Human Endogenous Retrovirus-K and TDP-43 Expression Bridges ALS and HIV Neuropathology

Abstract

Despite the repetitive association of endogenous retroviruses in human disease, the mechanisms behind their pathological contributions remain to be resolved. Here we discuss how neuronal human endogenous retrovirus-K (HERV-K) expression in human immunodeficiency virus (HIV)-infected individuals is a distinct pathological aspect of HIV-associated neurological conditions, such as HIV encephalitis and HIV-associated neurocognitive disorders. Enhanced neuronal HERV-K levels were observed in the majority of HIV-infected individuals, and to a higher degree in brain tissue marked by HIV replication. Moreover, we highlight an important neuropathological overlap between amyotrophic lateral sclerosis and HIV encephalitis, that being the formation of neurotoxic TDP-43 deposits in neurons. Herein, we argue for enhanced transdisciplinary research in the field of ERV biology, using an example of how HERV-K expression has novel mechanistic and therapeutic implications for HIV neuropathology.

Keywords: NeuroAIDS; TDP-43; amyotrophic lateral sclerosis (ALS); human endogenous retrovirus-K (HERV-K); human immunodeficiency virus (HIV).

FIGURE 1

Endogenous retrovirus-K reverse transcriptase is induced in cortical tissue during human immunodeficiency virus (HIV) infection. (A) HIV-infected individuals, with HAND/HIV-encephalitis (HIV-E) or without HIV-E (HIV) expressed greater levels of endogenous retrovirus-K (HERV-K) reverse transcriptase protein in their cortical tissue, as compared to patients deceased with chronic systemic disease (control). Antibodies against the HERV-K reverse transcriptase protein (AbNova #H00002087-A01) and human TDP-43 (Protein Tech #10782-2-AP) were used for immunohistochemistry as previously described (Douville et al., 2011). (B) HIV replication in cortical tissue, as measured by HIV p24 protein immunostaining (mouse anti-HIV p24 Gag monoclonal, #24-4 NARRRP), is associated with significantly higher HERV-K reverse transcriptase expression. Mann–Whitney derived t-test, ^∗p < 0.05. (C) Significant correlation of neuronal HERV-K reverse transcriptase and TDP-43 protein levels in HIV⁺ patients. Representative immunohistochemistry images of TDP-43 protein, endogenous retrovirus-K reverse transcriptase (HERV-K RT), nucleic as measured by DAPI staining, and neurons as measured by Nissl staining in the cortical brain tissue of HIV-infected patients (HIV⁺) versus patients with systemic disease (control). Arrows indicate weak TDP-43 positivity in control tissue neurons. ALS-derived neuron with a TDP-43 deposit outside the nuclear boundary is indicated with an asterisk. (D,E) A strong correlation between HERV-K RT and TDP-43 expression in brain tissues. ImageJ analysis was used to quantify the density of HERV-K RT and TDP-43 staining within individual tissue samples (D) and within individual neurons (E) of HIV-infected and controls cortical brain specimens. Spearman correlation used to assess association between HERV-K RT and TDP-43 expression patterns.