How do human cells react to HIV infection?

Virginia Pierini was only six when she asked for a magnifying glass as her birthday gift. She wanted to observe the insects living in her family’s garden from a closer perspective. Since this early time, her curiosity and excitement to learn something new have been great drives throughout her life. At a later moment, a personal experience influenced her to be interested in even smaller entities: viruses. “During my time at university, my passion shifted to human molecular biology and an internship in a laboratory of a Kenyan nonprofit organization that works with HIV-positive kids, inspired me to study HIV later on”, tells Virginia.

The basic anatomy of HIV: the viral structure is composed of its genome and enzymes packaged inside a capsid, which is further covered by an envelope. This envelope is composed of cell membrane from where the virus was produced.

HIV (human immunodeficiency virus) is a virus that destroys cells of our immune system. This system protects our bodies from invaders, such as microorganisms or toxins. Most of the time, our immune responses are good, and we soon recover from infections and intoxications. But HIV is a tricky invader. This virus not only disables factors that want to destroy it, but its genetic code is often changing. On the other hand, our immune system is only able to fight quickly against something that it had already met before. If HIV is constantly changing, it makes the job of our defense system very hard. As a consequence, during an HIV infection, the system becomes exhausted with time. Now it no longer fights other infections with the same efficiency. And this makes it easier for different invaders, including bacteria, fungi and other viruses, to enter our bodies and destroy our cells. As Virginia clarifies, “imagine a town surrounded by walls as a protection from external attacks. The town is our body. One dangerous enemy is HIV (…). HIV is like a fighter jet that flies in stealth mode. It shoots at the town walls and opens a breach to let other nasty viruses conquer and destroy the town”.

So it comes with no surprise that HIV infection is a burden for our organisms. And if not treated, it can evolve to AIDS (acquired immunodeficiency syndrome), a disease that still lacks a cure. The Italian scientist emphasizes the importance of studying this virus and its infection: “HIV is a threat for public health, with currently 38 million people infected in the world. Finding a cure or a vaccine is the final goal. To reach this goal, we need to understand how the virus works and how our body responds.” On top of that, despite the existence of antiviral treatment, which are drugs that reduce the amount of virus in the body, 33% of infected individuals have no access to these drugs. Yet, for 67% of the ones that receive the therapy, different side effects, such as nausea, diarrhea, and trouble sleeping may disturb their life quality, or discourage patients from sticking to the treatment. Thus, better ways to treat and prevent HIV infection are also needed.

HIV particles can be transmitted from an infected person to a healthy one through blood, breast milk, semen, rectal and vaginal fluids. When the virus succeeds and infects healthy individuals, it attacks cells of our immune system. These cells have labels around them that are recognized by HIV. Once the virus finds one of these immune cells, it fuses its packaging, the envelope, with the cell membrane. This allows all the content inside the viral envelope to be released inside the cell, promoting access the cell machinery to the virus. And that is all what HIV wanted: a little factory (the cell) where it can make copies of itself, which are released to the rest of the body, keeping the infection at full throttle.

The seven main stages of HIV life cycle: 1) When HIV attacks a cell, the virus attaches itself to molecules on the surface of the cell. 2) After HIV attaches itself to a host cell, the HIV viral envelope fuses with the cell membrane. 3) Once inside a cell, HIV releases and uses reverse transcriptase (an HIV enzyme) to convert its genetic material—HIV RNA—into HIV DNA. The conversion of RNA to DNA allows HIV to enter the cell nucleus and combine with the cell’s genetic material. 4)  Once inside the host cell nucleus, HIV uses an enzyme to insert its viral DNA into the DNA of the host cell. 5) Once HIV is integrated into the host cell DNA, the virus begins to use cell to create HIV proteins, the building blocks for more HIV. 6) During assembly, new HIV RNA and HIV proteins made by the host cell move to the surface of the cell and assemble into noninfectious HIV.  7) During budding, noninfectious HIV pushes itself out of the host cell. Once outside the cell, the new HIV exploits an HIV enzyme. This breaks up the proteins in the immature virus, creating the infectious virus.
Information and image extracted from CLINICAL INFO.HIV.GOV

