The AIDS Beacon » Immunity

Advances and Barriers To A Cure For HIV: Part 1 – Types Of HIV Cures

April Clayton — Thu, 12 May 2011 22:29:45 +0000

This article is the first in a four-part series that will investigate current research toward finding a cure for HIV, including advances, promising treatment strategies, and barriers to reaching a cure. Part 1 discusses general types of HIV cures. Part 2 discusses specific strategies for targeting latent HIV. Part 3 discusses gene therapy and therapeutic vaccines. Part 4 discusses barriers to obtaining a cure.

As researchers learn more about the workings of HIV and how it persists in the body even with antiretroviral therapy, scientists are increasingly optimistic that a cure for HIV can and will be found. However, most research is still in fairly early stages of development, and there are a number of barriers – including the safety of many currently proposed techniques – that must be overcome.

“We currently have no treatments that will eradicate HIV. However, over the next few years I anticipate that there will be an increasing number of clinical trials that will be designed to determine if these [new] strategies will have any impact on residual HIV in patients on combination antiretroviral therapy,” said Dr. Sharon Lewin, director of the Infectious Diseases Unit at Alfred Hospital in Australia and lead author of a recent review on research into potential cures for HIV.

“It is essential that these trials are safe and are designed to answer the question of whether [each] particular approach will ever be feasible,” she added.

During a LiveChat on the Science Magazine website today, several physicians gathered to answer questions from the public on the possibility of an HIV cure.

Dr. David Margolis, a professor of medicine at the University of North Carolina School of Medicine, stated during the LiveChat that a cure was still a ways off but that he thought the research community was making good progress.

“I will go out on a limb and say that in 10 years there will be functional cures (no disease [even] without therapy) in some people, but it will take longer than that to get to broadly applicable eradication therapy,” he said.

Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, was also cautiously optimistic. “Significant progress will be development of strategies to keep people off of ART [antiretroviral therapy] for longer and longer periods of time. This may be possible within three to five years,” he said.

Sterilizing Versus Functional Cures For HIV

While antiretroviral therapy has greatly improved the health and quality of life of people with HIV, it cannot cure HIV. As a result, patients must take antiretrovirals for life. While newer anti-HIV drugs have fewer side effects than older ones, lifetime use can still take its toll, with some of the drugs linked to long-term complications such as increased risk of heart disease (see related AIDS Beacon news).

In addition, it can be difficult to strictly adhere to the medications for so long, even though non-adherence can mean HIV rebound, drug resistance, and disease progression.

Instead, researchers are increasingly turning to the question of how HIV can be cured, or at least put into long-term or permanent remission without antiretrovirals. There are two strategies currently being investigated to cure HIV: sterilizing cures and functional cures.

The sterilizing cure method aims to eliminate all HIV-infected cells, completely purging HIV from the body. A functional cure aims for a remission state and long-term control of HIV, including low viral loads in the absence of antiretroviral therapy.

In her review, Dr. Lewin defined a sterilizing cure as one that reduces viral loads to less than 1 copy per milliliter of blood. A functional cure is one that reduces viral loads to less than 50 copies per milliliter of blood, either permanently or for an extended period of time.

The only current example of a sterilizing cure is from a case study of a man with HIV who had acute myeloid leukemia, a form of cancer that starts in the bone marrow.

This patient, nicknamed “The Berlin Patient,” received a bone marrow transplant – a medical procedure that replaces cancerous bone marrow with healthy donated bone marrow cells – from a donor with a mutated or alternate form of the CCR5 gene.

HIV requires the CCR5 protein, which is on the surface of white blood cells, in order to attach to and infect the cell. People naturally born with an alternate form of the CCR5 gene are almost entirely immune to HIV.

After the patient’s transplant he discontinued antiretroviral therapy. To date, after 45 months without treatment, doctors have been unable to detect HIV in his system.

Although The Berlin Patient proved that a sterilizing cure is possible, researchers have said his treatment is not feasible for most people with HIV.

“A strategy of using bone marrow transplantation with a CCR5 mutant donor is not a realistic cure for HIV given the toxicity and complexity of the treatment,” wrote Dr. Lewin and her coauthor in their review. Additionally, it is still not clear why and how HIV was eliminated in this patient, although scientists continue to study him.

Rather than trying to completely eliminate HIV from the body, some researchers instead have pursued a functional cure.

