By Vincent C. Marconi, M.D., and Mirko Paiardini, Ph.D.
For the first time in almost three decades of AIDS research, the international scientific community has undertaken a large-scale, concerted effort to discover a cure for HIV.
Several anecdotal reports and small clinical studies have provided some optimistic insights into the feasibility of HIV eradication. In 2009, the dramatic case study of Timothy Brown (the Berlin patient) ushered in an era of cure fervor(1). Brown was diagnosed with HIV in 1995, started antiretroviral therapy (ART) and did well for 11 years. Then in 2006, he was diagnosed with acute myelogenous leukemia (AML) and subsequently was treated with chemotherapy complicated by pneumonia and sepsis. His doctors then decided to try a different approach.
His doctors knew that a stem cell transplant might cure his AML. Using this opportunity, they chose a unique donor whose cells lacked the critical co-receptor (CCR5) necessary for the entry of HIV into cells. Their hope was to rebuild his immune system in such a way as to make his body resistant to HIV infection.
Shortly after receiving his â€œHIV-resistantâ€ stem cell transplant, Mr. Brown stopped taking ART and has never looked back. Now almost seven years later, he remains free of HIV despite careful examination of samples of his blood, brain, liver, lymph nodes, cerebrospinal fluid, intestinal tract and bone marrow.
Since that time, two other patients with HIV in Boston have undergone stem cell transplants for lymphoma. They were found this year to be â€œHIV-freeâ€ after stopping ART, despite having donors who did express CCR5. Only time will tell if these two patients remain aviremic indefinitely like Timothy Brown.
Although stem cell transplants appear to be effective in achieving a cure, the associated patient risks and financial cost have not made transplants the most attractive option. But they have demonstrated that HIV eradication is possible.
Obstacles to Eradication
In 2003, Dr. J.D. Siliciano and colleagues from Johns Hopkins Hospital published a study that many believed could have ended all hope for a cure(2). They showed that with current highly potent ART, it would take more than 70 years before all HIV-infected cells would completely disappear from the body. This observation was based on modeling the average decay rate of resting CD4 cells and other long-lived cells harboring HIV in a latent state. In the latent state, the HIV virus is integrated into the host genome as a provirus and is not transcriptionally active. These cells have an intrinsically long half-life, and because the provirus is not producing active virus, this HIV â€œreservoirâ€ remains protected from ART and immunologic clearance.
Even more daunting, Dr. Nicolas Chomont et al. posited in 2009 that some cells could maintain this HIV reservoir indefinitely through homeostatic proliferation. In other words, infected cells could create copies of themselves, including both the host and HIV genome(3).
Such an immortalized state could make eradication of this population of cells even more challenging. Because of this, scientists spearheading the cure agenda have been divided on whether the goal should be to eradicate every last HIV-infected cell from patients or not. This goal, known as a â€œsterilizingâ€ cure, may appear to be the ideal approach; however, it has been shown that only a small percentage of infected cells harbor a provirus that is even capable of productive infection.
Unfortunately, current methods to identify these cells are cumbersome and suboptimal. Therefore, a growing number of researchers are aiming for a less ambitious target of achieving a â€œfunctionalâ€ cure. A functional cure is analogous to conventional objectives for cancer chemotherapeutics. In this scenario, an individual would receive treatment that would reduce the reservoir to such an extent that ART could be stopped and the remaining HIV would be kept suppressed by the individualâ€™s immune system. Although this seems a somewhat radical approach, there are several examples where immunologic control of HIV occurs naturally or has happened after stopping ART.
Examples of HIV Control
In the absence of ART, the host anti-viral immune responses are incapable of controlling the virus, leading to a chronic infection that persists throughout life in most humans living with HIV. In contrast, a rare subset of individuals (<1 percent) infected with HIV, known as Elite Controllers (EC), can maintain undetectable viral loads for many years without ART.(4) These individuals are living proof that the human immune system is able to fully control HIV.
Further research has revealed that there are a variety of factors that contribute to the ability of ECs to maintain an undetectable viral load. These factors include the host immune response, host genetic factors(5) and viral factors. Understanding the main mechanisms allowing EC to control HIV replication without ART will, undoubtedly, represent an important step in HIV research. However, this knowledge will significantly impact HIV treatment and cure only if we can design therapeutic strategies and/ or vaccines that induce these mechanisms of control in the general population living with HIV.
Two recent studies generated excitement and optimism in the field regarding the possibility of achieving a â€œfunctionalâ€ cure without very complex, risky and expensive procedures such as stem cell transplants. Both looked at individuals treated early after initial infection with HIV.
The first, a case study of a Mississippi baby(6), garnered tremendous media attention. An infant was treated with ART starting at 30 hours after birth owing to a high-risk exposureâ€”the mother had a detectable viral load prior to delivery. Treatment was continued through 18 months of age because repeated testing by RNA and DNA met criteria for HIV infection, but treatment was then discontinued. At 30 months of age, the child has remained virologically undetectable in plasma samples and peripheral blood mononuclear cells. Furthermore, HIV antibody testing has reverted to negative.