But, the immune system doesn’t simply allow infections to continue without fighting against them. In her Ph.D., Virginia studied how a protein that exists in our bodies helps to fight against HIV. Usually, after an infection is established, more viruses leave the host cells to infect others. On their way out, explains Virginia, “these new viruses rip off a piece of the cell membrane that becomes their envelope [the outer part of the virus].” She clarifies further, “it was discovered that a protein called SERINC5, that sits on the outer membrane of human cells, can be carried by new HIV viruses, on their membrane envelope”. This protein would work like secret agents that sneak into HIV fighter jets. But then what happens to the virus particles that end up carrying SERINC5 with them? “If some SERINC5 proteins come along with the cell membrane [and will be part of the virus envelope], virus particles are not able to enter other cells and infect them.” So is this protein the one alerting these other cells to avoid further infection? That is what Virginia investigated in her Ph.D. research.

At the beginning of her study, Virginia knew that SERINC5 helps to protect from HIV infection and that it interferes with its propagation. But it was not clear whether this protein could inform other cells when HIV is approaching, “whether the secret agents could warn the town, on the arrival of the fighter jets, to fire back,” according to her. Thus, in a paper published this year, in which Dr. Pierini is the main author, she and her colleagues “found that cells can feel the presence of those virus particles that have SERINC5 on their envelope and fire back by secreting (…) molecules, called cytokines, which trigger an inflammation in response to the virus”. Coming back to the town vs. invaders analogy, the paper describes “that the secret agents can warn the town by making the HIV fighter jets visible, losing their stealth mode. The town shoots at the HIV fighter jets with fireballs, which are pro-inflammatory cytokines and are among our body deadly weapons against intruders”.

That sounds like good news, right? After all, it seems like our body has a way to protect us from HIV. Since it not only can make the virus visible again to our defense system but also trigger an inflammation response against it. But why does HIV produce such an aggressive infection in humans anyway? One reason may be another discovery suggested by Pierini’s paper. “HIV is very smart and evil because it has soldiers, viral proteins called Nef, (…) that throw the secret agents (SERINC5) off the jets before they could alert the town”, she explains.

In the fight between our body and HIV, our body is like a town and HIV is a dangerous enemy, which is like a fighter jet that flies in stealth mode. The HIV fighter jets shoot at the town walls and open breachs to let other invaders to conquer and destroy the town. But our bodies have special agents that sneak into HIV fighter jets, called SERINC5, which warn the town on the arrival of the jets. As a consequence, our body fires back with cytokine fireballs, trying to control the HIV invasion. But HIV has the help of one of its soldiers, the restriction factor Nef, to throw the secret agents out of the fighter jet, what allows it to continue the invasion. Image by Virginia Pierini.

The puzzle still misses many pieces, though. With her work, Virginia shows “that our body has a potent weapon, SERINC5, against the virus, but HIV is cunning like a fox and found a way to overcome it”. But she ponders, “SERINC5 is not the only weapon, thus we need to continue studying to find a way to use other weapons to beat HIV. The life of many people is in danger because of HIV. To find a strategy to beat it up, we need studies like mine to understand what the weapons that we have at our disposal are, and how HIV would respond”. Also, “it is unclear how the cells recognize virus particles carrying SERINC5. Who sees the HIV fighter jets approaching the town? What component of the jet do they see, to recognize that is HIV and not the jet of an ally?”. All questions to be answered in future studies.

Gradually, more studies like Virginia’s are helping us to better learn how HIV infection works and how our cells react to it. With hope, we will soon have improved prevention methods and treatments, and eventually a cure for all those affected by this ingenious virus.

Dr. Pierini took five years and four months to complete her doctoral studies at Heidelberg University. When asked what encouraged her to start and continue her project, she replied “throughout my Ph.D., I tried not to lose sight of the long-run perspective of the basic research I was doing. The ultimate goal is to help those who live with HIV and suffer because of it. This always kept me motivated”. Besides science, in her free time, Virginia loves “traveling the world and learning about other cultures and cuisines.” She also enjoys dancing, reading, and studying the German language.

After completing her Ph.D., now Virginia is working as a postdoctoral researcher at Heidelberg University. You can find more information about her career here.

Thank you a lot, Virginia, for sharing your work and story with us!

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