In this issue of TreatmentUpdate, we have mentioned some of the proposed and existing experiments to awaken HIV inside resting CD4+ T cells in ART users so that the proportion of HIV-infected cells in the body can be reduced. However, once HIV is activated in such cells, the fate of the cell is unknown. For instance, an HIV-infected cell that has been stimulated from rest into activity could do the following:
- produce many copies of HIV and then die
- because it has started to produce HIV, the immune system can recognize that it has been infected and killer T cells (CD8+ cells) can attack and destroy it
- it can briefly produce a small number of copies of HIV and then go back into a state of rest, evading the immune system and harbouring the capacity to produce HIV in the future
The latter result is concerning because laboratory experiments with latently infected cells and the HDAC inhibitor vorinostat have uncovered a weakness of the immune systems of many HIV-positive ART users: Their immune systems appear unable to mount or sustain an effective response against HIV.
Most vaccines are licensed to prevent infections -- including measles, mumps and polio -- that were once generally widespread in high-income countries. However, researchers have become intrigued with the potential for therapeutic vaccines for HIV-positive people. Such vaccines would be used to stimulate the immune system, particularly CD8+ cells, to help them better recognize and attack HIV-infected cells. Stimulating the immune system with a therapeutic vaccine is likely to become necessary before volunteers are exposed to some of the drugs mentioned earlier in this issue of TreatmentUpdate that can bring HIV out of hiding.
In the 1980s, when doctors were struck by the sudden outbreak of AIDS-related infections in young, previously healthy adults, they assessed the immune systems of their patients. Tests revealed a severe degree of immunologic impairment. Later, immunologists would uncover a strange finding: Cells of the immune systems of people with HIV would behave as if they were exhausted. Such cells expressed proteins or markers on their surface suggesting that they would shortly self-destruct, a process called programmed cell death, or apoptosis. A large proportion of the immune system's cells, particularly T cells, even if they are not infected with HIV are very susceptible to apoptosis. This has been confirmed in laboratory experiments with fresh cells and HIV and the closely related virus, SIV (simian immunodeficiency virus). Together, these finding suggest that viruses such as HIV and SIV have evolved to subvert the immune system without having to infect every one of its cells. These viruses can do this by causing the immune system to display proteins or markers on their surface that researchers call death receptors.
Although ART significantly reduces HIV's ability to infect new cells and allows the immune system to partially repair itself, such repairs are incomplete. Analyses of cells of the immune system from SIV-infected monkeys and HIV-positive humans taking ART suggest that within the lymph nodes and lymph tissues, cells of the immune system still display death receptors, albeit at a reduced level compared to SIV-infected monkeys and HIV-positive humans who are not taking ART.
Rejuvenating the immune system by reversing the impact of death receptors on cells may be one avenue for researchers to pursue. In experiments with monkeys infected with SIV and in separate preliminary studies in HIV-negative people with cancer, researchers have used specialized antibodies to attempt to disable death receptors on cells of the immune system. This has enhanced the ability of such cells to attack germs and tumours. If such therapies become licensed for the treatment of cancer as some are expected to be within the next year, researchers will be able to have access to them for testing in HIV-positive people. By reversing the impact of death receptors, researchers may be able to help the immune system better recognize HIV-infected cells and destroy them.
- Meyaard L, Otto SA, Jonker RR, et al. Programmed death of T cells in HIV-1 infection. Science. 1992 Jul 10;257(5067):217-9.
- Herbeuval JP, Nilsson J, Boasso A, et al. Differential expression of IFN-alpha and TRAIL/DR5 in lymphoid tissue of progressor versus nonprogressor HIV-1-infected patients. Proceedings of the National Academy of Sciences USA. 2006 May 2;103(18):7000-5.
- Herbeuval JP, Grivel JC, Boasso A, et al. CD4+ T-cell death induced by infectious and noninfectious HIV-1: role of type 1 interferon-dependent, TRAIL/DR5-mediated apoptosis. Blood_._ 2005 Nov 15;106(10):3524-31.
- Herbeuval JP, Nilsson J, Boasso A, et al. HAART reduces death ligand but not death receptors in lymphoid tissue of HIV-infected patients and simian immunodeficiency virus-infected macaques. AIDS_._ 2009 Jan 2;23(1):35-40.
- Barblu L, Herbeuval JP. Three-dimensional microscopy characterization of death receptor 5 expression by over-activated human primary CD4+ T cells and apoptosis. PLoS One. 2012;7(3):e32874.
- Rosignoli G, Cranage A, Burton C, et al. Expression of PD-L1, a marker of disease status, is not reduced by HAART in aviraemic patients. AIDS_._ 2007 Jun 19;21(10):1379-81.
- Trautmann L, Janbazian L, Chomont N, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nature Medicine. 2006 Oct;12(10):1198-202.
- Yan J, Sabbaj S, Bansal A, et al. HIV specific CD8+ T cells from elite controllers are primed for survival. Journal of Virology. 2013; in press.
- Nasi M, Riva A, Borghi V, et al. Novel genetic association of TNF-α-238 and PDCD1-7209 polymorphisms with long-term non-progressive HIV-1 infection. International Journal of Infectious Diseases. 2013; in press.
- Xu H, Wang X, Lackner AA, et al. CD8 down-regulation and functional impairment of SIV-specific cytotoxic T lymphocytes in lymphoid and mucosal tissues during SIV infection. Journal of Leukocyte Biology. 2013; in press.
- Palmer BE, Neff CP, Lecureux J, et al. In vivo blockade of the PD-1 receptor suppresses HIV-1 viral loads and improves CD4+ T cell levels in humanized mice. Journal of Immunology. 2013 Jan 1;190(1):211-9.
- Hatano H, Jain V, Hunt PW, et al. Cell-based measures of viral persistence are associated with immune activation and programmed cell death protein 1 (PD-1)-expressing CD4+ T cells. Journal of Infectious Diseases. 2013; in press.
- Dyavar Shetty R, Velu V, et al. PD-1 blockade during chronic SIV infection reduces hyperimmune activation and microbial translocation in rhesus macaques. Journal of Clinical Investigation. 2012 May 1;122(5):1712-6.
- Estes JD. Enhancing immune responses to limit chronic immune activation during SIV. Journal of Clinical Investigation. 2012 May 1;122(5):1611-4.
- Casazza JP, Bowman K, Adzaku S, et al. Therapeutic vaccination expands and improves the function of the HIV-specific memory T cell repertoire. Journal of Infectious Diseases. 2013; in press.
- García F, Climent N, Guardo AC, et al. A dendritic cell-based vaccine elicits T cell responses associated with control of HIV-1 replication. Science Translational Medicine. 2013 Jan 2;5(166):166ra2.