One natural example of a functional cure can be found in elite controllers. Elite controllers are individuals infected with HIV whose immune systems are able to naturally control the virus without antiretroviral drugs. These individuals successfully maintain stable CD4 (white blood) cell counts and low or undetectable viral loads.

Elite controllers also have a significantly smaller amount of latent HIV in their cells – HIV that lies dormant and, in most people with HIV, will reactivate if antiretroviral therapy is stopped. Latent HIV is a major barrier to curing HIV.

Previous studies have shown that elite controllers have strong HIV-specific immune responses, and some elite controllers have variations in a particular gene, called HLA-B, that offers protection against HIV infection (see related AIDS Beacon news).

Researchers are highly interested in further understanding how elite controllers manage HIV and avoid disease progression, since this could help with identification of new methods to treat people with HIV or development of an HIV vaccine.

Current strategies for curing HIV encompass both treatment with drugs and use of more sophisticated and experimental techniques, such as gene therapy. To date, most of these efforts are still fairly preliminary. However, a few have made their way into clinical trials and have shown some promising results. These efforts will be discussed in greater detail in Parts 2 and 3 of this series.

For more information, please see the review in the journal AIDS (abstract) or the Science LiveChat website. For more information about the potential for an HIV cure, please see Part 2 (targeting latent HIV), Part 3 (gene therapy and therapeutic vaccines), and Part 4 (obstacles to a cure) of this series.

Early HIV Treatment May Help Prevent Irreversible Immune System Damage

Kieryn Graham — Fri, 15 Oct 2010 19:32:22 +0000

Results of a new study suggest that people with HIV who begin antiretroviral therapy soon after infection may better retain the ability to fight off other infectious diseases than people who begin treatment later.

“Our work…suggest[s] that more clinical trials should be aimed at comparing early-treated and chronic-treated patients by a variety of different immunologic parameters,” said Dr. Susan Moir, lead author of the study, in correspondence with The AIDS Beacon.

The findings shed light on a group of immune cells called B cells and how early initiation of antiretroviral therapy (ART) may help prevent irreversible damage to the immune system.

B cells are a type of immune cell. They make antibodies, proteins that help the immune system identify and fight infectious pathogens like bacteria and viruses.

Memory B cells are a special type of B cell that are formed after infection with a pathogen. Their role is to remember how to make antibodies to that particular kind of virus or bacteria.

Memory B cells are the reason a person who catches an illness, like the chicken pox, becomes immune to it thereafter. Vaccines work by prompting memory B cells to make antibodies to the virus or bacteria from the vaccine, creating immunity.

In contrast, “exhausted” B cells are nonfunctional and cannot produce antibodies.

In this study, scientists measured the amount and type of B cells in blood samples taken from three groups of men. The first (“early treatment group”) contained men who had been HIV positive for six months or less and had not yet started ART. The second group (“late treatment group”) had been HIV positive for a while, in some cases several years, but had also not yet started ART. The third group contained men who were HIV negative.

At the start of the study, all the men who had HIV started taking antiretroviral therapy.

Results showed that at the start of the study, both groups of HIV-positive men had fewer B cells in their blood than the HIV-negative men. Once the two groups of HIV-positive men began ART, the number of B cells in their blood began to rise in a similar manner.

However, the types of B cells in the two HIV-positive groups differed significantly throughout the study.

Men who started antiretroviral therapy early were able to achieve numbers of memory B cells similar to those in HIV-negative men; men who started treatment late, however, continued to have low levels of memory B cells. Furthermore, men who started treatment late had greater numbers of immature B cells, while men who started ART early were able to reduce their levels of undeveloped B cells to those of HIV-negative men.

The late-treatment group also had significantly more exhausted B cells than the other two groups of participants, even after one year of ART.

To investigate how these differences in the types of B cells present affected the immune system, researchers also examined how the two groups of HIV-positive men responded to an influenza vaccine at the start of the study and one year after beginning ART.

Results showed that one year after starting antiretroviral therapy, men who had started treatment early had a greater number of B cells that successfully made anti-influenza antibodies compared to the late-treatment group.

This suggests that starting antiretroviral therapy early in the course of HIV infection allows patients to better fight off other infections than if they start ART later.

Dr. Moir said follow-up studies are planned but noted that it is difficult to find eligible participants. Most people who have had HIV for a while stay current on their vaccines, while those who have just been diagnosed usually receive the vaccines when they start ART.

“[This] means we cannot measure the before and after effects of ART on vaccination response,” said Dr. Moir.

“We are nonetheless continuing to investigate these questions and trying to find simpler schemes. We also continue to measure responses to HIV itself, which also differed between the two groups,” she added.

