Over the course of the HIV epidemic's 30-year history, advances in treatment and prevention have saved many lives. HIV is now a manageable chronic disease, though to be clear, there are still many difficulties that come with it. While treatment successes are in large part thanks to antiretroviral therapy, one of the world's leading HIV researchers argues that there are other areas and questions we need to address.
"Certain myths or misconceptions about this infectious disease have been emphasized and other potentially beneficial concepts have received less attention. A true long-term solution to HIV infection merits an appreciation of alternative ideas and findings that could be beneficial in the ultimate control of HIV/AIDS," Jay A. Levy, M.D., writes in a paper recently published in the journal Trends in Molecular Medicine.
Here are the six key questions Levy urges HIV researchers to keep in mind when investigating and designing new trials.
Is HIV Infection a Universally Fatal Diagnosis?
For a small percentage of people living with HIV, known as long-term nonprogressors (LTNP) or elite controllers (EC), the virus is controlled without any treatment. These individuals are able to keep very low viral loads for at least 10 years and even over 35 years. "We can learn a great deal about prevention of disease and infection by studying these exceptional people who have survived without AIDS or have warded off infection," Levy argues.
Is the Body's Innate Immune Response as Important as the Adaptive Immune Response?
The innate immune response is the body's first line of defense against foreign invaders such as HIV. If HIV is able to get past the innate immune response, then the adaptive immune response kicks in. For some people, despite repeated exposures to HIV, they remain HIV negative. Therefore, to discover new ways of prevention, Levy points out the importance of studying the innate immune system and harnessing this early response against HIV.
How Do CD8+ T Cells Combat HIV?
While the entire immune system is complex and important in fighting HIV, one in particular, the CD8+ T cell, has been of long-time interest to HIV researchers. However, how it responds to HIV is still not fully understood and Levy calls for more research into understanding this cell.
The CD8+ T cell is mainly thought to control HIV by killing off infected cells. But Levy points out an alternative way that this cell controls HIV, which is by secreting factors that suppress the virus without killing the infected cell. This in turn allows the infected cell to continue functioning, but without HIV replication or cell death. More research into this response could lend itself to the development of an HIV vaccine, Levy explains.
When Should Antiretroviral Therapy Be Given?
Certainly, this is one of the most debated questions in HIV. Despite all the attention given to when treatment should start, we still don't have a clear consensus, as evidenced by all the differences in treatment guidelines around the world. The concerns include: long-term side effects, toxicities, adherence, drug resistance, financial burden, mental and emotional stress, and all the issues that we've lumped under the term "inflammation."
While antiretroviral therapy has helped increase the life expectancy of people living with HIV to close to that of the general population, "Prescribing [antiretroviral therapy] for a lifetime is like giving chemotherapy forever," Levy writes. "Future studies may very well indicate that toxicities will eventually result in many treated individuals."
Many guidelines suggest starting treatment immediately, but Levy cautions that more attention needs to be paid to drug toxicities and potential drug-resistant viruses.
What Strategies Should Be Considered for an HIV Vaccine?
Much of the focus in HIV vaccine research has been on antibodies, particularly broadly neutralizing antibodies (bNAbs) that can neutralize HIV. However, these antibodies are rare and develop over time, often after HIV has already infected cells. The current challenge is getting these bNAbs to develop before HIV exposure (one strategy is priming the immune system with engineered viral vectors that look like HIV on the outside, but are harmless).
Looking for broadly neutralizing antibodies is helpful, but Levy notes the relative low success of these trials, and calls for more investment into other strategies that enhance more parts of the immune system, such as the innate immune response. Levy also emphasizes studying individuals who are highly exposed to HIV, but remain HIV negative, for clues.
What Approaches Should Be Encouraged for an HIV Cure?
The first person cured (and still cured) of HIV, Timothy Brown, received a stem cell transplant from a donor who had a natural resistance to HIV because of a rare genetic mutation. Brown was able to inherit this genetic resistance himself and became immune to HIV. Because of Brown's case, there has been a lot of interest in recreating this type of cure easily and safely (because stem cell transplants are still very dangerous procedures).
Instead of dangerous transplantations, Levy points to gene therapy research, which attempts to edit a person's genetic material, as a strategy that's worth more investigation. If we can somehow edit a person's genes to mimic the response seen by Timothy Brown, or at least make it so that a person can persistently control HIV without treatment, then perhaps that's the key to a functional cure, Levy argues.