HIV-1 target cells in the CNS

Abstract

HIV-1 replication in the central nervous system (CNS) is typically limited by the availability of target cells. HIV-1 variants that are transmitted and dominate the early stages of infection almost exclusively use the CCR5 coreceptor and are well adapted to entering, and thus infecting, cells expressing high CD4 densities similar to those found on CD4+ T cells. While the "immune privileged" CNS is largely devoid of CD4+ T cells, macrophage and microglia are abundant throughout the CNS. These cells likely express CD4 densities that are too low to facilitate efficient entry or allow sustained replication by most HIV-1 isolates. Examination of CNS viral populations reveals that late in disease the CNS of some individuals contains HIV-1 lineages that have evolved the ability to enter cells expressing low levels of CD4 and are well-adapted to entering macrophages. These macrophage-tropic (M-tropic) viruses are able to maintain sustained replication in the CNS for many generations, and their presence is associated with severe neurocognitive impairment. Whether conditions such as pleocytosis are necessary for macrophage-tropic viruses to emerge in the CNS is unknown, and extensive examinations of macrophage-tropic variants have not revealed a genetic signature of this phenotype. It is clear, however, that macrophage tropism is rare among HIV-1 isolates and is not transmitted, but is important due to its pathogenic effects on hosts. Prior to the evolution of macrophage-tropic variants, the viruses that are predominately infecting T cells (R5 T cell-tropic) may infect macrophages at a low level and inefficiently, but this could contribute to the reservoir.

Fig. 1

Successful HAART blocks new infection but does not affect cells already infected with HIV-1. Therefore, the remaining viral production (and viral load) is directly related to the lifespan of the cells infected prior to initiating HAART. In essentially all patients infected with HIV-1, viral load (VL) decays rapidly upon initiation of HAART with a half-life of approximately 1 to 2 weeks in the blood (indicated by the solid red line) and cerebrospinal fluid (CSF; solid blue line), which is consistent with virus produced from infected CD4+ T cells in both compartments. In rare cases, patients will have the same rapid decay of VL in the blood but will have a much slower decay in the CSF (dashed blue line). This indicates that in these patients viruses are being produced in CD4+ T cells in the blood but are being produced by a longer-lived cell, likely perivascular macrophages or microglia, in the CSF.