Model of HIV-1 infection in the central nervous system.

<p>CD4⁺ T cells are represented by open circles, macrophages are represented by the irregularly shaped cells, monocytes are represented by open circles labeled with an M, blood plasma viral variants are represented by the red virus particles, and CNS compartmentalized viral variants are represented by the blue virus particles. (A) HIV-1 infection in the CNS of a subset of asymptomatic subjects without detectable compartmentalized virus or CSF pleocytosis. All HIV-1 detected in the CSF decays rapidly after the initiation of therapy, suggesting that CSF virus is coming from a short-lived cell type. (B) HIV-1 infection in the CNS of asymptomatic and neurologically symptomatic subjects with compartmentalization, high CSF pleocytosis and rapid viral decay. In this model, local CNS virus is able to replicate to higher titers during periods of immunodeficiency and stimulate an inflammatory response in the CNS. Uninfected CD4⁺ T cells that migrate into the CNS can become infected by compartmentalized HIV-1 produced by macrophages and microglia in the CNS, and then amplify the local CNS-compartmentalized virus to higher concentrations. Thus, a rapid decay rate for compartmentalized virus is detected after the initiation of antiretroviral therapy. (C) HIV-1 infection in the CNS of neurologically symptomatic subjects with slow viral decay. Our data indicate that compartmentalized variants in the CSF of HAD subjects are originating from long-lived macrophages and microglia in the CNS, resulting in a slow decay rate for compartmentalized virus. We propose that periods of profound immunodeficiency allow compartmentalized virus in the CNS to replicate to high titers, and that in the absence of other lymphocytes (such as CD4⁺ T cells) peripheral, uninfected monocytes may migrate into the brain parenchyma in large numbers and differentiate into perivascular macrophages. These macrophages can then become infected by compartmentalized HIV-1 variants in the CNS and support viral replication at detectable levels.