This article is the third 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 become more optimistic that a cure for HIV will be found, they are pursuing a number of different possible strategies, including highly experimental techniques like gene therapy and therapeutic vaccines.

At this point, no one knows for sure what the most successful avenue to a cure will be.

“It took 10 years to get good ART [antiretroviral therapy], and another five to get really great ART. Eradication is likely to be harder. But we might find new tools from unexpected areas,” said Dr. Steven Deeks, a professor of medicine at the University of San Francisco who participated Thursday in a LiveChat on HIV cures on the Science Magazine website.

“Most of the activity is now in the laboratory. There have been a few recent clinical successes, however, including the bone marrow transplant case (the so-called ‘Berlin Patient’). This clinical study has energized the field. There are several ongoing clinical studies,” he added.

In a recent review, Dr. Sharon Lewin, director of the Infectious Diseases Unit at Alfred Hospital in Australia, and Professor Christine Rouzioux from the Université Paris Descartes in France discussed the possibility of gene therapy and therapeutic vaccines for providing a cure for HIV.

Using Gene Therapy To Make Cells Resistant To HIV

One of the most exotic and experimental methods being tested to cure HIV is gene therapy. Gene therapy is an experimental approach that is currently in early stages of clinical testing. Gene therapy involves modifying the genetic information in a cell so that it becomes, for example, resistant to HIV infection (see related AIDS Beacon news).

In most cases, cells are taken from the patient’s body, genetically modified in the laboratory, and then injected back into the patient.

“There is intense interest in gene therapy,” said Dr. Deeks. “This interest is driven by the ‘Berlin Patient’ case as well as recent advances in gene therapy.”

The most advanced attempts at gene therapy so far are attempts to mimic the success of “The Berlin Patient,” a man who received a bone marrow transplant from a carefully selected donor with a mutated 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. Since his transplant, no sign of HIV has been detected in The Berlin Patient.

In one recent high-profile Phase 2 gene therapy clinical trial, HIV-positive people on antiretrovirals were injected with modified immune cells lacking the CCR5 protein. The therapy did not eliminate HIV in these patients, but it did successfully raise CD4 counts in patients whose immune systems had failed to recover after starting antiretroviral therapy (see related AIDS Beacon news).

This approach is the most successful seen so far.

Another approach under investigation is an RNA-based gene therapy. This strategy works slightly differently but is also aimed at reducing or eliminating CCR5, as well as slowing HIV replication. In a recent study, scientists used this approach in HIV-positive individuals undergoing a blood stem cell transplant to treat AIDS-related lymphoma.

Results showed that the treatment was well tolerated and that the gene therapy was successful, although results faded after four weeks. Nonetheless, the study offered a proof-of-concept that RNA gene therapy is possible.

Dr. Deeks noted that, while gene therapy has potential, it may not be particularly practical in the long run. “This approach is not likely to be widely available on a global basis. Although I am enthusiastic about the gene therapy approaches, I think we really need to focus on safe and easy-to-administer interventions that can be used in resource-poor and -rich environments,” he said.

Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), said during the LiveChat that more results on gene therapy trials can be expected. “Stay tuned. You will be hearing further news soon about the funding of these types of studies,” he said.

Therapeutic Vaccines

Another experimental approach to finding a cure for HIV is the development of therapeutic vaccines. Therapeutic HIV vaccines work by enhancing the body’s natural immune response, helping to control HIV in people already infected with the virus. This is in contrast to preventative vaccines, which are used in HIV-negative individuals to prevent infection.

Researchers hope that therapeutic vaccines could be used to reduce or eliminate the need for HIV treatment. To date, the use of therapeutic vaccinations in HIV patients on antiretroviral therapy has not been successful.

However, results from two recent studies in Simian Immunodeficiency Virus (SIV)-infected monkeys have been promising. SIV is a retrovirus similar to HIV that infects primates; studying SIV can provide insight into potential therapies for HIV in humans.

In one study, monkeys were treated with antiretrovirals, a vaccine containing live but inactivated SIV virus, and a drug targeting the immune system. In the second, the monkeys were given a vaccine with a genetically modified version of cytomegalovirus (CMV) that had been designed to stimulate the immune system against SIV.

Results showed that monkeys in both trials had significant control of viral replication after receiving the vaccines; in the CMV study, half the monkeys achieved undetectable SIV levels.

Dr. Fauci stated during the LiveChat that he was optimistic about the implications of the recent CMV monkey study for the chances of a therapeutic vaccine.

“The ability of this [CMV] vector vaccine approach to suppress existing virus infection in such an effective way could play a major role in a ‘functional cure’ by allowing discontinuation of antiretroviral therapy, by inducing a potent enough immune response to keep the viral reservoir suppressed, although not eliminated,” he said.

Dr. Fauci also said that therapeutic vaccines are one of the NIAID’s first goals toward an HIV cure.

“My goal for HIV cure research in the short term (2011) is to pursue the arena of therapeutic vaccine trials to suppress virus rebound in the face of discontinuing of therapy,” he said.

“In the longer run (2012 and beyond), we are looking at developing and testing new classes of drugs that can eliminate reservoirs. Modified stem cells research is also a priority,” he added.

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 1 (general types of HIV cures), Part 2 (targeting latent HIV), and Part 4 (obstacles to a cure) of this series.