidovudine were positive. CONCLUSIONS: The incidence of AIDS dementia complex in patients with AIDS declined after the introduction of systematic treatment with zidovudine; the AIDS dementia complex might be prevented by inhibiting viral replication in the central nervous system.