Elevated cerebrospinal fluid levels of monocyte chemotactic protein-1 correlate with HIV-1 encephalitis and local viral replication.

OBJECTIVE: To investigate whether the CC-chemokine monocyte chemotactic protein (MCP)-1 could play a role in the pathogenesis of HIV infection of the central nervous system. This hypothesis was suggested by previous observations, including our finding of elevated cerebrospinal fluid (CSF) levels of this chemokine in patients with cytomegalovirus (CMV) encephalitis. DESIGN AND METHODS: CSF levels of MCP-1 were determined in 37 HIV-infected patients with neurological symptoms, and were compared with both the presence and severity of HIV-1 encephalitis at post-mortem examination and CSF HIV RNA levels. MCP-1 production by monocyte-derived macrophages was tested after in vitro infection of these cells by HIV. RESULTS: CSF MCP-1 levels were significantly higher in patients with (median, 4.99 ng/ml) than in those without (median, 1.72 ng/ml) HIV encephalitis. Elevated CSF MCP-1 concentrations were also found in patients with CMV encephalitis and with concomitant HIV and CMV encephalitis (median, 3.14 and 4.23 ng/ml, respectively). HIV encephalitis was strongly associated with high CSF MCP-1 levels (P = 0.002), which were also correlated to high HIV-1 RNA levels in the CSF (P = 0.007), but not to plasma viraemia. In vitro, productive HIV-1 infection of monocyte-derived macrophages upregulated the secretion of MCP-1. CONCLUSIONS: Taken together, these in vivo and in vitro findings support a model whereby HIV encephalitis is sustained by virus replication in microglial cells, a process amplified by recruitment of mononuclear cells via HIV-induced MCP-1.

Herpes simplex virus infections of the central nervous system in human immunodeficiency virus-infected patients: clinical management by polymerase chain reaction assay of cerebrospinal fluid.

A duplex polymerase chain reaction (PCR) assay for DNA from herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) was applied to cerebrospinal fluid (CSF) from 918 human immunodeficiency virus (HIV)-infected patients with neurological symptoms. HSV-1 or HSV-2 (HSV-1/2) DNA was found in 19 patients (2%). For the 258 patients for whom a diagnosis was confirmed at autopsy, the sensitivity and specificity of PCR analysis for the diagnosis of HSV-1/2 encephalitis were 100% and 99.6%, respectively. Three patients with CD4+ cell counts of > or = 170/microL had HSV-1 central nervous system (CNS) infections (two) or HSV-2 meningitis (one). Sixteen patients with CD4+ cell counts of < 40/microL had HSV-1 CNS infections (two) or mixed HSV-1/2 and cytomegalovirus encephalitis (14). The response to antiviral treatment, which was assessed clinically and by CSF PCR analysis, was variable in the patients with the highest CD4+ cell counts and poor in those with more severe immunosuppression. CSF PCR analysis is of value for the diagnosis and follow-up of treatment of HSV-1/2 CNS infections in HIV-infected patients.

Cerebrospinal fluid HIV-1 RNA levels: correlation with HIV encephalitis.

OBJECTIVE: Neuropathological abnormalities induced by HIV-1 are not always predictable on the basis of the presence of HIV-related neurological symptoms. HIV-1 RNA load was measured in the cerebrospinal fluid (CSF) of HIV-infected patients to verify whether it could be a marker of HIV-induced neuropathology. DESIGN AND METHODS: Histopathological and immunohistochemical examination of the brain for HIV-1 p24 antigen was performed in 50 HIV-infected patients with neurological symptoms; patients were defined as having HIV encephalitis in the presence of HIV-related lesions or HIV-1 p24 antigen-positive cells. Quantitative polymerase chain reaction for HIV-1 RNA was retrospectively applied to CSF samples that had been drawn 1-60 days prior to death from these 50 patients; paired plasma samples of 28 patients were also analysed. RESULTS: The CSF HIV-1 RNA copy numbers were significantly higher in 22 patients with HIV encephalitis than in 28 patients without (median, 4.77 log10 versus 3.45 log10 copies/ml; P = 0.0003). No correlation was found between CSF HIV-1 RNA load and the presence of opportunistic brain pathologies at post-mortem examination or between HIV-1 RNA loads in paired CSF and plasma samples. CONCLUSIONS: High CSF HIV-1 RNA levels are associated with HIV encephalitis, regardless of the presence of opportunistic brain diseases or HIV-1 RNA levels in plasma. Quantitative CSF HIV-1 RNA may therefore be used as a specific marker of HIV-induced neuropathology.

Cytomegalovirus infections of the nervous system.

Experimental evidence and pathological observation indicate that human cytomegalovirus (HCMV) has a tropism for cells of the nervous system, including both neuronal and glial cells. As demonstrated in animal models, after a viremic phase, the virus may reach the brain, where it may cause mild infection or severe encephalitis. The nervous system is one of the principal target organs in congenital HCMV infections and in HCMV-infected AIDS patients. In the former case, mortality is high and neurological sequelae, such as mental retardation, are frequent; in the latter it may lead to a progressively wasting encephalopathy and death within a few weeks. The diagnosis of the nervous system manifestations due to HCMV can now rely upon the detection of HCMV DNA in cerebrospinal fluid by means of polymerase chain reaction. However, the current antiviral treatments of these complications are of limited effect.

Serum polymerase chain reaction for cytomegalovirus DNA for monitoring ganciclovir treatment in AIDS patients.

The virological response to antiviral treatment of cytomegalovirus (CMV) infection in patients with AIDS can be monitored by the identification and quantification of CMV pp65 antigen in blood polymorphonuclear leukocyte cells (PMNL). To assess the value of nested polymerase chain reaction (PCR) in serum for therapy follow-up, we compared PCR and pp65 antigenemia results in 21 acquired immune deficiency syndrome (AIDS) patients with CMV infection, before and after 3 weeks of intravenous ganciclovir at standard doses. pp65 antigenemia was positive in 18/21 (86%) patients at the start of the therapy and in 2/15 (13%) at the end of therapy. CMV DNA was found in serum from 18/21 (86%) patients at the beginning of therapy and in 3/21 (14%) patients after 3 weeks of therapy. A clinical improvement was seen in 16/21 (76%) patients: 11/16 (69%) were negative by both PCR and antigenemia at the end of ganciclovir treatment. The sensitivity and specificity of serum PCR versus the antigenemia assay were 85% and 81%, respectively. Nested PCR on serum can be useful for treatment follow-up of CMV infection in patients with AIDS. It can be used where antigenemia cannot be performed and in retrospective studies.