Deluge of Mutant Coreceptor Discoveries Pave Way for Therapeutic Advances in HIV, Allergy, Arthritis
'Steady stream of papers'
With the identification of naturally occurring genetic mutations that can protect against HIV infection and disease progression, academic scientists and pharmaceutical company investigators have rushed to look into ways to mimic these effects. Many teams are trying to develop molecules that could block the CCR5 and CXCR4 receptors or enhance production of the chemokines that naturally bind to these receptors. TAG's Gregg Gonsalves brings us up to date on this burgeoning area of molecular research and notes that chemokine biology in HIV infection has joined an already vigorous effort to find new ways to treat inflammatory diseases such as allergic airway inflammation, arthritis, and ischemia-reperfusion injury.
The field of HIV co-receptorology has exploded since the landmark discovery a couple of years ago of two surface proteins that HIV needs to get into its host cells in addition to the CD4 molecule. Those coreceptors, called CXCR4 and CCR5, allow for the entry into cells of, respectively, T-cell tropic and macrophage-tropic strains of the virus. CCR5-using strains are generally thought to be the viral strains transmitted from person to person. They generally predominate early in disease and are associated with slower disease progression. CXCR4-using strains, by contrast, predominate later in the course of HIV infection and are associated with faster CD4+ T-cell decline and disease progression. The notoriously lethal "syncytium-inducing" viral isolates seen later in disease have been shown capable, however, of using both the CXCR4 and CCR5 co-receptors.
The expansion of co-receptor usage to include CXCR4 doesn't seem to knock out the ability of these viruses to use CCR5. Both of these hijacked receptors are the docking stations for a class of soluble proteins called chemokines (i.e., SDF-1, RANTES, MIP-1-alpha and MIP-1-beta) which the immune system uses to communicate. After grabbing onto its host cells' CD4 molecule, the virus latches onto the chemokine receptor using parts of its own envelope. It fuses with the cell membrane, injecting its RNA into the cytoplasm where it is reverse transcribed into DNA. Once transcribed, it heads for the nucleus.
Since the discovery of these two original coreceptors for HIV, a host of other molecules have cropped up with the same perverted purpose. They include the chemokine receptors (CCR2b, CCR3, CCR8, and US28) and other chemokine-like receptors with innocuous sounding names like BOB and BONZO and letter-number combos like STRL33, TYMSTR, GPR15 and V28. Recent work, however, has shown that these other receptors -- with the possible exception of CCR3 -- are generally not used to gain entry into cells by primary isolates (viral strains coming directly from patients rather than laboratory-derived strains of HIV), although primary isolates of SIV (HIV's simian cousin) have been shown to use some of these other receptors.
One of the other exciting discoveries revolving around HIV co-receptors was the identification of individuals who were protected from infection by macrophage-tropic strains of the virus. The CD4 cells of these individuals were found to contain a 32-base pair deletion in both of the genes for the CCR5 receptor. These mutations are seen in only a small percentage of people of European descent (about 10% have mutations in one of the genes and about 1% have mutations in both of them) and are not present in people of Asian or African ancestry. This mutation, however, even if present in both genes, does not protect against infection with T-cell tropic strains of HIV, since productive infection with CXCR4-using, T-cell tropic strains does occur on occasion (10% or fewer of primary infections studied to date).
Individuals with the same deletion in only one of the genes for the receptor have increasingly been shown to benefit from slower disease progression and in some, but not all studies, also show reduced susceptibility to infection with HIV. This protection seems to result from a combination of reduced expression of CCR5 on cells and increased production of the chemokines (RANTES, MIP-1-alpha and MIP-1-beta) that are the natural binding agents (or "ligands") for this receptor. This means that HIV has fewer CCR5 receptors for docking onto cells and less of a chance to find CCR5 receptors that are not being already used by these binding proteins.
Subsequent to the discovery of these salutory genetic mutations, researchers went out hunting for other genetic correlates of these phenomena. In short course, several other mutations in the gene for CCR5 have been uncovered. One of them is called "m303." This genetic mutant encodes a truncated and non-functional CCR5 receptor. When the m303 mutation is found in combination with the earlier reported 32-base pair deletion in one of the CCR5 genes, resistance to HIV infection appears to be strengthened. But m303 is an extremely rare mutation; the significance of other mutations in the CCR5 gene that have been described to date has not been well characterized.
There is also a mutation in the gene for the chemokine receptor CCR2, which seems to delay HIV disease progression. This is a common variant of the gene, and the mutation seems to be linked with another mutation in the promoter for the gene for CCR5. (A promoter is a regulatory element associated with a gene which promotes the transcription of the DNA of that gene into RNA by the RNA polymerase.) A mutation in both of the genes for SDF-1, which binds to and blocks HIV's access to the CXCR4 receptor, also seems to strongly delay disease progression. This may be simply be due to increased production of SDF-1.
Recent work has identified a mutation in the CCR5 promoter alone which strongly delays progression of disease. This is a very common variant and is found in almost 60% of people of European descent studied so far. Importantly, the mutation has also been found in 43% of people of African descent, 47% of people of Asian descent and in 68% of people of Latino descent. This mutation may function by down regulating the production of CCR5, rather than through a direct effect on the nature of the receptor itself.
Many groups are continuing to search for genetic correlates that may protect against or enhance the susceptibility to infection with HIV -- or slow or speed disease progression in infected individuals. We can expect to see a steady stream of papers on this topic in the years ahead. With the identification of naturally occurring genetic mutations that protect against HIV infection and disease progression, academic scientists and pharmaceutical company investigators have rushed to look into ways to mimic these effects. Many teams are trying to develop molecules that could block the CCR5 and CXCR4 receptors or, alternatively, enhance production of the chemokines' natural ligands. Chemokines are also important factors in many inflammatory diseases. And the search for ways to modify chemokine biology in HIV infection has joined an already vigorous effort to find new ways to treat diseases such as allergic airway inflammation, arthritis, and ischemia-reperfusion injury. But a word of caution: chemokines are important mediators of the immune response, and tinkering with these molecules and their receptors will need to be done carefully in order to avoid impairing the body's immune defenses -- or setting off unwanted and dangerous inflammatory responses. Nonetheless, the work of basic researchers is once again paving the way for new advances in the treatment of HIV disease.
This report was based on two recent papers: Zhang L, He T, Huang Y et al. Chemokine coreceptor usage by diverse primary isolates of Human Immunodeficiency Virus type 1. J Virol 72(11):9307-12 and McDermott DH, Zimmerman PA, Guignard F et al. CCR5 promoter polymorphism and HIV-1 disease progression, Lancet 1998;
|HIV Coreceptors and Their Known Ligands, To Date|
|CCR2b||MCP-1, MCP-2, MCP-3 MCP-4|
|CCR3||Eotaxin, RANTES, MCP-2, MCP-3 MCP-4, MCP-5|
|CCR5||MIP-1a, MIP-1b, RANTES|
|Source: Balter M, Science 280 (5365): 825.|