Antiretrovirals therapy for ALS
In the 1990s, antibodies against foamy viruses were detected in serum of SALS patients (Alfahad and Nath, 2013) and a clinical study was initiated to treat SALS patients positive for antibodies against the foamy virus human spuma retrovirus (HSRV), with zidovudine, though it showed no clinical benefit (Westarp et al., 1993). Later, the implication of HSRV in ALS patients was challenged (Rosener et al., 1998) and currently foamy viruses are not considered to participate in ALS (Alfahad and Nath, 2013).
Human endogenous retroviruses (HERV) represent approximately 8% of the human genome. They are divided into three classes I, II and III based on tRNA-primer binding site. HERV-K elements belong to class II carrying a complete ORF for gag , pol and env and can produce virus-like particles (Griffiths, 2001). Expression of HERV-K was found in a subgroup of ALS patients (Mayer et al., 2018; Douville et al., 2011). TDP-43 regulates the expression of HERV-K through binding to the long terminal repeats of the retrovirus (Li et al., 2015). Theenv viral protein is probably responsible for ALS symptoms since transgenic mice expressing the env gene under a neuronal specific promoter show loss of upper and lower motor neurons (Li et al., 2015). Approved anti-HIV reverse transcriptase inhibitors block the replication of HERV-K viral particles by inhibiting the HERV-K reverse transcriptase (Contreras-Galindo et al., 2017; Tyagi et al., 2017), while the integrase inhibitor raltegravir could also block HERV-K viral particle replication (Tyagi et al., 2017). Based on these data, in terms of the ongoing clinical trial (NCT02437110), ALS patients with elevated (>1000 copies/ml) HERV-K levels are treated with a combination of four anti-HIV drugs, darunavir, ritonavir, dolutegravir, tenofovir alafenamide. Thus, this study has been designed based on molecular analysis of ALS patients and its completion will define the role of endogenous retroviruses in ALS. The presented ALS subgroups and the compounds that can be directed for their specific treatment are summarized in Figure 1.