Twenty-five years ago this fall, effective treatment for HIV became a reality. The first class of HIV drugs that was approved, the NRTIs, had worked to a degree, but even using two NRTIs together, they were quickly outsmarted by the ever-mutating virus. Then, in 1996, two new classes of HIV drugs were approved: the protease inhibitors (PIs) and the NNRTIs. Combining two NRTIs with either a PI or an NNRTI to arrive at the appropriate antiretroviral therapy (ART) regimen did the trick.
For people living with HIV (PLWH) who had health insurance or other access to care, these new regimens were not only lifesaving—they also restored immune systems battered by the virus, so that people on what was then called highly active antiretroviral therapy (HAART) soon had normally functioning immune systems that allowed them to live more or less normal, healthy lives.
But challenges remained, such as potentially serious safety issues and hard-to-tolerate side effects. In addition, too many pills that had to be taken too many times a day made these regimens hard to stick to and live with. Over time, things improved, and today, many PLWH have a life expectancy, and what you might call a “health expectancy,” nearly the same as people without HIV.
In addition to effective treatment, we can now also use HIV drugs as effective prevention—pre-exposure prophylaxis (PrEP). Moreover, a PLWH whose virus is suppressed by ART for at least six months cannot transmit (pass on) the virus through sex, a fact also known as undetectable equals untransmittable (U=U).
Why a Cure?
A cure for HIV, however, remains elusive. Even with effective treatment and prevention, a cure is an important goal. Of course, for PLWH, a cure would mean an end to the need for ongoing treatment. Today, long-acting drugs are the future of HIV treatment—but no treatment at all would of course be the ideal goal for the 38 million PLWH globally. In addition, a cure would bring us closer to the global eradication of HIV and AIDS, not only saving and improving countless lives, but easing the substantial burden that HIV places on health care systems at local, regional, and national levels as well.
For these and countless other reasons, government, academia, non-governmental organizations, and the private sector are engaged in intensive efforts to develop a safe, affordable, and scalable cure for HIV. Like treating HIV, curing HIV may require a combination of drugs or procedures that target the virus in different ways. Because of the clever and insidious ways HIV takes up residence and sets up shop in the human body, a cure for HIV may take one of two basic forms or may require both—and, researchers say, it is not expected for at least another decade. These two approaches are called (1) treatment-free remission and (2) viral eradication. We’ll take a look at each of these below.
Off Treatment and Still Undetectable
One approach to curing HIV is called treatment-free remission, or ART-free remission. This approach is also called a “functional” cure, because it would render HIV harmless without eliminating HIV from the body completely.
ART does a great job at eliminating HIV from the circulating blood of a PLWH, which is what keeps those on ART healthy and makes it impossible for those who are virally suppressed for at least six months to transmit HIV to their sexual partners (U=U). But even with viral suppression by ART, HIV remains hidden in a so-called HIV reservoir made up of immune system cells (primarily CD4 cells) that contain HIV in the form of HIV DNA (called proviral DNA). Such HIV is called “latent,” because it hides from detection by the immune system—and these cells are called “resting,” because they are not actively producing new copies of the virus.
When latently infected, resting immune cells are reactivated, they begin to churn out new copies of fully active HIV. This explains why PLWH need to remain on ART throughout their entire life—if ART stops, detectable virus comes back.
Finding ways to prevent the latent reservoir from becoming productive after stopping ART is thus a major focus of research into a cure for HIV today. This kind of sustained ART-free remission, sometimes called a functional cure, would allow a PLWH to keep latent virus suppressed without daily medication. Researchers are investigating a number of different strategies for achieving ART-free remission of HIV.
Most approaches to achieving sustained ART-free remission involve altering the immune system to induce long-term control of HIV. Researchers attempt to manipulate the immune system by targeting HIV and HIV-infected cells or changing the behavior of immune cells to better address the infection.
One promising intervention for achieving ART-free remission is broadly neutralizing antibodies, or bNAbs. These powerful proteins can block nearly all HIV strains from infecting human cells in the laboratory and facilitate the killing of cells that have already been infected. While bNAbs develop naturally in some people with HIV, they usually do so either in amounts too small to provide a significant benefit or too late after infection to control the quickly replicating and mutating virus.
Studies are now underway in animals and people who have been taking ART to see if periodic infusions or injections of bNAbs can keep HIV suppressed after ART is stopped. Scientists are developing bNAbs with improved attributes, including greater potency and longer duration in the body, and are testing treatment with combinations of two or three bNAbs.
Eliminating the Virus Completely
The other main approach to curing HIV is called viral eradication, which means ridding the body completely of the virus, including the proviral DNA in latently infected cells. This is also called a “sterilizing” cure, because it eliminates the infection, as well as a “classic” cure, that is, a cure in the truest sense of the word. The strategies being explored in this category have fanciful names like “shock and kill” and “block and lock,” among others.
