In the United States, HIV/AIDS has largely been rendered a chronic health condition by the development of highly active anti-retroviral therapy (HAART), a combination of anti-HIV medications with a thoroughly proven track record. However, HIV/AIDS is still a condition that weighs heavily on the minds of at-risk populations in the United States, and it remains a scourge in less developed countries, where it is still a leading cause of death. Notably, last year, President Obama directed an additional $100 million be spent researching a cure for HIV/AIDS. However, a cure has been very difficult to obtain, even considered a quixotic quest by many infectious disease researchers who see vaccination and management of HIV/AIDS as a chronic condition as more viable public health options for addressing the AIDS crisis.
Recently, as reported in The New York Times, doctors proclaimed a child cured of HIV after initiating aggressive treatment with antiretroviral drugs within a day of birth. However, discovery of actively replicating HIV in this child three years after the unusually aggressive treatment tempered the optimism of the original report. While extreme approaches such as the therapy attempted with this child have yet to be fully tested, and novel public health approaches such as pre-exposure prophylaxis with the drug Truvada are in the early stages of adoption, a true cure for HIV remains elusive.
The problems inherent to curing HIV are legion; the virus integrates its genetic information into host cells and forms hidden pockets of infection that drugs and other therapies have difficulty reaching, called reservoirs. These reservoirs are infected by the virus but do not actively replicate it under normal conditions, effectively hiding the infected cells from immune surveillance and targeted therapies. Even if antiretroviral drugs are able to eliminate all of the actively replicating virus at a given time, the viral reservoirs can reactivate, effectively reinfecting the otherwise "cured" individual. Despite 30 years of research on HIV replication, scientists still have a poor understanding of where viral reservoirs are located and how to go about eliminating them. Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases and a prominant AIDS researcher, has gone on record calling HIV reactivation from viral reservoirs "a very mysterious situation."
Fortunately, despite the complications presented by viral reservoirs, a number of new strategies for curing and preventing HIV infection are on the horizon. One of these strategies, known as vectored immunoprophylaxis, is particularly promising. It sounds like something straight out of a science fiction movie — use a second virus to introduce genes into an individual that reprogram cells to fight off the immunodeficiency virus. Notwithstanding the far-fetched elevator pitch, this therapeutic approach has gained a lot of traction in recent years, and many high-profile researchers actively pursue it in their laboratories.
David Baltimore, a Nobel laureate and one of the co-discoverers of the viral reverse transcriptase enzyme that makes HIV the difficult-to-cure virus it is, has published numerous articles detailing his laboratory’s approach to vectored HIV immunoprophylaxis.
At its core, the Baltimore lab’s strategy centers on using a virus called adeno-associated virus (AAV) to introduce HIV-fighting genes to muscle cells. The genes delivered by the AAV vector encode proteins that bind and neutralize HIV particles before they can infect cells, called anti-HIV antibodies. Once a muscle cell is infected by the AAV, it becomes an anti-HIV antibody factory, secreting large amounts of the protective antibody into the bloodstream. In high concentrations, secreted over a long time, these antibodies can prevent infection with HIV as well as reactivation of HIV replication from viral reservoirs in an infected individual, removing the necessity for daily dosing with anti-retroviral drugs.
The vectored immunoprophylaxis approach overcomes one of the most challenging aspects of HIV treatment and prevention, namely that it is extremely rare for an individual to naturally produce antibodies that are broadly protective against HIV, and it is even more challenging to induce such antibody production through immunization. By directly introducing genes that hard code the protective antibodies, it is not necessary to instruct the immune system in how to make these antibodies. Rather than teach the body a complicated recipe, the body is instead supplied with a lifetime supply of the finished product.
Based on the promise of the vectored immunoprophylaxis approach, development of the technology has been rapid. The first real tests of anti-HIV vectored immunotherapy have already been performed in rodent models of infection. These initial studies showed the approach to be highly effective in mice that were engineered to have human-like immune systems and thus become susceptible to HIV infection. Indeed, when these humanized mice were infected intravenously or vaginally with diverse strains of HIV, those that received anti-HIV vectored immunotherapy were thoroughly protected from HIV infection.
Despite the promise of vectored immunoprophylaxis for HIV, many technical issues remain before the technology can be widely adopted in human patients. In the early mouse model studies described above, some mice developed low levels of HIV replication isolated to the mucosal lining of the genitals, suggesting that protection may not be complete.
As well, the AAV vectors used in these studies present a number of challenges for use in human patients. For one, some patients have antibodies to AAV that they acquired through natural infection with viruses related to the AAV strains used for vectored immunoprophylaxis. This issue can be mitigated if not eliminated by using rare AAV strains as vectors, however.
A second problem is that some patients may be sensitive to the high levels of circulating anti-HIV antibody created by the vectored immunoprophylaxis approach, effectively developing an allergy to it. Without an engineered “off switch” built in to the AAV that delivers the anti-HIV antibody gene, patients face being poisoned with antibody production that persists for upwards of 10 years. Current approaches to prevent this potentially disastrous condition from occurring involve encoding a suicide switch along with the anti-HIV antibodies in the AAV vector, thereby allowing AAV to be inactivated by infecting sensitive patients with a second virus that flips this suicide switch.
Taken together, early results with vectored immunoprophylaxis suggest that this approach may be a useful weapon in the fight against the HIV/AIDS epidemic. While challenges remain, it is not unreasonable to expect results from clinical trials with human subjects to be published in the near future. Along with HAART, drug-based pre-exposure prophylaxis, and classical immunization approaches, vectored immunoprophylaxis demonstrates a lot of promise as a means of eliminating HIV/AIDS from the human population.
