Compartmentalized intrathecal immunoglobulin synthesis during HIV infection - a model of chronic CNS inflammation?

Abstract

HIV infects the central nervous system (CNS) during primary infection and persists in resident macrophages. CNS infection initiates a strong local immune response that fails to control the virus but is responsible for by-stander lesions involved in neurocognitive disorders. Although highly active anti-retroviral therapy now offers an almost complete control of CNS viral proliferation, low-grade CNS inflammation persists. This review focuses on HIV-induced intrathecal immunoglobulin (Ig) synthesis. Intrathecal Ig synthesis early occurs in more than three-quarters of patients in response to viral infection of the CNS and persists throughout the course of the disease. Viral antigens are targeted but this specific response accounts for <5% of the whole intrathecal synthesis. Although the nature and mechanisms leading to non-specific synthesis are unknown, this prominent proportion is comparable to that observed in various CNS viral infections. Cerebrospinal fluid-floating antibody-secreting cells account for a minority of the whole synthesis, which mainly takes place in perivascular inflammatory infiltrates of the CNS parenchyma. B-cell traffic and lineage across the blood-brain-barrier have not yet been described. We review common technical pitfalls and update the pending questions in the field. Moreover, since HIV infection is associated with an intrathecal chronic oligoclonal (and mostly non-specific) Ig synthesis and associates with low-grade axonal lesions, this could be an interesting model of the chronic intrathecal synthesis occurring during multiple sclerosis.

Keywords: Cerebrospinal fluid; Encephalopathy; Human immunodeficiency virus; Immunoglobulins; Intrathecal synthesis.

Fig. 1

Specific and non-specific intrathecal synthesis (ITS). Left panel. Null values of ITS are located in the shaded area. Much of the IgG level in CSF comes from a passive transudation from blood (A), proportional to BBB permeability (approximated by Q_Alb = Alb_CSF / Alb_Ser). Q_Lim(IgG) = (0.93 ∗ (Q_Alb² − 6)^0.5 − 1.7) ∗ 10^− 3 is the maximal level of blood-borne CSF IgG. Levels of CSF IgG higher than Q_Lim are intrathecally synthesized (B). (Q_Alb and Q_IgG are multiplied with 10³). Right panel. The fraction of intrathecally synthesized IgG (F_s) against specific viruses is plotted (mean and extreme values) among the whole intrathecally synthesized IgG in various CNS infections (Bonnan, 2014). F_s are commonly low in CNS infections and F_s against HIV is the lowest of the CNS infections. Hence, most of the intrathecally synthesized IgG in HIV infection are non-disease-specific. HSVE: HSV-encephalitis; SSPE: subacute sclerosis panencephalitis; VZVE: VZV-encephalitis.

Fig. 2

Lymphocytes traffic/maturation and intrathecal IgG synthesis associated with HIV infection in central nervous system (CNS). Upper panel. B-lymphocytes reacting against HIV are recruited in CNS where they may undergo a local proliferation; intrathecal IgG synthesis mirrors serum synthesis. Oligoclonal IgG synthesis restricted to CSF may be a consequence of local affinity maturation of B-lymphocytes. CSF IgG partly originates from passive diffusion through BBB and explains mirror pattern of OCB. Lower panel. Lymphocytes directed against non-HIV antigens are non-specifically recruited in the inflamed CNS and synthesize non-specific antibodies (i.e., anti-measles).