by Rose Filoramo
figures by Daniel Utter

A Report that Changed History

On June 5th, 1981, the Center for Disease Control and Prevention (CDC) released a medical report documenting something peculiar: within the span of one year, five previously healthy men from Los Angeles were all diagnosed with an incredibly rare lung infection. Scientists and health professionals were baffled. The infection normally only affected people with extremely weak immune systems—what had happened to these men? This mysterious breakdown of the immune system would later become known as Acquired Immune Deficiency Syndrome or AIDS. AIDS is caused by infection with Human Immunodeficiency Virus (HIV). This virus has ended millions of lives and remains a formidable foe. Even after thirty-five years of tireless work we are still trying to find a way to beat HIV once and for all. Why is a cure so elusive?

What is HIV and how does it cause AIDS?

Think of our cells as tiny factories. Our DNA, or genetic code, serves as a blueprint for manufacturing all the different pieces of molecular machinery that our cells need to survive. Viruses, like HIV, cannot reproduce without the help of our cellular factories. They must infiltrate our cells and highjack the manufacturing equipment located within. They do this in a very sneaky way: by inserting a “DIY Virus-Making Guide” into our DNA (Figure 1). That way, when cells read the “instructions” encoded in its blueprint DNA, the cell also reads the viral instructions, and the cell will be tricked into making new viruses, in the form of proteins, alongside normal cell machinery.

Figure 1: The HIV lifecycle. A. HIV binds to the surface of an immune cell. B. HIV tricks the cell into letting it inside, allowing the viral RNA and protein to spill into the inside of the cell. C. The viral protein reverse transcriptase converts the HIV RNA to DNA. D. Viral DNA is incorporated into the immune cell DNA. E. Infected cells read viral DNA as if it were their own and produce HIV RNA and proteins. These are used for the manufacture of new viruses.
Figure 1: The HIV lifecycle. A. HIV binds to the surface of an immune cell. B. HIV tricks the cell into letting it inside, allowing the viral RNA and protein to spill into the inside of the cell. C. The viral protein reverse transcriptase converts the HIV RNA to DNA. D. Viral DNA is incorporated into the immune cell DNA. E. Infected cells read viral DNA as if it were their own and produce HIV RNA and proteins. These are used for the manufacture of new viruses.

HIV is a member of a particular group of viruses called retroviruses. The “retro” part of these viruses relates to the “backwards” way in which their genetic information is stored. While some viruses use the same type of genetic blueprint material as we do—DNA—retroviruses use another type of material called RNA. RNA might sound familiar because we actually use it too. For us, it serves as a working copy of particular parts of the original genetic blueprint, like a temporary carbon copy. The RNA copy of the DNA is taken from the nucleus, think like the “main office,” of the cell to the cytoplasm, or the “factory floor” and used as instructions to make proteins (our cellular machinery). HIV must use a special piece of viral machinery called reverse transcriptase to transform their RNA into DNA (Figure 1C). This conversion is necessary if the viruses are going to trick our cells into reading their genetic material as if it were our own, as our instructions are written in DNA (Figure 1D). Because retroviruses must convert their genetic material from RNA to DNA, instead of DNA to RNA (like us), we call them “backwards” or “retro.”

HIV preferentially targets the cells of the immune system as its host. Though a cell might not notice these unwelcome intruders at first, as the rate of HIV manufacture increases, the immune cell hosts can often die. This death can occur for several reasons, including 1) the production of virus sapping resources from normal cell activities, or 2) killing by other immune cells that recognize sick and infected cells. This widespread death of immune cells weakens the immune system to the point that it can no longer protect against even the most benign of germs. It is at this point, when the immune system is so intensely compromised, that the HIV infection transitions into the more serious AIDS. The most common cause of death for patients with AIDS is opportunistic infections, or infections with ordinary germs that take advantage of a highly weakened immune system.

Control, But Not A Cure

Since the beginning of the AIDS epidemic, globally over 70 million people have been infected with HIV and about 35 million have died from the complications of AIDS. The burden of death remains exceptionally high in countries where new HIV drugs, called highly active anti-retroviral therapies or HAART, are not readily available. In developed nations like the United States, key advances in HAART have nearly tripled the life expectancy of young adults infected with HIV. This therapy involves a cocktail of three different drugs that target the virus’s replication and ability to infect new cells from multiple angles. This intensive therapy regimen helps counter the ability of HIV to evolve resistance to the drug treatment. HAART has been extremely effective in preventing the death of immune cells and the deadly progression to AIDS. However, people with HIV must remain on treatment indefinitely—otherwise the infection could resurface again. The question remains: why can’t HAART cure HIV infection?

Figure 2: HAART and the problem of viral latency. A. Panel A depicts immune cells at various points of infection with HIV. B. HAART stops HIV from replicating and infecting new cells. However, it cannot remove viral DNA that has already been integrated into immune cells. C. Over time, if HAART is continued, both infected and uninfected cells will eventually die and be replaced (in blue). However, some immune cells can mature into long lived “memory cells” (in green). These cells allow viral DNA to hide out for long periods of time. This is referred to as latent HIV.
Figure 2: HAART and the problem of viral latency. A. Panel A depicts immune cells at various points of infection with HIV. B. HAART stops HIV from replicating and infecting new cells. However, it cannot remove viral DNA that has already been integrated into immune cells. C. Over time, if HAART is continued, both infected and uninfected cells will eventually die and be replaced (in blue). However, some immune cells can mature into long lived “memory cells” (in green). These cells allow viral DNA to hide out for long periods of time. This is referred to as latent HIV.

