By Anthony Hickey, PhD
As a young child during the early 1980s, I was only vaguely aware of the AIDS (Acquired Immunodeficiency Syndrome) epidemic that was spreading throughout the world. While I knew that AIDS was a fatal and incurable disease, I was unaware of the relentless battle that scientific and medical professionals waged in our hospitals and laboratories.
As I got older and my studies shifted towards the sciences, I learned about the biological mechanisms employed by Human Immunodeficiency Virus (HIV), the pathogen that causes AIDS. By the time I began my doctoral training in 2005, much of the horror and uncertainty of the epidemic had faded. HIV infection no longer carried the death sentence once associated with it, becoming instead a chronic but treatable condition. This month’s NICHD Exchange meeting, entitled “HIV: From Epidemic to Elimination,” celebrated the significant victories achieved against HIV and served as a potent reminder that we have a long way to go before a cure is found.
Dr. Lynne Mofenson, the first presenter, began her talk with a brief history of the HIV epidemic. In particular, she highlighted NICHD’s involvement in managing and preventing perinatal and pediatric HIV infection.
In 1986, the federal government aimed to educate the public about HIV and institute measures for transmission prevention. By 1987, the treatment era for HIV had begun with the antiviral drug AZT (azidothymidine or zidovudine). Much of the focus during this time, however, was the treatment of HIV-infected adults and not children. To fill this void, the NICHD formed the Pediatric, Adolescent, and Maternal AIDS Branch (now MPIDB) in 1988, which conducted the first multisite clinical trial for HIV-infected children. Through the program’s efforts, the NICHD demonstrated the efficacy of intravenous immunoglobulin for the prevention and treatment of secondary bacterial infections in these young patients.1
In 1990, in order to expand pediatric treatment options to include antiretroviral drugs, the NICHD and the National Institute of Allergy and Infectious Diseases (NIAID) joined forces. Together, the institutes conducted important clinical trials, including the historic ACTG 076 trial, which demonstrated that AZT reduces maternal transmission of HIV by up to 67 percent. The trial was instrumental in obtaining FDA approval for the use of AZT by HIV-infected pregnant women.2
In 1995, NIAID and NICHD formed the Pediatric AIDS Clinical Trial Group (PACTG), a branch of the ACTG in which pediatric and maternal studies were given priority. With this came the expansion of maternal and pediatric studies to countries outside of the United States. In subsequent years, the combined efforts of NICHD and NIAID through the PACTG have been responsible for the identification and approval of multiple new treatments and/or combination treatment regimens for pediatric HIV infection, and have significantly reduced maternal transmission of HIV on a global level.
Despite this great progress, however, Dr. Mofenson reminded the audience that we are still very short of our goal to eradicate maternal HIV-transmission. In addition, the long-term effects of in utero exposure to HIV and/or anti retroviral drugs on growth and development are unknown. NICHD has therefore established the Pediatric HIV/AIDS Cohort Study (PHACS), an ongoing longitudinal study documenting the health and development of these children.
Given the successes of antiretroviral therapy (ART), how close are we to finding an actual cure for viral infection? The next speaker, Dr. Rohan Hazra, posed three specific questions:
- Why is it so hard to cure HIV?
- Have we cured anyone?
- Will we cure anyone?
To understand why HIV is so hard to cure, one must know a little about the pathogen’s infectious life cycle. HIV is a retrovirus that infects activated CD4+ T-cells (among other cell types) by integrating its genetic information directly into the host’s genome. Most of the cells, once they become infected, either die or actively begin to produce infectious virions. A very small percentage of these infected T-cells become long-lived memory cells, and rather than producing active virions, they allow the newly integrated viral DNA to remain dormant. This creates a latent viral reservoir.
ART is only effective against active viral replication and infection. Its withdrawal results in a relapse and an increase of viral titers due to the resurgence of actively replicating virus. Unfortunately, these latently infected cells are able to persist throughout the lifetime of an infected patient, which means that ART must be administered for life.3 The latent HIV reservoir, therefore, renders ART insufficient to cure HIV infection.
