Amyotrophic lateral sclerosis (ALS) is a progressive, invariably fatal neurologic disorder resulting from upper and lower motor neuron degeneration, which typically develops during the sixth or seventh decade of life, and is diagnosed based on standard clinical criteria. Its underlying cause remains undetermined. The disease may occur with increased frequency within certain families, often in association with specific genomic mutations, while some sporadic cases have been linked to environmental toxins or trauma. Another possibility, first proposed in the 1970s, is that retroviruses play a role in pathogenesis. In this paper, we review the published literature for evidence that ALS is associated either with infection by an exogenous retrovirus or with the expression of human endogenous retroviral (HERV) sequences in cells of the central nervous system. A small percentage of persons infected with the human immunodeficiency virus-1 (HIV-1) or human T cell leukemia virus-1 (HTLV-1) develop ALS-like syndromes. While HTLV-1 associated ALS-like syndrome has several features that may distinguish it from classical ALS, HIV-infected patients may develop neurological manifestations that resemble classical ALS although it occurs at a younger age and they may show a dramatic improvement following the initiation of antiretroviral therapy. However, most patients with probable or definite ALS show no evidence of HIV-1 or HTLV-1 infection. In contrast, recent reports have shown a stronger association with HERV, as analysis of serum samples, and postmortem brain tissue from a number of patients with a classical ALS has revealed significantly increased expression of HERV-K, compared to controls. These findings suggest that endogenous retroviral elements are involved in the pathophysiology of ALS, but there is no evidence that they are the primary cause of the syndrome.

Neurocognitive disorders are a feared complication of HIV infection, especially in the post anti-retroviral era as patients are living longer. These disorders are challenging in terms of diagnosis and treatment. The clinical syndrome has evolved driven in part by comorbidities such as aging, drug abuse, psychiatric illnesses, and a metabolic syndrome associated with the use of antiretroviral drugs. Additionally some individuals may develop a fulminant immune reconstitution syndrome. Hence management of these patients needs to be individualized. The focus of research in the HIV field has recently switched towards elimination of the HIV reservoir as a means of combating long-term HIV complications. However these approaches maybe suitable for limited populations and might not be applicable once the HIV reservoir has been established in the brain. Further, all clinical trials using neuroprotective or anti-inflammatory drugs for treatment of HIV-associated neurocognitive disorders have been unsuccessful. Hence neurological complications of HIV infection represent the biggest challenge facing HIV researchers and there is a critical need for developing new diagnostics and approaches to treatment for these disorders.

Objective: To determine whether there is activation of human endogenous retrovirus K (HERV-K) in amyotrophic lateral sclerosis in HIV infection and whether it might respond to treatment with antiretroviral drugs. Methods:In this case series, we present 5 patients with HIV infection who subsequently developed motor neuron disease involving both upper and lower motor neurons. We monitored HERV-K levels in plasma of 4 of these patients.Results: Three patients who received antiretroviral therapy had reversal of symptoms within 6 months of onset of neurologic symptoms and the other 2 had slow neurologic progression over several years. Three patients in whom the levels were measured at onset of neurologic symptoms showed elevated HERV-K levels that responded to optimization of antiretroviral therapy for CNS penetration.