27 Sep 2011 - Potent combination therapy for HIV, commonly called ART or HAART, can greatly reduce production of HIV, raise CD4+ cell counts and result in improved health. However, small amounts of HIV continue to be produced despite excellent medication-taking habits (a behaviour called adherence) by HIV-positive people. This persistence of HIV means that no amount of ART can cure chronic infection with this virus. Therefore, HIV-positive people will have to take ART for the rest of their lives.
It is not clear if adherence to complex ART regimens can be maintained for the many decades of a person's life. Moreover, HIV infection appears to cause changes to the immune system that persist despite the use of ART. Such changes to the immune system, involving an increase in chemical signals that favour unnecessary inflammation, may increase the risk of complications arising from prolonged HIV infection and affect many organ-systems (such as the bones, brain, heart, lungs and so on) as people age.
The ideal way to resolve this problem of lifelong pill taking and accumulating damage from excess inflammation would be to cure HIV infection. Research teams in high-income countries are exploring different approaches to this issue, including potential genetic therapy for HIV. Before delving into this approach, we first present some background information.
Know your co-receptors
HIV needs to use different receptors in order to get inside and infect a cell. These receptors are found on the surface of a cell. The first receptor that HIV needs is called CD4. After attaching itself to CD4+ cell, HIV then needs one of the following two co-receptors to gain entry:
HIV that prefers to use the CCR5 co-receptor is called R5 tropic and HIV that prefers to use CXCR4 is called X4 tropic. Some types of HIV use both co-receptors; these are called dual or mixed tropic (D/M).
Researchers in Berlin, Germany, have successfully carried out stem-cell transplants in an HIV-positive man who had cancer. The donor from whom the cells were harvested had what researchers call the delta-32 mutation. People with this rare mutation do not express CCR5 receptors on their cells. This mutation renders them only partly resistant to HIV infection-they can still be infected by X4 strains of the virus. Because the Berlin patient now appears to be cured of HIV, researchers in other parts of the world think that interfering with cells' ability to express CCR5 might duplicate the success of the Berlin patient in other HIV-positive people.
One approach to gene therapy
The Sangamo Biosciences Corporation has developed a genetic therapy (called SB-728-T) that suppresses the formation of CCR5 receptors on CD4+ cells. For this therapy, CD4+ cells are first extracted from an HIV-positive person. The cells are taken to a laboratory where they are infected with a harmless modified virus that carries genetic material and instructs cells to stop producing CCR5 receptors. The specific virus used in these experiments is called an adenovirus and generally does not cause harm to humans. In the lab, the infected cells are stimulated to make copies of themselves. These copies are then infused into the HIV-positive person.
Sangamo has funded a clinical trial to test the safety and preliminary effectiveness of this therapy in San Francisco. In a study with nine HIV-positive male volunteers, different participants received the following doses of modified cells:
- 3 people - 1 billion cells
- 3 people - 2 billion cells
- 3 people - 3 billion cells
The average profile of participants when they entered the clinical trial was as follows:
- age - mid-50s
- CD4+ count - 384 cells
- viral load - less than 48 copies/ml
- length of time HIV positive - 21 years
At the recent 51 st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held in Chicago from September 17 to 20, 2011, researchers released updated results from their ongoing experiments with gene therapy in nine HIV-positive people. Safety studies are very important for genetic therapies, as there is the potential that such therapies may inadvertently trigger the development of tumours. Cancers have occurred in previous experiments with gene therapy in HIV-negative people.
In the Sangamo-sponsored study, participants have been monitored for about a year (ranging between 115 and 561 days). None of the participants has died and no life-threatening complications have emerged. However, all participants experienced mild side effects within the first 24 hours after infusion of the modified CD4+ cells, including:
Five participants developed side effects of moderate intensity such as:
- back pain
One participant developed severe back pain.
All participants exuded a garlic-scented body odour. This was probably related to a preservative used in the infusion. Fortunately, all side effects resolved within 48 hours after the infusion.
Results-Changes to CD4+ and CD8+ cells
After an infusion, CD4+ cell counts increased rapidly, with most participants having a count that was 200 cells higher than their pre-study value.
Over the course of a year after the infusion, CD4+ cell counts gradually declined to their pre-infusion levels.
CD8+ cell counts initially fell but then rose, and a year after the infusion participants had, on average, 100 more CD8+ cells than they did at the start of the study.
These changes in CD4+ and CD8+ cells are interesting but they occurred in the blood. Much of the body's burden of HIV and most of its CD4+ cells are not in the blood; they are distributed in lymph nodes and tissues throughout the body. Many lymph nodes and tissues are scattered around the intestinal tract. So to assess changes there, researchers removed a tiny sample of mucosal tissue from the rectum of participants at different times in the study. Analysis of these samples found CD4+ cells that had been modified (that is, missing their CCR5 receptors) as a result of gene therapy.
