Figure 1: HIV-1 particles assembling at the surface of an infected macrophage. Since first being detected in 1981, AIDS has claimed the lives of approximately 34 million people.
The human immunodeficiency virus (HIV) infection and its more advanced counterpart, acquired immunodeficiency syndrome (AIDS), affect approximately 34 million people worldwide, with the number of infected patients growing by over two million every year (1). Since first being detected in 1981, AIDS has claimed the lives of almost 30 million people around the world (1). Scientists have searched for a cure for years without success, but the treatment of Timothy Brown, also known as the “Berlin Patient,” may change that forever.
Overview
HIV harms its hosts by targeting immune cells, which leaves infected individuals prone to opportunistic infections. HIV initially attaches to proteins called CD4 receptors. These receptors, found on the surface of white blood cells, aid in the recognition of foreign substances (2). The main targets are T-helper cells, which fight infection by activating other immune cells (2). HIV must also interact with a chemokine receptor on the cell that binds to cell-signaling molecules (2). Once the virus binds to the target cell, it enters and releases its genetic contents into the cytoplasm (2).
HIV is a retrovirus, meaning that its genetic information is stored in the form of single-stranded RNA. Before the virus can overtake the cell, an enzyme called reverse transcriptase must convert this RNA to double-stranded DNA. This viral DNA integrates itself into the DNA of the cell, creating infected DNA called a provirus. The provirus subsequently replicates to create more HIV viruses using the host’s own biological machinery (2). The exact mechanism that the virus uses to kill immune cells is unknown, but its effects have been identified.
Depending on the person and the severity of infection, the time between infection and the initial manifestation of symptoms, ranging from rashes to fatigue, varies from months to years (3). An individual is diagnosed with AIDS when he or she is HIV positive, has a CD4+ T cell count below 200 cells/mm3, and/or has an AIDS-related infection, which can take years to develop (3). These AIDS-related infections include several types of cancer and a range of parasitic, viral, fungal, and bacterial infections such as tuberculosis and meningitis. These infections, not HIV, are the direct cause of death in most patients (3).
History of Treatment
Early treatment of HIV/AIDS in the 1980s used antiretroviral drugs that blocked the enzyme necessary to convert RNA to DNA (4). In the early stages of treatment, doctors used one drug at a time to block HIV. However, after years of this method, they realized that the virus could quickly develop resistance, rendering a one-drug approach ineffective (4).
With the development of different types of antiretroviral drugs targeting different enzymes in the HIV life cycle, doctors now use highly active antiretroviral therapy (HAART), a “cocktail” of HIV drugs (4). By using this method, when the virus develops a resistance to one drug, two or three other drugs may still suppress the virus by blocking different stages in viral development. This treatment has only been able to slow the progression from HIV to AIDS, but new stem cell treatments may give hope to HIV/AIDS patients around the world.
The Berlin Patient
Timothy Brown had been infected with HIV for almost eleven years when he was diagnosed with acute myeloid leukemia. This cancer affects both bone marrow–a tissue that helps form blood cells–and white blood cells (5). To treat both his acute myeloid leukemia and HIV at the same time, doctors had to come up with a new treatment protocol beyond HAART and chemotherapy to keep Brown alive.
Dr. Gero Hutter, an oncologist from Berlin, decided to give Brown a stem cell transplant with peripheral blood stem cells from a matched donor (5). These stem cells can differentiate into healthy CD4+ T cells and replace formerly infected, cancerous cells (6).
This donor’s cells differed from Brown’s in that they were homozygous for a 32 base pair deletion in the part of DNA that codes for chemokine receptor 5 (CCR5) (5). This receptor is one of the aforementioned co-receptors that HIV uses to infect host cells. This 32 base pair deletion prevents the production of a normal, active CCR5 receptor (5). Without this receptor, HIV cannot enter and infect host cells, and the virus cannot replicate (5).
Before the first transplant, Brown underwent an intense round of chemotherapy and total body irradiation to kill diseased white blood cells. Following the transplant, both chemotherapy and HAART were halted until Brown had a relapse of acute myeloid leukemia (6). He then underwent another round of chemotherapy and a second transplant, which then left him free of cancer and with an undetectable load of HIV (6).
After the transplants, healthy donor-derived CD4+ T-cells reconstituted Brown’s immune system (6). Further testing showed that T-cells throughout his body had the same rare mutation found in the donor that prevented the HIV virus from infecting cells. This meant that CD4+ T-cells derived from Brown’s body could not be found in the immune system (6). Replacement of host cells with donor cells also reduced the amount of HIV virus in Brown’s body, thus further reducing the chance that Brown’s new cells could be infected (6).
Controversy
Doctors had not expected Brown’s HIV to become completely undetectable (5). Instead, they believed the virus would attempt to infect T-cells during immune reconstitution via a different co-receptor called CXCR4 (6). However, there is still a possibility that HIV may lie latent somewhere in Brown’s body.
Due to the significance of Brown’s case, researchers around the world are interested in studying him. Recently, a team at the University of California, San Francisco found traces of viral nucleic acid in blood cells and tissue samples that did not match the virus found in Brown at the outset of infection (7). However, researchers at the University of California, San Diego conducted similar tests and found no traces of HIV in Brown’s system (7).
