Evolving character of chronic central nervous system HIV infection

Abstract

Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system (CNS) begins early in systemic infection and continues throughout its untreated course. Despite a common cerebrospinal fluid inflammatory response, it is usually neurologically asymptomatic for much of this course, but can evolve in some individuals to HIV-associated dementia (HAD), a severe encephalopathy with characteristic cognitive and motor dysfunction. While widespread use of combination antiretroviral therapy (ART) has led to a marked decline in both the CNS infection and its neurologic severe consequence, HAD continues to afflict individuals presenting with advanced systemic infection in the developed world and a larger number in resource-poor settings where ART is more restricted. Additionally, milder CNS injury and dysfunction have broader prevalence, including in those treated with ART. Here we review the history and evolving nomenclature of HAD, its viral pathogenesis, clinical presentation and diagnosis, and treatment.

Fig. 1

Schematic diagram of the salient systemic and central nervous system (CNS) disease components of human immunodeficiency virus (HIV) infection. CNS HIV infection and immune responses originate as extensions across the blood–brain and blood–cerebrospinal fluid barriers (horizontal dashed line) of their systemic counterparts, though with variable selection and local evolution depending on the stages of disease, and likely individual host factors. Within the nervous system, both the virus and immune responses may alter the integrity and function of the CNS in the depicted triangle of pathogenetic components.

Fig. 2

Changes in blood and cerebrospinal fluid (CSF) biomarkers with disease progression. The panels show the changes in key biomarkers across seven subject groups as described in the text. The blood CD4 counts (A) define the division of the four neuroasymptomatic (NA, includes neurologically normal and those without overt or clinically recognized neurologic complaints before recruitment into the cohort) and shows the early reduction during PHI and the low counts in the HIV-associated dementia (HAD) group; the numbers under the columns show the number of subjects in each group as previously described. Notably, the CD4+ T cell counts in the HAD group (median 55, IQR 35–160 cells/µL) were comparable to those of the combined NA 50–199 and NA < 50 groups (median 59, intraquartile range [IQR] 20–122 cells/µL; p = 0.31, Mann-Whitney). Plasma (B) and CSF (C) HIV RNA concentrations showed different patterns of change over the subject groups, most notably in the NA group with CD4+ T cells < 50 µL. Elevated CSF WBC counts (D) were common in all HIV-infected groups except in the NA subjects with blood CD4+T cell counts < 50 cells/µL (p < 0.01 to < 0.0001, Kruskal-Wallis test and Dunn’smultiple comparison test). CSF neopterin (E) was elevated in all HIV-infected groups, increased when CD4+cells fell below 350 cells/µL and was notably elevated in the HAD group. CSF NFL (F) was high in all the HAD subjects, but also elevated in > 25% of those with CD4+ counts between 50–199 cells/µL and nearly 75% of those with CD4+ cells below 50 cells/µL.

Fig. 3

Model of types of central nervous system (CNS) infection reflected in cerebrospinal fluid (CSF). Systemic infection is shown on left and CNS on right. Acute and chronic infection by T-tropic, CCR5-using (R5) viruses generally derive from circulating systemic virus populations and likely relate to transport into the CSF by CD4+ T cells with limited or short-lived local amplification. Only occasionally do these undergo clonal amplification, one form of compartmentalization, and rarely do they further evolve and diversify locally. This contrasts to macrophage- (M-) tropic HIV-1 populations, which do not require high CD4 levels to infect cells and can propagate within the CNS in macrophages and related cells—comprising the second and more pathogenic type of compartmentalized infection associated with HIV encephalitis and HIV-associated dementia HAD. The location and events underlying emergence of M-tropic viruses in the CNS remain uncertain. An independent evolution occurs systemically with the emergence of T-tropic CXCR4-using (X4) viruses systemically in some patients; these are associated with low-blood CD4 cells and rapid progression, and may be found in CSF. However, there is no evidence that they are directly neuropathic. In fact, R5 viruses continue to predominate in patients with low CD4 cells, but are not included in the bottom portion in this crowded figure. The figure derives from concepts developed by Swanstrom and colleagues in their work on CSF-virus phylogeny and tropism.