How HIV Infects Cells

from Project Inform's PI Perspective #20, November 1996
"Basic Science Discovery: Opening the Door on HIV"

Recent news reports heralded the identification of proteins found on immune cells, one called CKR5 and another called fusin, which play a key role in understanding how HIV infects cells. Though these discoveries may not have any immediate effect on the welfare of people with HIV, over time they may lead to important advances in HIV treatment, prevention and research.

One way HIV disables the immune system is by infecting and destroying CD4+ T-cells. These cells are critical in managing immune responses and if they are depleted, immune defenses are weakened. When HIV and related infections enter the body, CD4+ T-cells, operating through a network of chemical interactions, instruct other cells to disable the invading organism. The CD4 protein on the surface of these and other cells is a key protein that HIV links up with to enter the cells. CD4 is like a doorway that HIV uses to gain entry into the inner working of the cell. Experiments suggest that the CD4 protein itself is not enough to allow viral entry into cells. It has long been believed that there is a second doorway that the virus needs to open in order to infect a cell. Scientists think they have identified the second doorway and they have learned that it may be different for different types of cells. One is CC-CKRS, or CKR5 for short, and another is fusin. CKR5 exists on a broad range of cells which can be infected by HIV, including T-cells and macrophages. Fusin on the other hand, is primarily found on CD4+ T-cells and only appears to serve as a doorway for certain strains of virus. Both are important and each may play different roles in facilitating HIV infection of different cells at different times and under different circumstances. CKR5 appears to be important when NSI strains (the strains most common in early disease) of HIV are prevalent, while fusin appears to be more important when SI strains (a more aggressive strain typically found in later stages of disease) of HIV predominate.

NSI, or Non-Syncitium Inducing, strains of HIV are the most common sexually transmitted form of the virus. This type of virus preferentially infects macrophages, rather than T-cells. As HIV-disease progresses, SI or Syncitium Inducing, strains of the virus may become more prevalent in an individual. SI strains of HIV prefer to infect T-cells. It is unclear why the virus converts from an NSI to an SI strain in some people. The SI strain of HIV is more aggressive and its prevalence correlates with more rapid disease progression. Additionally, antiviral drugs generally have less activity against SI strains of HIV. About 50% of people who die of AIDS still have a predominant NSI strain of virus. The most obvious difference between someone with an NSI versus an SI strain is that people with an SI strain experience more rapid decline in CD4+ T-cell counts, as the SI virus preferentially infects and destroys these cells. People with the SI strain tend to have a 3 to 5 fold increase in the rate of disease progression.

Collectively, the back-to-back discoveries of the chemokines and the CKR5 receptor site shed new light on how HIV infects cells and why there is so much difference in response from one person to the next.

In addition to being a cell surface protein important for HIV entry into cells, CKR5 is also a receptor for beta-chemokines. For many years it has been supposed that CD8+ cells produce a factor capable of suppressing HIV infection of CD4+ cells. Last year Dr. Robert Gallo's group identified such a factor, which appears to be a combination of chemicals (called chemokines): MIP-1-alpha, MIP-1-beta and rantes. The fact that CKR5 not only blocks HIV entry into CD4 bearing cells, but also is a receptor for these chemokines explains two important aspects of the interaction between the immune system and the virus. When the CD8+ cells effectively make a large quantity of the chemokines, they may fill up and block the "doorway" for infection provided by the CKR5 protein. Conversely, when levels of the chemokines are low or absent, the virus is free to more easily infect cells because the CKRS receptor protein is readily available to it. Collectively, the back-to-back discoveries of the chemokines and the CKRS receptor site shed new light on how HIV infects cells and why there is so much difference in response from one person to the next.

Other studies suggest that that some people with defects in their CKR5 receptor protein may have some immunity to HIV infection. This defect has been linked to a specific gene, called CCRS, which can be inherited from one's parents. The study appeared to show that when a person inherited a defective version of this gene from both parents, they had very high resistance to infection with HIV. Some people may inherited a single defective version of the gene from one parent, but there is as yet insufficient data to know whether this confers partial protection. This study was extremely small and the defective receptor was found on only two of fifteen people who were thought to be exposed to HIV, yet remain uninfected. However, other studies have reported that approximately 1 in 100 Caucasians carried 2 defective copies of the gene. Similar defective genes have yet to be identified in people of other races, but scientists believe it is only a matter of time before this happens.

Undoubtedly there will be more in the news about the CCR5 gene and the CKRS and fusin proteins and their role in HIV. Certainly these discoveries are important, but how they will be applied to new directions in treatment research remain to be seen.

Clinical Implications
Researchers are already experimenting, in test tubes, with approaches that may be useful in blocking the CKR5 and fusin receptors. Two approaches are possible. One is to artificially give more of the chemokines to people whose CD8+ cells are not producing these chemicals in adequate quantities. The other is to develop methods for directly blocking the receptor sites. Either way, such therapies should diminish the opportunity for HIV to infect new cells. The challenge of either approach is to do this without interfering with the normal function (whatever it is) of the chemokines and the CKRS receptor sites. The bottom line is that these discoveries may someday be important in HIV therapies, but at the current time further research is necessary to confirm the findings and to develop ways to interfere with the cell proteins.

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