Nonetheless, the traces of viral nucleic acid have caused many to question whether Brown has really been cured, but researchers at both institutions assert that these segments of viral DNA are either contaminants or are not actively replicating (7). Either way, Timothy Brown no longer has actively replicating HIV in his system, and most experts deem him cured.
Figure 2: Scanning electron micrograph of HIV-1 budding (in green) from cultured lymphocyte. AIDS-related infections include several types of cancer and a range of parasitic, viral, fungal and bacterial infections such as tuberculosis and meningitis. Image courtesy of C. Goldsmith (CDC).
Further Treatments and Future Directions
While Brown is the first patient to be cured of HIV, he may not be the only one. Two men in Boston, both of who suffered from HIV infection and lymphoma, a type of blood cancer, are also HIV-free following stem cell transplants. Unlike Brown, these patients received bone marrow transplants from donors who were not homozygous for the 32 base pair deletion (8). Instead, doctors simply kept these patients on HAART while they underwent stem cell transplantation (8).
Donor cells helped rid the patients’ bodies of infected cells by replacing them while the HAART protected the donor cells from infection (8). Both patients saw reduced levels of HIV the first few months after transplantation, and over three years later, HIV was undetectable in both patients (8). However, both patients are still on HAART, so researchers are hesitant to call this method a “cure” (8).
Other researchers are trying to find treatments to rid the body of HIV without costly and dangerous stem cell transplants and surgeries. Researchers at the University of North Carolina at Chapel Hill recently discovered that vorinostat, a drug normally used to treat certain lymphomas, could awaken hidden HIV viruses in affected patients (9). Vorinostat inhibits histone deacetylase, an enzyme that condenses and silences DNA, thus enabling HIV to hide in cells. In this case, inhibition of the enzyme enables the production of the HIV virus and allows for the identification of infected cells that may serve as viral reservoirs (9). With the proper treatment, methods such as this could potentially lead to elimination of the virus from the body.
In France, scientists have tried to recreate elite controllers, patients who are HIV positive but whose bodies are able to prevent the virus from replicating and destroying their immune systems. Researchers identified and treated individuals with HAART for three years within ten weeks of infection (10). After years without treatment, these patients still have detectable levels of HIV, but, like the bodies of elite controllers, their bodies can control the virus (10). Charline Bacchus, the leader of this study, explained that HIV lies mainly in short-lived T cells in these patients and believes that this difference helps the infection from spreading (10).
Additional areas of exploration include gene therapy to alter patients’ DNA, the creation of more targeted drug treatments, and other ways to bring the virus out of its latent stage and identify it. The two viable paths to a cure identified by scientists are total elimination of the virus from the host–a sterilizing cure–and the strengthening of the immune system, which enables it to fight off HIV–also known as a functional cure.
Conclusion
While researchers have made great strides in the fight against HIV/AIDS, there is still much work to be done. Other options discussed throughout this article are still in early stages of development and may only work in a small percentage of patients. The most successful treatment to date, stem cell transplants, are highly expensive and have a high mortality rate, ranging from 20 to 35 percent depending on the facility and condition of the patient (11). Furthermore, early treatment of HIV may only strengthen the immune system in five to 15 percent of patients (10).
There is still much to learn about HIV and the way it affects cells before an appropriate cure accessible to all infected patients can be found.
Contact Stephanie Alden at stephanie.l.alden.16@dartmouth.edu
References
1. WHO, UNICEF, UNAIDS, Global HIV/AIDS Response 2011 (WHO Press, Geneva, Switzerland, 2011).
2. The HIV Life Cycle (May 2005). Available at aidsinfo.nih.gov/contentfiles/HIVLifeCycle_FS_en.pdf (23 December 2012).
3. AIDS (2012). Available at http://www.nlm.nih.gov/medlineplus/ency/article/000594.htm (26 December 2012).
4. M. Shernoff, R. A. Smith, HIV Treatments: A History of Scientific Advance (July 2001). Available at http://www.thebody.com/content/art30909.html (27 December 2012).
5. G. Hutter et al., Long-term control of HIV by CCR5 delta32/delta 32 stem-cell transplantation. N. Eng. J. Med. 360, 692-698 (2009).
6. K. Allers et al., Evidence for the cure of HIV infection by CCR5 delta 32/delta 32 stem cell transplantation. Blood 117, 2791-2799 (2011).
7. J. Cohen, Evidence that man cured of HIV harbors viral remnants triggers confusion (2012). Available at http://news.sciencemag.org/scienceinsider/2012/06/evidence-that-man-cured-of-hiv.html (24 December 2012).
8. International AIDS Society, New HIV cure research released at the XIX International AIDS Conference (26 July 2012). Available at http://www.aids2012.org/Default.aspx?pageId=384 (27 December 2012).
9. N. M. Archin et al., Administration of vorinostat disrupts HIV-1 latency in patient on antiretroviral therapy. Nature 487, 482-485 (2012).
10. C. Bacchus, paper presented at 19th International AIDS Conference, Washington, D.C., 22-27 July 2012.
11. Bone marrow transplantation (2012). Available at http://www.surgeryencyclopedia.com/A-Ce/Bone-Marrow-Transplantation.html (1/2/13)