Progress So Far
With over 30 HIV antiretrovirals and 11 prevention strategies, we have been able to think aspirationally about getting to a world without HIV/AIDS. Achieving that goal is realistic, but still requires a lot of research. Anthony Fauci, M.D., director of U.S. National Institute of Allergy and Infectious Diseases (NIAID), discussed the critical challenges that remain, including our mixed progress toward a cure or vaccine, while speaking at the 20th International AIDS Conference (AIDS 2014) in Melbourne, Australia.
According to the 2014 UNAIDS Gap Report, we now have 35 million people living with HIV, with 2.1 million new HIV infections in 2013 (down 38% since 2001) and 1.5 million AIDS deaths in 2013 (down 35% since 2005). While incidence and mortality numbers have lowered significantly, they could be lowered completely with the discovery of an HIV cure.
A cure is defined as the "permanent remission of disease following cessation of treatment," according to Fauci. With infectious diseases, this has traditionally meant the eradication of the microbe; however, with certain diseases, such as cancers, it means the absence of relapse for life or a defined period of time. Regardless, in order to prove an HIV cure, we need to be able to identify biomarkers of the HIV reservoir, which is notoriously difficult to locate or measure.
Moreover, with HIV, we simply do not know how long the virus needs to be in remission after stopping antiretroviral therapy (ART) before we can confidently consider an HIV-positive person to be "cured."
The Role of the HIV Reservoir
To help us better understand the HIV reservoir, Fauci broke it down into two buckets: qualitative and quantitative aspects. Qualitatively, the reservoir can be categorized by "body compartment type," "cell type" and "status of virus."
- "Body compartment type" includes gut-associated lymphoid tissue, peripheral lymphoid tissue, brain and other tissue types.
- "Cell type" includes central memory CD4+ T cells, effector memory CD4+ T cells, transitional memory CD4+ T cells, naive CD4+ T cells, monocytes/macrophages and follicular dendritic cells with trapped virus.
- The "status of virus" can either be "defective" or "replication competent," the latter of which is actually a very small percentage.
Quantitatively, the amount of time between initial infection and beginning ART determines the baseline size of the HIV reservoir. In fact, the reservoir can form earlier than HIV viremia can even be detected. All of these factors confound how we look at the HIV reservoir, according to Fauci.
In addition, the reservoir is very persistent, in that even after years of treatment and viral suppression, the reservoir remains. It usually only takes a couple of weeks after discontinuation of ART for the virus to rebound.
Addressing the HIV Reservoir: Eradication
To deal with the reservoir, there are two possible ways that many researchers have been pursuing: eradicating the reservoir or controlling viral rebound with sustained virologic remission.
Eradication strategies include:
- Flushing the virus out by activating the latently infected cells, also known as "shock and kill." So far, researchers have been able to "shock," but not "kill."
- Directing immunotoxic therapy at the reservoir, which gets rid of some cells, but not all.
- Stem-cell transplants with CD4 cells that have a key CCR5 mutation -- the deletion of a specific gene -- which so far has only worked in one patient, Timothy Brown. Stem-cell transplants involving CD4 cells without the CCR5 mutation, as seen in the Boston patients, seemed successful initially, but months after stopping treatment the virus rebounded.
- Gene therapy, using zinc finger nucleases (ZFNs) to modify the CCR5 receptor. This has shown some promise, but research is still in early stages.
Beyond the Mississippi Child
Treating HIV as early as possible still seems to be one of the keys to eradication, as seen with the "Mississippi Child." Even though it was disappointing that the child's virus rebounded, the fact that the child appeared to remain virus-free for so long is still a promising development.
The case has also raised some critical questions, including: What mechanism kept the virus from rebounding for 27 months without treatment? What triggered the rebound? From what cell type and body compartment type did the virus rebound?
To try to answer these questions and others, IMPAACT Study P1115 will attempt to ethically recreate the "Mississippi Child" scenario, by identifying and treating HIV-positive infants within 48 hours after birth. According to Fauci, sustained virologic remission in babies could be translated to the same outcome in adults, as long as they share potential commonalities -- e.g., early initiation of ART, favorable quantitative and qualitative aspects of the HIV reservoir, and relative preservation of immune function.
Addressing the HIV Reservoir: Control
Controlling viral rebound, or having sustained virologic remission, without treatment could also be a viable "cure." The VISCONTI study, in which 14 patients were started on treatment during acute infection and subsequently showed no significant viral rebound after discontinuing treatment, gives us some interesting insight. Because they have very low levels of virus after a long period of stopping treatment (four to almost 10 years, depending on the person), they can be considered "post-treatment controllers." However, according to Fauci, another study that treated patients during acute infection showed that the level of viral control achieved after stopping antiretroviral therapy was limited.
Post-treatment control may be sustained by natural HIV-specific immunity, which appears to have been the case in the VISCONTI study. However, a number of studies are beginning to look into other ways to sustain post-treatment control, including the passive transfer of HIV-specific antibodies and therapeutic vaccination.
The Vaccine Challenge
Classic vaccines look to mimic natural responses to infection. However, a successful HIV vaccine needs to improve on these natural responses. HIV is very different because the body's natural response to infection is quite poor, especially considering:
- Without ART, damage caused by the virus almost invariably progresses.
- The body produces autologous neutralizing antibodies, but only after several months; sadly, they do not adequately control the virus.
- Broadly neutralizing antibodies may effectively control the virus, but these antibodies take at least two years to appear -- and they do so in only 20% of patients.
- HIV is never completely cleared after established infection.
- There's no protective immunity against superinfection.
Vaccine studies have been done since 1987, but none showed any efficacy until 2009, when a trial known as RV144 showed a modest 31% HIV risk reduction in participants taking a prime-boost vaccine containing ALVAC and AIDSVAX. This result reignited hope in the vaccine research field.
Currently, much of the field is focused on broadly neutralizing antibodies, which can target a number of vulnerable sites on the HIV envelope. But before we even think about an effective vaccine, a crucial question needs to be answered: Can these broadly neutralizing antibodies actually be used to prevent and treat infection?
According to Fauci, the answer is yes -- at least based on mouse and non-human primate models. Studies are underway or being planned to see if we can induce these broadly neutralizing antibodies in humans.
One of the strategies being explored is known as B cell lineage vaccine design. The idea is to go back to the classic vaccine paradigm, which mimics the body's natural response to infection. Because HIV mutates, it pushes the B cell lineage response to create broadly neutralizing antibodies -- but, as stated earlier, this can take at least two years, which is obviously too late to stop an initial infection.
Therefore, if we can somehow mimic HIV and use "iterative immunogens" for sequential immunizations -- not the same immunogen with boosts -- and if we can find a way to quickly induce broadly neutralizing antibodies, then we may have a successful vaccine. This approach is being actively pursued by researchers.
A World Without AIDS
"Even if we can induce sustained remission in a reasonable proportion of people, that would greatly enhance the treatment armamentarium. If we add a vaccine to our combination prevention -- with both of these, we may wind up with not only a possibility of a world without AIDS, but a durable world without AIDS," Fauci stated.
"My own children -- I have three daughters: 27, 25 and 22 -- they have never seen a world without AIDS. So perhaps if we attain these critical advances in science, they'll be able to tell their children about a world that once had AIDS that no longer does," he concluded.