After explaining HIV biology, Dr. Hazra introduced the history of Timothy Brown (also known as the Berlin Patient), the only person to date who has been declared cured of HIV infection. This individual was an HIV-positive patient who received a complete blood stem cell transplant after whole body irradiation as treatment for leukemia. The transplanted cells expressed a mutated version of the CCR5 protein, a molecule on the cell’s surface that normally acts as a co-receptor for HIV entry. Such a mutation renders these cells “immune” to HIV infection. Upon discontinuing his use of ART over half a decade ago, Timothy Brown’s virus titer levels continue today to remain below or near detection limits.4 Therefore, the answer to the second question is yes, but…
…Despite the success of this procedure, Dr. Hazra explained that such treatment would not be accessible or practical on a population-wide scale. Dr. Hazra then posited a rhetorical question: Should we still strive for a cure even though HIV-infected individuals live relatively normal lives with ART treatment? He closed with a reminder that HIV infection affects more than the biology and physical well-being of the individual. It also impacts social life and subjects the individual to the stigma associated with chronic HIV infection. Dr. Hazra concluded that this was reason enough to persist with the battle against HIV.
The next presentation, given by Dr. Leonid Margolis, dealt with finding new HIV therapies from established drugs. Dr. Margolis began his talk by voicing his dissatisfaction with the use of monolayers and cloned cell lines as models for HIV infection. Instead, he prefers human tissue samples for study because tissues contain multiple cell types and more closely recapitulate the environment in which HIV infection progresses.
For example, the antiviral drug Acyclovir, developed over 30 years ago for use against herpes virus infection, had previously been shown to be ineffective against HIV in cloned tissue culture cells and monolayers. Yet, Acyclovir demonstrates antiviral activity against HIV in human tissue specimens. Why this disconnect? Herpes virus-specific enzymes convert Acyclovir into a form that is active against HIV replication. Cloned cell lines are usually free of herpes virus, but many human tissue samples are not.
The Margolis lab has shown that Acyclovir’s modified derivative suppresses HIV replication. But perhaps more importantly, it is effective against strains of HIV that have developed resistance to other antiretroviral agents. Thus it has the potential to be used in combination therapy regimens.5
The final speaker, Dr. Susan Newcomer, described her experience with a large epidemiological study in KwaZula-Natal, South Africa. The study examined HIV transmission and treatment on a population-wide level. She explained that such an epidemic cannot be thought of as a single unit, but instead as several smaller epidemics within a large area, each with its own unique characteristics based on the location and timing of the outbreak. Specific geographic targeting of an area is a more cost-effective means to study an outbreak. The challenge of using such an approach, however, is the social stigma associated with the area being under surveillance, and it is not uncommon for researchers to face resistance to their efforts.
Dealing with an epidemic such as HIV requires the participation of an entire community and not just the efforts of individuals. A significant challenge to epidemiological studies is compliance. Dr. Newcomer discussed that women are more likely to receive treatment for HIV infection than men, which can result in disproportionate counts during surveys. Another complicating factor in the prevention and treatment of HIV infection is the political and social fallout resulting from open discussion of HIV transmission routes. HIV is a sexually transmitted disease, and the subject of sex is often taboo in many communities, making it difficult to discuss the use of contraceptives and sexual partner choices. Dr. Newcomer implored NICHD to be at the forefront of both cellular and social developments against HIV transmission.
Obstacles throughout the last few decades have made HIV a difficult virus to work with, let alone cure, and not all of them have been biological. The latent reservoir has thus far been the biggest barrier to finding a complete cure or a means of remission. Social and economic barriers have been the biggest enemy on the prevention front. In spite of these barriers, tremendous progress has still been made against this pathogen. A disease that carried a death sentence has been transformed into a chronic, treatable condition for many individuals. That said, we cannot afford to become complacent with the success we have already had.
And so, NICHD will continue to champion MPIDB’s mission to support and conduct domestic and international research related to the epidemiology, diagnosis, clinical manifestations, pathogenesis, transmission, treatment, and prevention of HIV infection and its complications, both in the United States and globally.
References
- “Intravenous immune globulin for the prevention of bacterial infections in children with symptomatic human immunodeficiency virus infection.” (1991). The National Institute of Child Health and Human Developments Intravenous Immunoglobulin Study Group. N Engl J Med. 1991, 25(2):73-80.
- Connor, et al. (1994). “Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment.” Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 331: 1173-80.
- Barouch and Deeks. (2014). “Immunologic strategies for HIV-1 remission and eradication.” Science. 345: 169-74.
- Hütter et al. (2009). “Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation.” N Engl J Med. 360: 692-8.
- Vanpouille, et al. (2012). “Exploiting the anti-HIV-1 activity of acyclovir: suppression of primary and drug-resistant HIV isolates and potentiation of the activity by ribavirin.” Antimicrob Agents Chemother. 56: 2604-11.
