STRUCTURE AND EXPRESSION OF GP120
The structure of the HIV envelope gp120 is critical in dictating not only the tropism of the HIV strain but also the antigenicity of the HIV. The envelope is organized into spikes on the outside of the virion.
The exterior of each spike is composed of the envelope gp120, which is noncovalently associated with each subunit of the trimeric gp41 complex.1 The amino acid sequence of the gp120 consists of five conserved regions (C1 to C5) interspaced with five variable regions (V1 to V5). V1 to V4 create the surface-exposed loops anchored by disulfide bonds at their bases.2 Both conserved and variable regions are highly glycosylated with carbohydrate moieties, accounting for 50% of the mass of gp120.3 The conserved regions of the surface-exposed gp120 are involved in the interaction with the gp41 ectodomain and the host-cell receptors that recognize the virus. The envelope glycoprotein is folded into a complex three-dimensional structure such that noncontiguous regions physically associate and create binding sites for host-cell receptors.Neutralizing antibodies isolated from HIV-infected individuals recognize both conserved and variable regions of the gp120 structure. Antienvelope antibodies that recognize specific strains of HIV are directed at epitopes in the V2 and V3 loops of the gp120. The glycosylation pattern of the envelope glycoprotein likely modulates the immunogenicity and antigenicity of the gp120, for the surface-exposed glycoprotein is the main target for neutralizing antibodies during natural infection.4 Broadly neutralizing antienvelope antibodies recognize epitopes in discontinuous and conserved regions of the glycoproteins. The most abundant of the antibodies recovered from HIV- infected humans are directed at the CD4 receptor binding site on the gp120 envelope.2
HIV-1 virus has two tropisms differentiated by their ability to infect and replicate in specific cells and by the surface co-receptors used to infect host cells.
Both HIV tropic strains replicate in primary CD4+ T cells, but only some strains infect and replicate in monocyte-derived macrophages or transformed T cell lines. The macrophage-tropic HIV strains (also called M-tropic or R5) can infect and replicate in macrophages but not in T cells. Similarly, T cell tropic (T-tropic or X4) HIV strains replicate in T cell lines but not in macrophages. Dual tropic isolates have also been described that can infect and replicate in both cell types. Additional work demonstrates that the gp120 on R5-tropic strains of HIV recognize and bind to the CCR5 chemokine co-receptor as well as to the CD4 receptor on a host cell. The gp120 on X4-tropic strains of HIV bind to the CXCR4 chemokine co-receptor in addition to the CD4 receptor of a host cell.5The tropism of the HIV strain profoundly influences the pathogenesis of the disease. R5- or M-tropic strains are preferentially transmitted, are responsible for most cases of sexually transmitted HIV infection, and are found during the early stages of infection.6-7 In contrast, X4 or T cell (T)- tropic strains develop in a subset of patients over time and are associated with a faster depletion in CD4+ T cells. Unlike R5 strains, X4 strains are also linked with a depletion of CD8+ T cells.8’9 It is not clear how or why the virus transforms in an infected individual from an R5 to an X4 virus. However, the presence of dual tropic strains of virus may represent a transition or transformation of the viruses over the course of infection.10
Extensive studies of the virus have shown that the tropism of the virus is determined by the amino acid sequence of the envelope gp120. In particular, the amino acid sequence in the V3 loop of the envelope will determine which chemokine co-receptor the virus recognizes and, therefore, which cell type the virus can infect and subsequently replicate. Chimera studies between R5 and X4 strains have shown that mutations in the V3 loop, sometimes as little as one amino acid residue change, may alter the tropism of the virus.11 This suggests that there is plasticity in the determinants of viral tropism. It appears that more basic residues in the V3 loop of gp120, resulting in an overall more negative charge, tend to create an X4 strain.12
In addition to the virion-associated form, gp120 can be detected as a soluble form in the blood of infected patients. Both forms of envelope glycoproteins are capable of binding CD4 and chemo- kine co-receptors, but only the whole virus can infect cells and be internalized.13-15