Saturday, 10 March 2018

Pathways To A Cure For AIDS

Written By: Amber Dance, Knowable Magazine

Medications can control HIV, but not eliminate it. Scientists hope to one day vanquish it completely.
Before the disease was even understood, its deadly nature was apparent. Between 1979 and 1983, the CDC recorded 3,064 cases in the United States alone, and 1,292 deaths — a 42 percent fatality rate. By 1994, AIDS was the leading cause of death for Americans ages 25 to 44. That's changed in recent decades, thanks to antiretroviral therapies. These drugs prevent the virus from copying itself and have transformed HIV into a largely manageable chronic condition. Today, someone with the human immunodeficiency virus who sticks with the daily drug regimen can expect to live a near-normal lifespan, says Robert Siliciano of the Johns Hopkins Medical Institute in Baltimore.

Although HIV infection is no longer the death sentence it once was, it remains a major health concern.
Despite this progress, the virus is far from vanquished. At the end of 2016, about 37 million people around the world were HIV-positive, and 1 million died that year. Not everyone can afford, tolerate or manage the drug therapy. Some do not have access to it. And the drugs can have side effects, such as liver damage and heart disease.

Antiretroviral drugs put the HIV dragon to sleep, but can't slay it. The virus lurks in "reservoirs" throughout the body, ready to jump back into action if people stop their antiretroviral meds. These reservoir T cells can be found all over the body, but are often concentrated in the gut, spleen and lymph nodes.

However, rare cases of people who resist the disease are inspiring scientists to hunt for a cure. Much of HIV research has shifted from the search for new medications to work on potential vaccines or curatives, says Siliciano: "The whole world has changed."

Transmission


AIDS and HIV were first noticed among gay men in the 1980s. By 1983, the disease had also been found among female heterosexuals and users of injectable drugs, as well as hemophiliacs, who were infected from blood transfusions. The Red Cross began testing donated blood for HIV in 1985; this, plus antiviral treatment of blood products, has largely eliminated transfusions as a major cause of new infections.

Today, male homosexual contact remains a leading cause of infection, though heterosexual contact also accounts for a large portion of infections. Injectable drugs remain a major factor.


However, treatments can reduce the transmission of the virus. Antiretroviral therapy limits the amount of circulating virus in the body, and if an HIV-positive person's viral load is undetectable by current tests, they have virtually no risk of transmitting it to a sexual partner. It's not clear if the same holds true for drug users' needle sharing.

Uninfected people at high risk for the disease, such as intravenous drug users or the sexual partners of HIV-positive people, can minimize their risk through drug therapy called pre-exposure prophylaxis, or PrEP. This involves anti-HIV drugs that, when taken daily, are quite effective at reducing transmission.

In addition, a person who may have been exposed to HIV — such as a health care worker or rape survivor — can take antiretrovirals to prevent the infection from taking hold. This is called post-exposure prophylaxis, or PEP, and must be started within three days of exposure.

HIV can also be transmitted from a woman to her baby during pregnancy, birth or breast-feeding. If a pregnant woman takes HIV medication, and it's given to her baby for the first four to six weeks after birth, the risk is 1 percent or less that the child will contract HIV. It's not certain if treating a mother prevents transmission through breast milk.


Stages of HIV/AIDS


By attacking and killing the immune cells meant to fight disease, HIV weakens the immune system in progressive stages, characterized by shifts in the number of circulating viral genomes (viral load), immune cell populations and symptoms. It starts with acute infection, when a person might experience mild, flu-like symptoms. Then the disease goes dormant, usually for about a decade. Finally, if left untreated, the virus ramps up activity, and progresses to AIDS.

Acute infection Once it gets into the body, HIV infects immune cells called CD4 T cells. It's a retrovirus, which means it carries its genes as RNA, instead of DNA. The virus turns its genes into DNA and inserts them into the DNA of the host cell. It can then hijack the cell's machinery to make more copies of itself, upping viral load and making it easier to transmit the disease to someone else.