The idea of starting ART early is a controversial one, due to possible long-term side effects of antiretroviral drugs. A different clinical trial testing the effects of starting HAART when a person’s CD4 (white blood cell) count drops below 500 cells per microliter – earlier than the current recommendation of 350 cells per microliter – is currently underway.

The study, named Strategic Timing of Antiretroviral Treatment (START), is a joint effort by the University of Minnesota, the National Institutes of Health, various European HIV institutes, and several pharmaceutical companies.

The study is currently recruiting participants.

For more information, please see the study in the journal Blood (abstract). For more details on the START study, please see the clinical description at the United States Clinical Trials registry.

Presence Of Gene Mutation May Provide HIV Immunity And Resistance

Elisabeth Pernicone — Wed, 28 Oct 2009 01:02:12 +0000

Around 40,000 new HIV infections occur each year in the United States. However, a specific gene mutation present in about 10 percent of Caucasians may make them resistant to infection by HIV-1, with about one percent having almost full immunity.

Researchers have found resistance and high levels of immunity only against the HIV-1 strain. HIV-1 is the most prevalent type of HIV infection in the Western world. The HIV-2 strain was discovered in 1986 and mostly infects people in West Africa.

The mutation is in the gene for receptor CCR5, a protein on the surface of immune cells which the HIV virus binds to. In this mutation, there is a deletion of the 32nd base pair. This means that this gene consists of multiple base pairs and in some people the 32nd base pair is not present.

CD4 cells, which are white blood cells that help protect the body from foreign pathogens, contain the CCR5 receptor and are the main cells that are targeted during HIV infection. However, this mutation eliminates CCR5 expression on the surface of the cell, preventing HIV from binding to it.

This mutation appears to offer almost full immunity to those who inherit two copies of the gene mutation, one from each parent. Those who possess two copies are known as homozygous for the mutation. This accounts for about one percent of Caucasians.

Those who only inherit the mutation from one parent appear to have a higher resistance to infection and may even have slower disease progression in the case of infection. Those who possess one copy are known as heterozygous for the mutation. This occurs in about 10 percent of Caucasians.

This mutation is found in two to five percent of Middle Easterners and those of Indian decent. However, it has not been found in any African or Asian populations.

Several theories have been discussed as to why those of European descent seem to possess this mutation over other heritages.

One possible explanation is that this mutation occurred around the time of the Black Death in Europe. According to the Public Broadcasting Service, the areas hit hardest by the Black Plague match those where the gene for HIV resistance is the most common today.

Individuals who inherited the mutation from both parents still need to use caution to prevent HIV infection. The presence of a homozygous CCR5 mutation does not guarantee 100 percent immunity.

According to a study published in 2002 in The Lancet, there have been rare cases where HIV infection has occurred in those homozygous for the mutation.

Therefore, safe-sex practices still must be used when an HIV-negative individual is engaging in sexual activity or other high-risk activities with an individual who has the homozygous CCR5 mutation.

A 2001 study published in the Journal of Acquired Immune Deficiency Syndrome analyzed the prevalence and rate of infection for those homozygous and heterozygous in the CCR5 mutation.

Researchers observed that men who were heterozygous for the mutation had a 70 percent reduced risk of infection compared to those without the mutation.

A February 2009 study published in the New England Journal of Medicine analyzed the effects of transplanting the homozygous CCR5 mutation into a 40-year-old man. After receiving a stem-cell transplant from a CCR5 homozygous mutation donor, a procedure done to treat his leukemia, the man was able to discontinue HAART medication. HAART is typically composed of three or four antiretroviral drugs in combination.

Twenty months after discontinuation, his viral load, which is the amount of HIV in the blood, was still undetectable.

This phenomenon is not a new discovery, but new research on this topic is always occurring. In 1995, a researcher at the Institute of Human Virology at the University of Maryland School of Medicine, discovered that chemokines, or proteins secreted by cells in the immune system, blocked HIV-1 in a test tube experiment.

The CCR5 mutation’s effects have been studied in relation to other illnesses such as smallpox and multiple sclerosis.

However, studies have also been conducted potentially linking the presence of this mutation to an increased risk for the acquisition of West Nile Virus and Hepatitis C.

Testing for this mutation appears to be mostly research based. It is performed at only select laboratories. Ask your physician for more information on gene testing.

For more information on the study analyzing CCR5 implantation, visit the New England Journal of Medicine.