A possible cure for HIV/AIDS?

There are a number of new techniques for attacking HIV, the virus that causes AIDS, that are in the early stages of research and development. More research will be needed to see if they prove out before they can begin human trials. But the experiments are exciting because, in combination, the various therapies could possibly cure HIV/AIDS, at least in theory. But as already stated, we’re only at the early stages of this research.

Let me walk you through the latest.

Possible new method to destroy HIV sequestered in human cells

Information from a recent conference has demonstrated some interesting results in the search for a cure for HIV.

One of the main reasons that HIV is so difficult to cure is that the virus can infect some cells (T cells, dendritic cells and some others) and lie dormant there for years. So even with an unmeasurably low viral load in serum, there is still HIV hidden in cells. As time passes, this some of this virus reactivates and is released into the serum again while in other cells it continues to remain dormant. So antiretroviral medications can clear the serum of virus, but not these cells that harbor resting virus.

Scanning electron micrograph of human immunodeficiency virus (HIV), grown in cultured lymphocytes. (Photo credit Photo Credit: C. Goldsmith, CDC)

Scanning electron micrograph of human immunodeficiency virus (HIV), grown in cultured lymphocytes. (Photo credit Photo Credit: C. Goldsmith, CDC)

A research team tried a technique that can be used in cancer chemotherapy to wipe out these nests of virus infected cells. They used an antibody that will attach to those cells that are infected with HIV. Attached to the antibody is a tiny dose of a radioactive substance. The antibody-radioisotope, when applied to a mix of healthy and HIV infected cells, targets the infected cells and binds to them. It holds the isotope close to the cell until the cell dies from exposure to low-level radiation. The cell disintegrates and the cellular debris and the HIV are cleaned up by the body’s immune system. Since the radioisotope is only bound to the infected cells, healthy cells in the vicinity are not harmed.

So far, this has only been done in cells cultured in the lab and in animals. But it may be one method of destroying the reservoir of HIV in infected people, allowing them to finally clear all of the virus and be cured. The next step will be beginning the initial trials in humans.

Alternate method to remove proviral DNA from reservoir cells

When HIV enters human cells it can blend with the host cell’s DNA. It can direct the cell to produce many copies of the HIV virus or it can lie dormant for some period of time. It is this pool of dormant virus that makes the HIV become virtually immortal (see above). Antiretroviral medications can do nothing against the embedded proviral DNA. The method described above may be able to wipe out those cells containing the HIV genetic material using radiation. However, this kills the infected cells some of which are T cells that may already be in short supply. The method described below, can remove the tainted DNA and allow the cell to survive.

Researchers isolated a viral enzyme (Cre) that acts to help get the viral genetic material into the host cell’s DNA and maintain it there. They genetically engineered Cre, making an altered enzyme that is called Tre. Tre, instead of helping the virus incorporate its nucleic acids into the human cell’s genome, as Cre would, does the reverse. It clips out the viral genes. Once the viral genes have been removed, the host cell’s DNA may repair itself and the cell may be able to survive, unlike the radioisotope approach used above.

This approach (using Tre) in humans would probably require gene therapy to allow Tre to be produced in all infected cells. So far, this work has only been done successfully in mice. That means that actually using it as a possible cure is still years in the future. But this may supply another mechanism to attack HIV. This method, and the one described above, may both serve to eradicate the HIV reservoirs that have prevented a cure to date.

Preventing T cell dysfunction

T cells (CD4 cells) are lymphocytes that are necessary for a robust immune response. They can function in different ways to provide protection against non-self molecules. They can act to help B cells (other lymphocytes that produce antibodies) mature, they can activate cytotoxic T cells and macrophages that will then remove foreign substances. They can become activated and then produce cytokines (small proteins like interferon) that can act to neutralize and/or destroy invading viruses.

In patients infected with HIV the number of T cells decreases. HIV infects T cells (and some other cell types). These infected T cells may die as a result of the infection itself or may be killed by CD8 lymphocytes that recognize these T cells as infected. As CD4 cells decrease, the part of the immune response known as cell-mediated immunity begins to fail. As that happens, the patient is left open for infection by opportunistic pathogens. So the infected T cells are underperforming their roles in immunity because of the HIV burden they contain. Additionally, the remaining uninfected T cells sometimes become weakened and are classified as “exhausted.” That is, they are not working as well as they should. Until recently, it wasn’t known why these T cells became exhausted.

New research has shown a possible mechanism that has also suggested a way to prevent this happening to T cells. Scientists have exposed populations of T cells to high concentrations of HIV antigens. What they found was that when the T cells were surrounded by so much antigen, they became overwhelmed. The excess antigen triggered the T cells to produce a chemical named sprouty-2. Sprouty-2 is normally present in small amounts in T cells. In cells exposed to high concentrations of HIV antigens, the T cells produced a lot of sprouty-2. Sprouty-2 acts to help regulate T cell function, among other things. When it is present in high concentrations, it effectively weakens the T cell, “exhausting” it. The cell is much less able to function effectively and, therefore, its ability to activate other cells, produce interferon and other cytokines is impaired.

The researchers think that perhaps by inhibiting sprouty-2 they can prevent the T cells from becoming exhausted and allow them to maintain function. If that is possible, then this may be another mechanism that can help prevent T cell death and help prevent opportunistic infections.

A possible cure for HIV/AIDS?

This is some exciting new information. The proposed treatment with antibody-bound radioisotopes, combined with antiretroviral therapy could possibly be curative, at least in theory. Even if the sprouty-2 research doesn’t lead to a viable treatment to help maintain healthy T cells, it has at least given researchers more insight into another part of the HIV puzzle.

Mark Thoma, MD, is a physician who did his residency in internal medicine. Mark has a long history of social activism, and was an early technogeek, and science junkie, after evolving through his nerd phase. Favorite quote: “The most exciting phrase to hear in science... is not 'Eureka!' (I found it!) but 'That's funny.'” - Isaac Asimov

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