Mechanisms of attachment of HIV-1 to CD4 positive and negative cells and the role in virus infectivity

Although fusion of HIV-1 membranes with target cell membranes requires CD4 and one of the chemokine receptors, the role of these receptors in HIV-1 binding to cells is unclear. The aims of this study were to: (1) evaluate HIV-1 T cell line adapted (TCLA) and primary isolate (PI) binding to CD4 + and CD4− cells, (2) investigate the mechanism(s) of enhanced infectivity of bound virus and (3) determine the role of CD4, chemokine receptors, gpl20/gp4l, and other factors that contribute to binding. Similar amounts of virus bound to infectable CD4+ and nonpermissive CD4− cells at similar levels. When cultured with T cells, bound virus was up to 17 times more infectious than similar amounts of cell-free virus. The enhanced infection by virus bound to CD4− cells was not due to stimulatory signals provided by the CD4− cells or infection of the CD4− cells. However, anti-CD 18 antibody substantially reduced virus replication in T cells suggesting that cell-bound virus is efficiently passed to T cells during cell-cell adhesion events. The presence or absence of CD4 on cells had little effect on the amount of virus that bound to cells, and antibodies to CD4, chemokine receptors or gp120/gp4l did not block virus binding. PI and TCLA virus had different but consistent binding patterns; PI bound at relatively high levels to primary cells but at low levels to cell lines, while TCLA virus bound at high levels to all cells. The binding pattern was maintained when TCLA virus was passaged in primary cells. These studies show that HIV binds to CD4− cells, and once bound, remains infectious for T cells. This binding could represent an important route for infection of T cells in vivo. These experiments also suggest that the early attachment events of both TCLA and PI are CD4− and gp120-independent, and that the virus-producing cell and cellular molecules influence HIV binding. Understanding these interactions is important since it may be possible to use therapeutic agents to reduce virus binding and therefore transmission to uninfected persons or virus replication in infected persons.