Lab tests with CD4+ cells arising from gene therapy suggest that these cells can produce copies of themselves and release appropriate chemical signals when faced with a germ (in simulated tests).
Taken together, that some of the modified CD4+ cells migrate to the mucosa and seem to perform adequately in lab experiments, suggest that the modified cells are functional and behave as unmodified CD4+ cells should. This finding is reassuring, as researchers were not sure how modified CD4+ cells would perform in people.
Not a cure
All participants were taking ART prior to and, with one exception, after the infusion of gene therapy. One participant, nearly a year after receiving gene therapy, decided to interrupt ART for 28 weeks. As is common with treatment interruption, his CD4+ count fell and his viral load rose. Specifically, his CD4+ count fell from a pre-treatment-interruption level of about 500 cells to roughly 300 cells within the first six weeks of interrupting ART. Simultaneously, his viral load rose from less than 50 copies/ml prior to interrupting ART to well over 100,000 copies/ml six weeks after the interruption.
By the 28 th week of the treatment interruption, his CD4+ count rose to just over 400 cells and his viral load was about 25,000 copies/ml.
Such trends in CD4+ cell counts and viral load have been observed in patients who interrupted ART and who were not in this study. So it is not clear at present what role gene therapy played, if any, in the changes in viral load and CD4+ cells seen during this one participant's treatment interruption. But what is clear is that this participant's CD4+ cells are still susceptible to HIV despite a single infusion of gene therapy and that his infection was not cured. This is likely the case with the remaining participants.
Early days yet
It is not realistic to expect that a single infusion of gene therapy-an approach that is highly experimental-can cure HIV infection in people at this point in time. It may take multiple infusions of the same gene therapy over a period of years or infusions of a more effective formulation of gene therapy before outcomes such as a cure can be considered. Indeed, an infusion of Sangamo's gene therapy product only protects a portion of a person's CD4+ cells from HIV. Sangamo's team has not yet released data about the tropism of HIV in the man who interrupted ART. That is, does his HIV prefer to use CCR5, CXCR4 or both co-receptors? Such an analysis of his HIV's tropism is important when making preliminary evaluations about this therapy. But bear in mind that the present study was primarily designed to assess the safety of Sangamo's product and therefore cannot provide definitive evidence about its effectiveness. However, the study will provide important data that Sangamo can use to help plan future experiments. Also, its promising results may encourage other researchers and companies to enter the field of genetic therapy for HIV.
The American drug regulatory agency, the Food and Drug Administration, requires that volunteers in experiments with genetic therapies be monitored for up to 15 years after receiving such therapy. This is cumbersome and expensive but necessary because gene therapy is still experimental medicine.
Several other trials using different formulations of gene therapy in HIV-positive people are underway or planned in the United States.
-Sean R. Hosein
- Deeks SG. How to escape treatment. Nature. 2011 Aug 31;477(7362):36-7.
- Boasso A, Royle CM, Doumazos S, et al. Over-activation of plasmacytoid dendritic cell inhibits anti-viral T-cell responses: a model for HIV immunopathogenesis. Blood . 2011 Sep 19. [Epub ahead of print].
- Bosinger SE, Sodora DL, Silvestri G. Generalized immune activation and innate immune responses in simian immunodeficiency virus infection. Current Opinion in HIV and AIDS. 2011 Sep;6(5):411-8.
- Sauce D, Larsen M, Fastenackels S, et al. HIV disease progression despite suppression of viral replication is associated with exhaustion of lymphopoiesis. Blood . 2011 May 12;117(19):5142-51.
- Hunt PW, Landay AL, Sinclair E, et al. A low T regulatory cell response may contribute to both viral control and generalized immune activation in HIV controllers. PLoS One . 2011 Jan 31;6(1):e15924.
- Deeks SG. HIV infection, inflammation, immunosenescence, and aging. Annual Review of Medicine. 2011 Feb 18;62:141-55.
- Hatano H, Delwart EL, Norris PJ, et al. Evidence of persistent low-level viremia in long-term HAART-suppressed, HIV-infected individuals. AIDS . 2010 Oct 23;24(16):2535-9.
- Sigal A, Kim JT, Balazs AB, et al. Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy. Nature . 2011 Aug 17;477(7362):95-8.
- Mitsuyasu R, Lalezari J, Deeks S, et al. Adoptive transfer of zinc finger nuclease CCR5 modified autologous CD4 T-cells (SB-728-T) to aviremic HIV-infected subjects with suboptimal CD4 counts (200 to 500 cells/mm 3 ). In: Program and abstracts of the 51 st Interscience Conference on Antimicrobial Agents and Chemotherapy , 17-20 September 2011, Chicago, Ill. Abstract HI-375.
CATIE-News is written by Sean Hosein, with the collaboration of other members of the Canadian AIDS Treatment Information Exchange, in Toronto.
From Canadian AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information Network at http://www.catie.ca
Source: CATIE: CANADIAN AIDS TREATMENT INFORMATION EXCHANGE