Cerebrospinal Fluid Viral Load and Intrathecal Immune Activation in Individuals Infected with Different HIV-1 Genetic Subtypes

Background: HIV-1 exhibits a high degree of genetic diversity and is presently divided into 3 distinct HIV-1 genetic groups designated major (M), non-M/non-O (N) and outlier (O). Group M, which currently comprises 9 subtypes (A-D, F-H, J and K), at least 34 circulating recombinant forms (CRFs) and several unique recombinant forms (URFs) is responsible for most of the HIV-1 epidemic. Most of the current knowledge of HIV-1 central nervous system (CNS) infection is based on subtype B. However, subtypes other than subtype B account for the majority of global HIV-1 infections. Therefore, we investigated whether subtypes have any influence on cerebrospinal fluid (CSF) markers of HIV-1 CNS infection. Methodology/Principal Findings: CSF HIV-1 RNA, CSF neopterin and CSF white blood cell (WBC) count were measured in patients infected with different HIV-1 subtypes. Using multivariate regression analysis, no differences in the CSF WBC count, neopterin and viral load were found between various HIV-1 subtypes

HIV-1 infection of the central nervous system. Markers of pathogenesis and antiretroviral treatment effects

Human immunodeficiency virus type 1 (HIV-1) invades the central nervous system (CNS) early in the course of infection and either directly or through opportunistic infections causes a spectrum of neurological complications. The most severe manifestation of HIV-1 CNS infection is AIDS Dementia Complex (ADC), which occurs in approximately 20% of untreated patients with AIDS. ADC is considered the result of a complex interplay between immune activation effects and viral replication in the brain, which ultimately leads to neuronal injury and death. Reliable markers to diagnose HIV-1 associated CNS injury, track disease progression, and identify patients at risk of developing ADC are lacking. Such markers would also be beneficial in evaluating the efficacy of antiretroviral treatment (ART) in the CNS, as well as to provide insights into the pathogenesis of HIV-1 CNS infection.HIV-1 elicits intrathecal cell-mediated and humoral immune activation. We found that ART effectively decreased the cerebrospinal fluid (CSF) concentrations of neopterin and beta2-microglobulin, but had little effect on the elevated IgG index. However, almost half of the patients still had slightly elevated levels of neopterin after 2 years of follow-up. Phylogenetic analyses have identified 3 distinct HIV-1 genetic groups. Group M, which is responsible for most of the global HIV-1 epidemic is further subdivided into subtypes and circulating recombinant forms (CRFs). Most of the current knowledge of HIV-1 CNS infection is based on studies of subtype B, which is predominant in the western world. However, subtypes other than subtype B are responsible for most of the epidemic outside the western world, and HIV-1 infections due to subtypes other than B are rapidly increasing across Europe. Markers of HIV-1 CNS infection such as HIV-1 RNA, neopterin, and white blood cell (WBC) count in CSF were measured and compared in patients infected with different HIV-1 subtypes. We did not find any significant subtype-specific differences in the neuromarkers evaluated in this study. Thus, subtypes do not appear to influence neuropathogenesis.Although there is no evidence of productive infection of neurons the end-result of HIV-1 CNS infection is neuronal damage and loss. We investigated the potential of CSF neurofilament (NFL), a sensitive indicator of axonal injury, as a marker of HIV-1 associated neurodegeneration. CSF NFL concentrations were higher in patients with ADC than in neuroasymptomatic patients, or patients with primary HIV-1 infection. Patients with severe ADC had higher CSF NFL levels compared to those with milder disease. CSF NFL declined with ART to the limit of detection in parallel with virological response and neurological improvement in patients suffering from ADC.Neurocognitive impairment remains a major concern in HIV-1 infection despite the success of ART. Studies on the pathogenesis, epidemiology, and the effects of ART on HIV-1 CNS infection are important to improve patient management

Demographic and clinical characteristics of the study patients.

<p>CDC–Centers for Disease Control and Prevention; IVDU–Intravenous drug use</p

Boxplots of the cerebrospinal fluid (CSF) and plasma/serum levels of HIV-1 RNA and neopterin, the CSF/P-RNA and CSF/S-neopterin quotients, the CD4+ T- lymphocyte and the CSF white blood cell (WBC) counts according to subtype.

<p>The number of available samples is shown by n. The P-values on the top right of each panel are calculated using Kruskall-Wallis test. The bar inside the box shows the median values, the bottom and top hinges of the box represent the 25th and 75th percentile. The dotted lines represent the normal reference values. Outliers are depicted by o, extremes by *. Circulating recombinant forms CRF01_AE and CRF02_AG are designated as AE and AG.</p