Identification of shared populations of human immunodeficiency virus type 1 infecting microglia and tissue macrophages outside the central nervous system

Infection of microglia and other cells of the macrophage/monocyte lineage i n the central nervous system (CNS) by human immunodeficiency virus type I ( HIV-1) underlies the development of giant cell encephalitis (GCE). It is cu rrently unknown whether GCE depends on the emergence of virus populations s pecifically adapted to replicate in cells of the monocyte/macrophage lineag e and whether this also leads to the specific targeting of macrophages in o ther nonlymphoid tissues. Autopsy samples from lymph node, brain (frontal r egion), lung, and full-thickness colon sections were obtained from nine stu dy subjects with GCE and from nine without. The two groups showed no signif icant differences in CD4 counts, disease progression, or treatment history before death. Genetic relatedness between variants recovered from lymph nod e and nonlymphoid tissues was assessed by sequence comparison of V3 and p17 (gag) regions using a newly developed method that scores the sample composi tion at successive nodes in a neighbor-joining tree. The association index enabled objective, numerical comparisons on the degree of tissue compartmen talization to be made. High proviral loads and p24 antigen expression in th e brain were confined to the nine individuals with GCE. GCE was also associ ated with significantly higher proviral loads in colon samples (median of t he GCE(+) group: 1,010 copies/10(6) cells; median of GCE(-) group, 10/10(6) cells; P = 0.006). In contrast, there were no significant differences in p roviral load between the GCE(+) and GCE- groups in lymph node or lung sampl es, where HIV infection was manifested predominantly by infiltrates of lymp hoid cells. V3 sequences from brain samples of individuals with GCE showed the greatest compartmentalization from those of lymph node, although sample s from other tissues, particularly the colon, frequently contained variants phylogenetically, related to those found in brain. The existence of shared , distinct populations of HIV specifically distributed in cells of the mono cyte/macrophage lineage was further indicated by immunocytochemical detecti on of CD68(+), multinucleated giant cells expressing p24 antigen in samples of lung and colon in two individuals with GCE. This study provides the bas is for future investigation of possible phenotypic similarities that underl ine the shared distributions of HIV variants infecting microglia and tissue macrophages outside the CNS.