Molecular Evolution: The HIV Envelope Protein

Abstract

Human immunodeficiency virus (HIV) particles, a.k.a. virions, can exist in the bloodstream of an infected individual. However, HIV replication or production of more HIV virions occurs within cells of the lymph nodes of an infected individual. HIV is capable of infecting multiple human cell types, but for simplicity’s sake, we will focus on HIV infection of CD4-positive immune cells, a.k.a. T helper cells. The HIV envelope protein (Env) is essential for binding to a human lymphocyte or T cell. Env is composed of two subunits, a transmembrane protein called gp41 and a surface protein gp120, which are attached to one another noncovalently (Fig. 1). This dimer associates with two other dimers forming the trimer that binds to CD4 receptors on the surface of the lymphocyte. CD4 receptors usually act as adhesion molecules to bind to other immune cells such as antigen-presenting cells, but HIV takes advantage of this receptor and uses it to bind to the T cell. A third type of receptor involved in this interaction, called a coreceptor, is also required for HIV infection. This coreceptor is located on the T cell. HIV also needs either the coreceptor CCR5 or the coreceptor CXCR4 to enter the cell. Different types of T cells will express CCR5 or CXCR4 on their cell surface. Regions within the gp120 subunit of the envelope protein interact with both CD4 and the coreceptor, causing conformational changes in the envelope protein. This initiates the fusion of the HIV and the T cell lipid membranes, ultimately leading to the insertion of HIV's RNA genome into the host cell, subsequent copying of the RNA genome into double-stranded DNA, integration into the host's genome, and production of new virus particles. Scientists have found that the fitness of an HIV virion is directly correlated with how fast it can infect a cell, so they are very interested in studying the evolution of gp120 in particular. The gp120 domain is important because it is a target for our immune system. The gp120 protein is composed of five hypervariable regions separated by constant regions. The V1/V2 region is involved in modulating the interaction of the envelope receptor with CD4. Both the V1 region and V2 region consist of approximately 40 amino acids each. The V3 region is important for modulating interactions with the coreceptors CCR5 and CXCR4. Little is known about the function of V4/V5, but the region has been shown to contain epitopes for neutralizing antibodies. The simian immunodeficiency virus (SIV) is very similar to HIV. In fact, HIV evolved from SIV. SIV is endogenous to nonhuman primate populations (chimpanzees, macaques, etc.). The Rhesus macaque serves as a model organism to study SIV infection and pathogenesis. There are many similarities between how SIV infects macaques and how HIV infects humans, although with some differences. Thus, scientists can learn much from experimenting with the SIV–macaque model to further determine molecular events during HIV infection of humans. Evo Edu Outreach (2008) 1:179–183 DOI 10.1007/s12052-007-0023-6