HIV infection alone doesn't kill T cells, and the immune cells can die in a few different ways. Some succumb to inflammation before the virus manages to replicate. Others die after the virus has inserted its genes within their own. And some die after the virus has replicated. That's because the HIV protease, a protein-cutting enzyme, also cuts T cell proteins, and this sets off a chain reaction leading to a form of cellular suicide.

Other T cells that die aren't themselves infected by HIV; they are uninfected "bystanders." Other factors, such as toxic HIV proteins in the bloodstream or the inflammation brought on by the viral infection, cause them to commit cellular suicide.

Chronic, latent infection Then the viral load drops. Infected T cells that survived the initial wave of infection often contain the viral genes, but don't make new viral particles. They aren't making HIV proteins, which allows them to hide from both the host immune system and anti-HIV drugs. These infected cells are the reservoir.

At this stage, the virus causes no symptoms other than, perhaps, swollen lymph nodes. This stage usually lasts for about a decade, but antiretroviral treatments can prolong it by keeping the virus in check.

Without treatment, HIV eventually ramps up its replication rate and viral load increases. Bystander cell death becomes more common. Symptoms emerge, such as fever and fatigue. With fewer active T cells, people become susceptible to infections, such as thrush or shingles, that a healthy immune system could probably fight off.

AIDS The progression to AIDS is defined as the point when there are only 200 CD4 T cells per one-thousandth of a milliliter of a person's blood (there should be 500-1,500). With so few of those cells, the body can no longer fight other infections effectively. These "opportunistic" infections include tuberculosis, toxoplasmosis and a fungus-caused version of meningitis.

Cure-like cases


HIV can be held in check-but could there be a cure? Scientists talk about two versions of a cure, says Siliciano. One is a "sterilizing" cure; this means getting rid of all the virus, as well as any reservoir T cells carrying its genes among their own. That will likely be hard to achieve.

The other option is a "functional" cure. This describes a situation in which a person is in remission, without need of antiretroviral treatment, even though some HIV remains in the reservoir. This would likely involve some modification to the immune system itself, to reduce chances of the virus re-emerging.

Scientists are intrigued by a few cases of people who resist HIV infection or, if infected, resist progressing to AIDS. Other treatments have managed to achieve temporary remission, without antiretrovirals, and one person has been cured, thanks to a bone marrow transplant.

Resistant individuals HIV gets into immune cells via human cell surface proteins called CD4 and CCR5. Certain people have mutant CCR5, rendering them immune to infection. This finding led to the development of CCR5 antagonists, which prevent the virus from infecting new T cells.

In control  Other people can be infected but are able to keep viral levels low, and T cell counts high, without any help from antiretroviral drugs. One category of these patients is "elite controllers," who have undetectable HIV after the initial infection; they make up less than 1 percent of the population. More common are "viremic controllers," who maintain HIV at low levels-fewer than 2,000 viruses per milliliter of blood. The exact proportion of HIV-infected individuals who are viremic controllers is uncertain. These and others make up a group, called long-term non-progressors, that maintain healthy T cell counts without treatment. In these people, the virus may eventually start replicating and attacking T cells. In one study, nearly 30 percent of controllers eventually saw their viral loads rise.


It's not certain why or how these people keep HIV in check, though scientists have many theories. There might be something unusual about the way their immune systems work. Defects in CCR5 might play a role in some people, for example. And elite and viremic controllers tend to have sustained inflammation, though it's not clear if that's beneficial. Figuring out what's special about the immune response of elite controllers could give scientists hints as to strategies for a functional cure.

Berlin patient  So far in HIV history, a sterilizing cure has happened exactly once, in Timothy Ray Brown, an American man studying in Germany. He was diagnosed with HIV in 1995 and then with leukemia about a decade later. To treat the blood cancer, doctors performed a bone marrow transplant in 2007, hoping to replace his cancerous blood cells with ones made from the bone marrow of a healthy donor. The donor also carried the CCR5 mutation. These HIV-resistant cells replaced the man's immune system.

