Differential CD4/CCR5 utilization, gp120 conformation, and neutralization sensitivity between envelopes from a microglia-adapted human immunodeficiency virus type 1 and its parental isolate

Human immunodeficiency virus type 1 (HIV-1) infects and induces syncytium f ormation in microglial cells from the central nervous system (CNS). A prima ry isolate (HIV-1(BORI)) was sequentially passaged in cultured microglia, a nd the isolate recovered (HIV-1(BORI-15)) showed high levels effusion and r eplicated more efficiently in microglia (J. M. Strizki, A. V. Albright, H. Sheng, M. O'Connor, L. Perrin, and F. Gonzalez-Scarano, J. Virol. 70:7654-7 662, 1996). The parent and adapted viruses used CCR5 as coreceptor. Recombi nant viruses demonstrated that the syncytium-inducing phenotype was associa ted with four amino acid differences in the V1/V2 region of the viral gp120 (J. T. C. Shieh, J. Martin, G. Baltuch, M. H. Malim, and F. Gonzalez-Scara no, J. Virol. 74:693-701, 2000). We produced luciferase-reporter, env-pseud otyped viruses using plasmids containing env sequences from HTV-1(BORI), HI V-1(BORI-15), and the V1/V2 region of HIV-1(BORI-15) in the context of HIV- 1(BORI)env (named rBORI, rB15, and rV1V2, respectively). The pseudotypes we re used to infect cells expressing various amounts of CD4 and CCR5 on the s urface. In contrast to the parent recombinant, the rB15 and rV1V2 pseudotyp es retained their infectability in cells expressing low levels of CD4 indep endent of the levels of CCR5, and they infected cells expressing CD4 with a chimeric coreceptor containing the third extracellular loop of CCR2b in th e context of CCR5 or a CCR5 Delta4 amino-terminal deletion mutant. The VH-r B15 and VH-rV1V2 recombinant viruses were more sensitive to neutralization by a panel of HIV-positive sera than was VH-rBORI. Interestingly, the CD4-i nduced 17b epitope on gp120 was more accessible in the rB15 and rV1V2 pseud otypes than in rBORI, even before CD4 binding, and concomitantly, the rB15 and rV1V2 pseudotypes were more sensitive to neutralization with the human 17b monoclonal antibody. Adaptation to growth in microglia-cells that have reduced expression of CD4 in comparison with other cell types-appears to be associated with changes in gp120 that modify its ability to utilize CD4 an d CCR5. Changes in the availability of the 17b epitope indicate that these affect conformation. These results imply that the process of adaptation to certain tissue types such as the CNS directly affects the interaction of HI V-1 envelope glycoproteins with cell surface components and with humoral im mune responses.