In the second study, Dr. Asier SÃ¡ez-CiriÃ³n and colleagues in the VISCONTI cohort showed that approximately 15 percent of individuals with HIV that initiated ART close to initial infection showed long-term control of viremia for several years after ART-interruption (median of 89 months)(7). Interestingly, these individuals, known as post-treatment controllers (PTCs), do not have the strong HIV-specific immune responses nor the favorable genetic factors (protective HLA B alleles) characteristics of EC. Remarkably, not only did PTCs show a lower viral reservoir on therapy, but they were also able to maintain or even reduce their meager viral reservoir while off ART.
Examination of the reservoir in these individuals showed that the types of cells infected with HIV in the reservoir differed when compared to those that did not control HIV. In fact, relatively few long-lived central memory T cells were infected compared to the short-lived effector memory T cells. These findings are consistent with those generated in sooty mangabeys, an African monkey species that do not progress to AIDS despite many years of infection with Simian Immunodeficiency Virus,(8) suggesting that strategies aimed at functional cure will need to not only reduce the size but also affect the â€œqualityâ€ of the HIV reservoir.
Current Cure Strategies
At present, several strategies are being explored to achieve a cure of HIV. One approach involves inducing latently infected cells to produce the virus again with the goal of purging the viral reservoir. This would lead to expression of viral proteins on the cell surface, allowing the host immune system to target these cells for clearance. It could also initiate a cell-signaling cascade leading to programmed cell death in these cells.
Several existing FDA-approved drugs and other novel compounds are currently being investigated, including histone deacetylase inhibitors (HDACi) and disulfiram. Although an initial study by Dr. David Margolis et al. demonstrated conversion of latent to productive infection in the presence of a single dose of the HDACi vorinostat, there did not appear to be a significant change in the overall size of the reservoir(9). This implied that despite reversing the latency step, there did not appear to be an increase in the death of these cells, at least over the period of observation in this study.
Another approach has been under consideration since the mid-1980s. Researchers have explored methods to enhance an HIV-infected individualâ€™s immune response to their own HIV, employing what have been called therapeutic vaccines. A form of â€œpassive immunityâ€ is also being considered. As one example, antibodies engineered to target HIV-infected cells and deliver a cytotoxin are currently under investigation.
Chronic HIV infection leads to chronic immune activation, as the immune system is continually fighting a pathogen. This leads to many of the comorbid conditions seen in those with HIV disease (for example, early heart disease) and plays a major role in CD4 cell loss.
In contrast to enhancing the immune system, some scientists have considered various methods to reduce this ongoing inflammatory state. By tempering this inflammation, expression of viral proteins and CCR5 are decreased, resulting in less effective HIV replication. In addition, less immune activation will have an effect of reducing bystander apoptosis of HIV-uninfected CD4 cells, potentially preserving critical immune function. Studies with a variety of biologic agents have been performed and are ongoing to pursue this possibility.
Gene therapy has shown some promise for the cure agenda as well. One particular strategy has been to render host cells resistant to HIV infection using zinc-finger nucleases(10). These proteins essentially disrupt expression of CCR5. In a sense, this recreates the conditions experienced by Timothy Brown after his stem cell transplantation.
A very practical approach to a cure has been to â€œoptimizeâ€ ART. By diagnosing and treating individuals soon after infection, the goal is to replicate the experiences of the VISCONTI cohort. This, coupled with better antiretroviral drugs with greater penetration into body sites and greater activity against resting CD4 cells and macrophages, may lead to a functional cure.
Ultimately, if anything has been constant throughout the past three decades of research and clinical care, it is that effective strategies are those that work in combination. It has become apparent that using multiple approaches will likely be required to achieve even a functional cure.
Currently, the concept of â€œkick and killâ€ is one such combination approach, wherein the latent reservoir is purged with medications like HDACi and subsequently targeted for cell death using therapeutic vaccines or immunotherapy. This could be coupled with improved ART and biological agents aimed at reducing chronic inflammation.
Although the promise of a cure and HIV eradication has been encouraging of late, this enthusiasm has been offset by many of the practical issues surrounding the pandemic at large. The costs associated with both discovery and implementation strategies must be balanced by the urgent need to get existing individuals living with HIV diagnosed, linked and retained on existing ART. For now, it is unclear precisely how or when this effort will be successful, but it is clear that it will succeed.
Vincent C. Marconi, MD is the Associate Medical Director of the Grady Health Systemâ€™s Infectious Disease Program and has a joint appointment in the Emory School of Public Health. He received his medical degree from Johns Hopkins University School of Medicine and completed his training in Internal Medicine and Infectious Diseases at Harvard Medical School. In 2005, Dr. Marconi maintains an ongoing collaboration that began in 2004 with colleagues at McCord Hospital in Durban, South Africa.
Mirko Paiardini, Ph.D. is an Assistant Professor in the Division of Microbiology and Immunology at Yerkes National Primate Research Center, and in the Department of Pathology and Laboratory Medicine of the Emory University School of Medicine. He completed his undergraduate and graduate work at the University of Urbino, Italy. Before joining Emory University in 2010, Dr. Paiardini was a research associate in the laboratory of Dr. Guido Silvestri at the University of Pennsylvania School of Medicine.
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