Brown has no detectable HIV DNA, and celebrated the 10-year anniversary of his cure in 2017. Scientists have tried to replicate this cure in a handful of others, but such a transplant is a risky option, only appropriate for someone who needs it for another reason, such as leukemia.

Boston patients  Aiming to replicate the Berlin results, doctors performed bone marrow transplants on two HIV-positive patients, also both men with blood cancers. This time, the donor marrow had normal CCR5, making it susceptible to HIV. The physicians hoped that if they provided antiretroviral therapy, the new bone marrow would stay uninfected, and destroy and replace the infected immune cells.

Initially, it seemed to work: no virus was detectable, two to four years post-transplant. But when the patients stopped antiretroviral therapy, HIV came back within months.

Mississippi baby  An HIV-positive infant started antiretroviral therapy at 1 day old. When retroviral treatment was stopped 15 months later, the virus did not immediately re-emerge, doctors announced in 2013. They hoped that the virus hadn't been able to set up a reservoir before the treatment began. However, HIV came back just before the child turned 4.

Though the Boston and Mississippi cases did not achieve cures, they did have unusually long remissions. Typically, stopping treatment results in viral rebound within weeks. Scientists think that in these people, the virus stayed latent in the reservoir until some other infection woke up the immune cells carrying it.

Cure strategies


The cure strategy receiving the most attention from scientists, says Siliciano, is called "shock and kill." The idea is to give a drug that will shock, or wake up, the sleeping dragon in the reservoirs so it will emerge, and then to kill it. Theoretically, that would result in a sterilizing cure.

There are several potential drugs for the "shock" part of the strategy. Certain cancer drugs, called HDAC inhibitors, may modify the latent HIV genes to activate them. One such candidate, vorinostat, was able to activate HIV genes in some patients. But so far, no shock medication has managed to do much about the reservoir size.

If doctors could create a successful shock, the next step would be to go in for the kill, eliminating any T cells carrying HIV or its genes. Ideally, a patient's immune system would do this job, but it may be necessary to kick-start it, perhaps with an HIV vaccine.

Vaccines work by training the body to make antibodies that grab onto an invader. One challenge is that HIV is constantly mutating, so as quickly as the body makes antibodies that should grab onto it, the virus changes its shape and slips out of their grasp. Vaccines to prevent or treat HIV have been under study for three decades. While studies and testing are ongoing, and vaccines remain a major research priority, there is no proven HIV vaccine available yet.



But in some patients, after years of the immune system's trying antibodies and having the virus evade them, there eventually arise "broadly neutralizing antibodies." These tend to have slightly larger variable regions, and can find and bind many versions of the virus. Scientists would like to create a vaccine that will trigger the creation of broadly neutralizing antibodies, but they haven't figured out how, says Siliciano.

Part of the problem, he adds, is that broadly neutralizing antibodies typically arise in people who have been untreated for years, as the virus and host evolve toward a détente. Scientists don't know how to mimic that lengthy evolutionary process in the lab, or in someone who's on antiretrovirals. Another issue is that broadly neutralizing antibodies might recognize not only HIV, but also normal human proteins or natural bacteria. The immune system tends to resist creating antibodies against its own body.

Another, related option would be to inject someone with the broadly neutralizing antibodies themselves. This would likely require less frequent dosing, and cause fewer side effects, than current HIV drugs.

Researchers are also working on possible gene therapies. These could work in a variety of ways. One option would be to snip the HIV genome out of infected T cells. Another would be to give a patient's cells the gene for a broadly neutralizing antibody. Or the therapy could alter a person's CCR5 gene to render cells immune.

Amber Dance is a freelance science writer in the Los Angeles area. This article was originally published on Knowable Magazine.

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