Reversing latency, trashing the reservoir. In the shock-and-kill scenario, scientists are exploring strategies that use drugs to “goose” the latently infected cells of the HIV reservoir to express HIV proteins on their outer surface. Once those resting cells start producing viral proteins, they can be spotted by an enhanced immune system—or by drugs—that destroy the infected cell. Currently, several latency-reversing drugs are being evaluated in the laboratory and in human clinical trials.
Fortifying immune cells against HIV. Left untreated, HIV destroys the immune system of most PLWH, leading over time to opportunistic infections, HIV-related cancers, and death. A small fraction of PLWH, however, maintain viral suppression even without ART. Somehow, their immune systems are protected naturally from the virus and its ravages.
In a related phenomenon, some people appear to have had significant exposure to HIV, but did not become infected—that is, their immune system protects them from HIV infection. If researchers could reproduce this level of resistance to HIV infection in the vast majority of PLWH who do not have it innately, it might be possible to thwart the virus and achieve a cure.
Stem cell transplantation. Beginning in the late 1990s, studies showed that people with stronger natural protection against HIV often had mutations in the gene that codes for a protein called CCR5 (this protein appears on the surface of human immune cells, and it is one of the proteins that HIV uses to enter and infect cells). When CCR5 does not function properly or is absent altogether, HIV can no longer infect immune cells. If researchers can block CCR5 function or eliminate expression of CCR5 altogether, they may be able to provide better control of HIV infection, or even eliminate HIV completely.
Some researchers suspected that if a PLWH were to receive a bone marrow transplant from a donor with the CCR5 mutation, the new bone marrow might reconstitute an HIV-resistant immune system in the transplant recipient. Bone marrow transplantation is a complex and risky process, so this theory could be tested only on PLWH who needed a bone marrow transplant to treat a life-threatening cancer.
While this approach has been tried many times, it has so far succeeded only twice. One of the two successful cases was known as “the Berlin patient” for many years before the transplant recipient revealed that he was an American named Timothy Ray Brown. Brown, a PLWH, had been diagnosed with acute myeloid leukemia, a cancer affecting white blood cells, while living in Germany. In 2007, Brown nearly died from the transplant—in the end, however, the bone marrow transplant not only cured his leukemia, but also eliminated HIV from his body.
Adam Castillejo, also known as “London Patient,” was the second person known to have been cured of HIV infection via a bone marrow transplant from a donor who had the CCR5 mutation. Castillejo suffered from Hodgkin lymphoma, a cancer affecting the lymph system. His bone marrow transplant took place in 2016. Brown, born in 1966, died in 2020 after a recurrence of his cancer. Castillejo, born in Venezuela in 1980, continues to thrive.
Gene therapy. While these cases of bone marrow transplantation provide “proof of concept” that HIV can be cured, a bone marrow transplant is a highly risky, intensive, and expensive procedure performed only to treat life-threatening conditions in the absence of other treatment options. It is not a realistic way to cure HIV in the millions of PLWH around the world, and to date, it has only been successful in curing HIV infection in Brown and Castillejo. It may, however, be possible to exploit the role of the CCR5 mutation to cure HIV using a type of gene therapy called gene editing.
In gene editing, DNA is inserted, deleted, modified, or replaced in the genome—the complete set of genetic information—of a living organism. In the case of an HIV cure, clinicians would remove immune cells from a PLWH, use gene editing to reprogram the CCR5 gene, and then put the cells back into the individual, a process called transfusion. Unlike bone marrow transplantation, gene editing does not require a donor with the CCR5 mutation, and the person undergoing the procedure does not risk life-threatening rejection of donor tissue. Some preliminary research has been done to date to assess the potential of gene editing as a strategy for both HIV treatment and a cure.
In addition, some experts have proposed using gene-editing technology to target proviral DNA, essentially cutting the proviral DNA out of latently infected cells. When HIV infects a cell, the virus inserts its own genome into the cell’s DNA. Recently developed biotechnology makes it possible to locate and remove these genes from latent cells using DNA-slicing enzymes. Animal studies have shown that gene-editing can cut proviral DNA from infected cells.
The challenge for bringing gene editing into clinical practice is figuring out how to deliver gene-editing enzymes to all the cells that make up the HIV reservoir without incurring any safety risks to the person receiving treatment—and so, much more research is needed.
As for when we might see one or several of these innovations benefit PLWH, according to researchers, there are many hurdles still to clear. “It’s always perilous to make predictions,” said Richard Jefferys, the director of the Cure Project at Treatment Action Group, a community-based research and policy think tank in New York focused on ending the epidemics of HIV, tuberculosis, and hepatitis C virus.
“But you could perhaps envision an intervention (or combination) that would facilitate HIV suppression after ART is stopped, with home viral load testing to allow people to monitor for viral load rebound. The challenge is that, as yet, no intervention has achieved prolonged post-ART viral-load control in a significant number of recipients.”