Fugitive HIV: The Problem of Viral Latency

One major roadblock to a curing HIV is something called viral latency. Viral latency describes the ability of certain viruses, like HIV, to enter a dormant or hibernating state within our cells. Like a criminal going off the grid, HIV can quietly hide out in cells until conditions improve (i.e. when a patient stops taking their drugs). While a fugitive might hole up in a remote mountain bungalow for 20 years, HIV hides in plain sight—inside an infected person’s DNA.

Why can’t HAART kill these viruses? The drugs within the cocktail that make up HAART only target HIV that are actively infecting new cells or are actively being manufactured by one of our cells (Figure 2). But remember, the production of new viruses can only occur if the cell is already busy making things for itself. What if the cellular factory was temporary shut down and abandoned? This is actually a normal feature of a subset of the immune cells that HIV infects. Some of these cells mature into long-lived dormant forms called “memory cells” (Figure 2C). Memory cells lead quiet lives, only jumping into action when they encounter very specific germs. A number of HIV-infected immune cells can also survive and mature into memory cells. These abandoned factories happen to be the perfect place for HIV to hide and hibernate until conditions improve for new infection.

Rise and Shine, Little Virus!

So how do we get rid of these slumbering viruses once and for all? For the last decade, scientists have mainly approached this problem experimentally using what they call a “shock and kill” therapy. This type of therapy relies on getting the viruses to start reproducing again, in hopes that the either viral growth or counter-attacks by the immune system will kill the infected memory cells. So, how does one wake up the sleeping HIV? Remember that HIV can only replicate if the cell that it has invaded is activated and busy making machinery for itself. So, the key is to wake the cell up too!

Members of the Wong Lab at UCSF recently discovered a drug that shows promise in rooting out latent HIV: vitamin A. The Wong lab was initially interested in vitamin A because of its projected ability to “wake up” both sleeping cells and HIV (Figure 3). In order to test it, immune cells were harvested from patients with latent HIV and treated with vitamin A. As expected, this treatment led to the reopening of the abandoned cellular factories and a huge burst of manufacturing activity by the cell—including viral products.

Unexpectedly, vitamin A seemed to have a second effect: it killed the latently infected cells (Figure 3C). Further experiments suggested that vitamin A was doing this by bolstering the cells’ antiviral defenses. One tactic used by the immune system is to instruct the virus-infected cell to “self-destruct.” The logic is—no more cellular factory, no more viral assembly line. Normally, HIV tricks its cellular host into ignoring its presence. That way it keep hijacking the cell’s machinery unimpeded. Interestingly, vitamin A seemed to interfere with this viral cloaking device and allowed the latently infected cells to recognize that they were sick and respond.

Figure 3: Vitamin A wakes up and kills latently infected cells. A. Even after effective HAART, integrated HIV DNA can linger for long time periods within memory cells (green). B. Treatment with vitamin A “wakes up” memory cells, causing them to manufacture both cellular and viral proteins. C. Vitamin A increases anti-viral immunity. This leads to the death of infected immune cells.
Figure 3: Vitamin A wakes up and kills latently infected cells. A. Even after effective HAART, integrated HIV DNA can linger for long time periods within memory cells (green). B. Treatment with vitamin A “wakes up” memory cells, causing them to manufacture both cellular and viral proteins. C. Vitamin A increases anti-viral immunity. This leads to the death of infected immune cells.

Are We Closer to a Cure?

Is vitamin A going to be the new miracle drug for patients with HIV? Unfortunately, it is too soon to know for sure. However, according to the Wong lab, plans for clinical trials are in the works. These studies will hopefully shed some light on the usefulness of this treatment in real people who may have responded well to HAART but cannot clear the latent HIV. Even though a complete cure might seem far off, the research done by the Wong lab and others holds the key to better understanding the complex lifestyle of HIV. There has been an explosion of work lately in this field. For example, some labs are even exploring using CRISPR technology to shock HIV out of hiding! By learning more about how latent HIV works and how to target it using new, creative treatment methods, we move closer and closer to an AIDS-free future.

Rose Filoramo is a sixth year graduate student in the Biological Sciences and Public Health Ph.D. program at Harvard University.

For more information:

  1. For more information on the HIV life cycle, see: https://aidsinfo.nih.gov/education-materials/fact-sheets/19/73/the-hiv-life-cycle
  2. For a video depicting HIV infection and interference by HAART, see: https://www.youtube.com/watch?v=C-zwPo3dzGg
  3. To learn more about the history of AIDS and HIV, see: http://www.amfar.org/thirty-years-of-hiv/aids-snapshots-of-an-epidemic/
  1. For more statistics about HIV and AIDS globally, see: http://www.avert.org/global-hiv-and-aids-statistics
  2. To learn more about how HIV evolves drug resistance, see: http://evolution.berkeley.edu/evolibrary/news/070301_hiv
  3. To read the original paper about the Wong Lab’s work on Vitamin A and viral latency, see: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004598/
  4. To read more about using CRISPR to “shock and kill” HIV, see: http://www.nature.com/articles/srep16277

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