CHEMOKINE RECEPTORS AND HUMAN IMMUNODEFICIENCY VIRUS INFECTION

Paul D. Bieniasz and Bryan R. Cullen

Department of Genetics and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710

Received 12/15/97 Accepted 12/19/97

2. INTRODUCTION

In common with all other retroviruses, the initial event in the life cycle of primate lentiviruses is association with specific cell surface receptors that mediate virus entry. Since the identification of CD4 as an essential component of the receptor for HIV and SIV more than a decade ago (1), it has been widely appreciated that additional cellular molecules are required for the entry of HIV/SIV into target cells (2-4; figure 1). It was shown at an early stage that the expression of CD4 on the surface of human cells could render them susceptible to infection by HIV-1 virions or HIV-1 enveloped pseudotypes, and also permitted envelope induced cell fusion (1). Conversely, expression of human CD4 on the surface of murine cells did not confer susceptibility to infection, although CD4-positive murine cells are fully competent for binding the viral envelope protein gp120. Later, it became clear that this observation also held true for HIV-2 and SIV and was not specific to murine cells (2-4). In fact, almost all non-human cells remain refractory to HIV-1 infection even when engineered to express human CD4, (although HIV-2 and SIV are somewhat less species restricted). In addition, it was shown that the resistance of CD4-positive murine fibroblasts to HIV-1 could be reversed by fusion with CD4-negative human cells, indicating that there is no dominant block to virus entry (5). Taken together, these observations strongly implied the existence of additional human cell specific cell surface molecules that participate in virus entry. Until recently, the identity of these `coreceptors’ had remained elusive. However the identification of several chemokine receptors as molecules that, in conjunction with CD4, can mediate the entry of HIV and/or SIV into target cells has led to an explosion in interest in this field, and a very rapid advance in our understanding of how primate lentiviruses infect target cells.

Figure 1. HIV envelope induced membrane fusion requires both CD4 a coreceptor. Expression of CD4 on the surface of a target cell is fully sufficient to permit envelope binding, but additional cell surface molecules are required for completion of the fusion reaction. Evidence suggests that the initial interaction of the viral envelope gp120 protein with CD4 triggers a conformational change enabling further gp120 interactions with the coreceptor. The identity of particular virus coreceptors and sequences which participate in the envelope interaction is isolate dependent. Following coreceptor binding, addtional conformational changes are thought to occur, resulting in the fusion of virus and target cell membranes.