Nonlymphoid reservoirs of HIV replication in children with chronic-progressive disease

Autopsy tissues from 2 cohorts of age-matched HIV-infected children with si milar plasma viral load (>10(5) HIV RNA copies/ml), but with distinct AIDS- associated disease manifestations, were examined for sites of persistent HI V replication. One group consisted of 3 children with severe lymphoid atrop hy and peripheral blood CD4(+) T cell counts of <10/mm(3). Another group wa s composed of 6 children with extensive hyperplasia of mucosal-associated l ymphoid tissues and blood CD4(+) T cell counts >500/mm(3). Hyperplastic bro nchiole- and gut-associated lymphoid tissues were characterized by extensiv e networks of germinal center follicular dendritic cells (FDC) containing l arge amounts of immune-complexed virion RNA. Conversely, pulmonary and gast rointestinal tissues from children with severe CD4(+) T cell depletion were devoid of any secondary lymphoid structures, yet these tissues also harbor ed high concentrations of HIV RNA. Dual in situ procedures showed that only macrophage (M phi) within these sites contained tat fusion transcripts, a product of post-transcriptional splicing and a correlate of productive infe ction. When examining explant cultures of M phi and FDC, only M phi harbore d HIV tat mRNA and only M phi demonstrated budding retroviral particles. He nce, germinal center FDC in secondary lymphoid tissues are key reservoirs o f immune-complexed HIV RNA and are likely to contribute to AIDS-associated lymphoproliferations; however, these cells do not support HIV replication, and failure to do so results from a post-transcriptional block in the virus life cycle. Moreover, gut and pulmonary M phi represent a lineage of cells that are permissive to HIV replication and contribute significantly to the high viral load in children with severe CD4(+) T cell depletion. It will b e important to identify the molecular mechanisms that allow for these highl y productive infections of M phi.