Sequencing the Biology of Entry: The Retroviral env Gene

Abstract

The surface envelope protein of any virus is major determinant of the host cell that is infected and as a result a major determinant of viral pathogenesis. Retroviruses have a single surface protein named Env. It is a trimer of heterodimers and is responsible for binding to the host cell receptor and mediating fusion between the viral and host membranes. In this review we will discuss the history of the discovery of the avian leukosis virus (ALV) and human immunodeficiency virus type 1 (HIV-1) Env proteins and their receptor specificity, comparing the many differences but having some similarities. Much of the progress in these fields has relied on viral genetics and genetic polymorphisms in the host population. A special feature of HIV-1 is that its persistent infection in its human host, to the point of depleting its favorite target cells, allows the virus to evolve new entry phenotypes to expand its host range into several new cell types. This variety of entry phenotypes has led to confusion in the field leading to the major form of entry phenotype of HIV-1 being overlooked until recently. Thus an important part of this story is the description and naming of the most abundant entry form of the virus: R5 T cell-tropic HIV-1.

Fig. 1

The retroviral Env protein. The viral Env protein exists as a trimer of heterodimers (SU/TM) embedded in the viral membrane (parallel wavy lines). The TM/transmembrane protein is orange with the lighter shade of orange indicating the cytoplasmic domain, the dark blue portion indicating the membrane-spanning domain, the gray regions representing the heptad repeats (hr1 and hr2) involved in the formation of the six helix bundle, and the red portion indicating the N-terminal fusion peptide. The green region represents the receptor binding/surface/SU protein, with the cleft indicating the receptor-binding region. The purple box indicates the region for HIV-1 that rearranges after binding CD4 to form the coreceptor binding site

Fig. 2

Pathways for the evolution of the HIV-1 Env protein entry phenotype. The major entry phenotype form for HIV-1 is the R5 T cell-tropic form. It uses CCR5 as the coreceptor, but requires a high density of CD4, as is found on T cells, for efficient entry. In vivo it evolves to switch coreceptor to use CXCR4. Alternatively, it can evolve to use a low density of CD4 to enter cells such as macrophages, which have a density of CD4 about 25-fold lower than that found on T cells. Also in vivo, these viruses are found in a closed conformation, i.e., resistant to neutralization, especially to antibodies targeting the epitopes exposed after binding CD4. In cell culture the virus follows another evolutionary pathway in which an open conformation is generated allowing the use of a low density of CD4 for entry. Presumably this enables more rapid entry under culture conditions. This can happen for both the X4 form of the virus and the R5 T cell-tropic form of the virus and should be considered an artifact of tissue culture adaptation