Background:  In > 30% of adults, HIV can enter the brain at an early stage and can also cause AIDS dementia complex (ADC). In chronically infected therapy naïve non-progressors who remain below detection for viremia and maintain robust T-cell counts, the HIV infection of the central nervous system and the cerebrospinal fluid (CSF) remains enigmatic. In this study we describe a rare case of an HIV-infected, treatment-naïve non-progressor, who has maintained high and stable CD4 and CD8 counts and was below detection for plasma viremia, but developed AIDS-related neurologic symptom.

Methods:  Full-length HIV-1 genomes were amplified over time (1992 to 2004), using long-distance PCR from peripheral blood cells and only in 2004 from the CSF. The genomes were sequenced by amplification of individual genomic regions. The individual genomic segments were cloned in PGEM-T vector and sequenced. Maximum likelihood and neighbor-joining algorithms were used for phylogenetic estimations. We used 1000 bootstrap estimates to predict the statistical support for phylogenetic relationships in blood and CSF. G-to-A hypermutation was analyzed using HYPER-MUT from the Los Alamos Database.

Results:  There was complete absence of viral evolution in vivo throughout the course of HIV infection in all blood-derived HIV-1 genomes between 1992 and 2004. This was attributed to the presence of stop codons in the p17, p24, and protease regions resulting from extensive G-to-A hypermutation in blood-derived virus. In late 2003, the patient started to show neurological symptoms and the lumbar puncture revealed 14,000 copies of HIV/mL in the CSF. Comparison of full-length genomes from blood and CSF in 2004 revealed only 1.4% divergence. All of the stop codons and G-to-A hypermutation were absent in the CSF-derived virus. This is the first evidence of complete absence of viral evolution in blood and low-level evolution in the CSF (< 1.4% divergence). The molecular analysis clearly showed that despite the attenuation of strain in blood compartment, the wild type strain could independently survive in the CSF for almost 17 years with extremely low-level replication and caused neurologic symptoms.

Conclusions:  The CSF may behave as a distinct viral compartment, which may not depend on disease stage. Importantly, the high CD4⁺ and CD8⁺ T-cell counts and below-detection plasma viremia may not protect against neurologic symptoms in some cases. HIV-infected non-progressors should opt for lumbar puncture examination.

Keywords: Neuropathogenesis and neurologic complications; Pathogenesis; Molecular epidemiology