Determinants of syncytium formation in microglia by human immunodeficiencyvirus type 1. Role of the V1/V2 domains

Microglia are the main reservoir for human immunodeficiency virus type 1 (H IV-1) in the central nervous system (CNS), and multinucleated giant cells, the result of fusion of HIV-1-infected microglia and brain macrophages, are the neuropathologic hallmark of HIV dementia. One potential explanation fo r the formation of syncytia is viral adaptation for these CD4(+) CNS cells. HIV-1(BORI-15), a virus adapted to growth in microglia by sequential passa ge in vitro, mediates high levels of fusion and replicates more efficiently in microglia and monocyte-derived-macrophages than its unpassaged parent ( J. M. Strizki, A. V. Albright, H. Sheng, M. O'Connor, L. Perrin, and F. Gon zalez-Scarano, J. Virol. 70:7654-7662, 1996). Since the interaction between the viral envelope glycoprotein and CD4 and the chemokine receptor mediate s fusion and plays a key role in tropism, we have analyzed the HIV-1(BORI-1 5) env as a fusogen and in recombinant and pseudotyped viruses. Its syncyti um-forming phenotype is not the result of a switch in coreceptor use but ra ther of the HIV-1(BORI-15) envelope-mediated fusion of CD4(+)CCR5(+) cells with greater efficiency than that of its parental strain, either by itself or in the context of a recombinant virus. Genetic analysis indicated that t he syncytium-forming phenotype was due to four discrete amino acid differen ces in V1/V2, with a single-amino-acid change between the parent and the ad apted virus (E153G) responsible for the majority of the effect. Additionall y, HIV-1(BORI-15) env-pseudotyped viruses were less sensitive to decreases in the levels of CD4 on transfected 293T cells, leading to the hypothesis t hat the differences in V1/V2 alter the interaction between this envelope an d CD4 or CCR5, or both. In sum, the characterization of the envelope of HIV -1(BORI-15) a highly fusogenic glycoprotein with genetic determinants in V1 /V2, may lead to a better understanding of the relationship between HIV rep lication and syncytium formation in the CNS and of the importance of this r egion of gp120 in the interaction with CD4 and CCR5.