Abstract
Compartmentalized HIV-1 replication within the central nervous system (CNS) likely provides a foundation for neurocognitive impairment and a potentially important tissue reservoir. The timing of emergence and character of this local CNS replication has not been defined in a population of subjects. We examined the frequency of elevated cerebrospinal fluid (CSF) HIV-1 RNA concentration, the nature of CSF viral populations compared to the blood, and the presence of a cellular inflammatory response (with the potential to bring infected cells into the CNS) using paired CSF and blood samples obtained over the first two years of infection from 72 ART-naïve subjects. Using single genome amplification (SGA) and phylodynamics analysis of full-length env sequences, we compared CSF and blood viral populations in 33 of the 72 subjects. Independent HIV-1 replication in the CNS (compartmentalization) was detected in 20% of sample pairs analyzed by SGA, or 7% of all sample pairs, and was exclusively observed after four months of infection. In subjects with longitudinal sampling, 30% showed evidence of CNS viral replication or pleocytosis/inflammation in at least one time point, and in approximately 16% of subjects we observed evolving CSF/CNS compartmentalized viral replication and/or a marked CSF inflammatory response at multiple time points suggesting an ongoing or recurrent impact of the infection in the CNS. Two subjects had one of two transmitted lineages (or their recombinant) largely sequestered within the CNS shortly after transmission, indicating an additional mechanism for establishing early CNS replication. Transmitted variants were R5 T cell-tropic. Overall, examination of the relationships between CSF viral populations, blood and CSF HIV-1 RNA concentrations, and inflammatory responses suggested four distinct states of viral population dynamics, with associated mechanisms of local viral replication and the early influx of virus into the CNS. This study considerably enhances the generalizability of our results and greatly expands our knowledge of the early interactions of HIV-1 in the CNS.
Highlights
While HIV-1 can be detected in both the cerebrospinal fluid (CSF) and brain tissue during the weeks after initial exposure [1,2,3,4,5,6,7], it is unknown when the virus begins replicating independently in the central nervous system (CNS)
HIV-1 CNS replication likely provides a foundation for brain injury and a potentially important tissue reservoir
To explore the character and timing of emergence of early HIV-1 CNS replication, we examined paired cerebrospinal fluid (CSF) and blood samples from 72 ART-naïve adults, with one-half having longitudinal samples, during the first two years following HIV-1 subtype B infection
Summary
While HIV-1 can be detected in both the cerebrospinal fluid (CSF) and brain tissue during the weeks after initial exposure [1,2,3,4,5,6,7], it is unknown when the virus begins replicating independently in the central nervous system (CNS). Compartmentalized, CSF/CNS replication is associated with severe HIV-1 clinical CNS dysfunction [1,10,11,12,13], genetically distinct virus can be detected in the CNS throughout the course of infection [4,10]. Two types of compartmentalization have been defined: one in which a few variants are rapidly expanded giving a CSF viral population of low complexity (clonal amplification) consisting of variants that require high levels of CD4 for entry (R5 T cell-tropic). The second type is characterized by a complex CSF viral population consisting of variants that can enter cells expressing low levels of CD4 (macrophage-tropic), indicative of a more prolonged period of isolated replication and evolution of the entry phenotype. The previous study had sparse assessment of longitudinal samples, and included no analysis of sources of compartmentalized HIV-1 within the CSF
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