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HIV and the AIDS pandemic
The Acquired Immunodeficiency syndrome (AIDS) is caused by infection with the Human Immunodeficiency Virus type 1 (HIV-1), a lentivirus that specifically targets the human immune system. To date, there is still no cure despite more than three decades of research.
HIV has such devastating effects on the immune system because it mounts a continuous attack against the very cells that coordinate regular immune responses, leaving the body vulnerable to normally harmless microorganisms. The virus targets a particular type of lymphocyte, called CD4 T cell or helper T cell, which orchestrates the immune response against a pathogen by activating several other immune cells, including CD8 T cells or cytotoxic T cells that are equipped to kill virus-infected cells. Over time, the HIV-induced loss of CD4 T cells causes AIDS, a state of progressive immune failure in which the body is susceptible to cancers and opportunistic infections with various microorganisms. In the end, these opportunistic infections and malignancies and not the virus itself are what cause the high morbidity and mortality associated with AIDS. Since its first identification in 1981, HIV-1 has infected about 75 million people worldwide and caused over 35 million deaths. The virus spreads via different routes, the most important of which are sexual transmission, percutaneous transmission (e.g. via contaminated needles) and perinatal transmission from mother to child.
The emergence of HIV-1 and HIV-2 is the result of several cross-species transmission events of Simian Immunodeficiency Viruses (SIVs) that naturally infect African primates. The highest HIV prevalence rate is in young adults in sub-Saharan Africa, but practically every country in the world is affected by the pandemic. Although antiretroviral treatment has reduced the AIDS death toll, the access to these drugs is far from universal and there is a significant gap in life expectancy between uninfected persons and HIV-infected patients on treatment. Therefore there is still an urgent need for better treatments and an effective anti-HIV vaccine.
HIV elite controllers and restriction factors
Most HIV-infected individuals will progress to AIDS within 10 years of the initial infection if they do not receive antiretroviral therapy (ART). ART significantly reduces the viral load in the blood of HIV patients and stabilizes their CD4 T cell numbers, but complete eradication of the virus has so far remained elusive due to the persistence of viral reservoirs.
The genetic background of HIV-infected patients plays an essential role in determining the rate at which the disease progresses. Elite controllers are individuals that are able to control viral replication to undetectable levels in the blood plasma even in the absence of antiretroviral therapy. Many elite controllers share a unique genetic trait, the expression of certain antigen-presenting HLA proteins, that are associated with lower viral loads and slower disease progression rates. However, interestingly, not all elite controllers possessing this particular genetic determinant progress at a slow rate, suggesting that other factors also play an important role in controlling HIV. Host restriction factors are a group of genes expressed by the human host cells that are able to counteract the virus in a variety of different ways: Restriction factors of the APOBEC family, for example, interfere with viral reverse transcription and other stages of the early viral life cycle, TRIMs inhibits the release of the HIV-1 capsid protein and tetherin prevents viral particles from being released from the infected cells, to name only a few.
Human endogenous retroviruses
Human endogenous retroviruses (HERVs) are ancient retroviruses that have infected humans and their primate ancestors for approximately the last 100,000 years. Over this time, many of these simple retroviruses have stably integrated into the human genome and co-evolved with the host. Today, HERVs comprise about 8% of the human genome, but they are considered to be largely silent and are generally not being expressed in healthy tissues. Their ability to replicate and produce infectious particles has largely been lost due to mutations that they have acquired over time. However, it has been reported that the proteins of one of the more recently integrated HERV family are being expressed in certain disease states, such as in autoimmune diseases and cancer. During HIV-1 infection, HERV proteins and messenger RNA can be detected in blood serum. The mechanisms that lead to expression of HERV messenger RNA during HIV-1 infection are still incompletely understood, but HIV-1 proteins are thought to play a role. Despite their status as self-antigens, HERV proteins are able to elicit an immune response in HIV-1-infected individuals and expression of these unusual antigens can be detected on HIV-infected cells.
Human T-cell leukemia virus type 1 (HTLV-1) is a delta family retrovirus that has infected humans for thousands of years. Approximately 10 to 20 million people worldwide are infected with HTLV-1, the majority of whom remain without symptoms for life. However, 1 - 5% of HTLV-1-infected individuals develop severe diseases, such as adult T-cell leukemia/lymphoma (ALT) and immune-mediated inflammatory disease involving the central nervous system, the eyes, the lungs and/or the skeletal muscles. Inflammation of the central nervous system in HTLV-1-infected subjects results in progressive spasticity and muscle weakness in lower extremities and is termed HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is currently no cure, vaccine or effective therapy for HTLV-1 infection, and the mechanisms for progression to HAM/TSP remain unclear.
The Nixon Lab is interested in understanding the mechanisms human host cells employ to control HIV-1 replication. We make use of samples from individuals that are able to control HIV infection in the absence of antiretroviral therapy (elite controllers) in comparison with samples from individuals that are not able to control HIV infection naturally as a means of understanding the innate immunity that enables some patients to progress slower to disease than others.
It has long been known that HIV elite controllers frequently express particular HLA class I haplotypes, but now there is growing evidence that there are additional innate mechanisms by which they control HIV infection. We have shown that elite controllers have an increased expression profile of host restriction factors, a group of host cell-intrinsic proteins acting against HIV (Abdel-Mohsen M et al., Retrovirology, 2013), and that even healthy individuals with these HLA class I alleles show increased expression of host restriction factors (Raposo RA et al., J Leukoc Biol, 2013). Furthermore, studies in collaboration with the Sasha lab at the Oregon Health and Science University (OSHU), Portland, have demonstrated that not only human elite controllers of HIV, but also rhesus macaques that naturally control infection with Simian Immunodeficiency Virus (SIV), a virus closely related to HIV, mount T cell responses against the APOBEC family of restriction factors (Champiat S et al., J Virol, 2013). We are currently expanding our previous research by characterizing the restriction factor profiles of HIV elite controllers in comparison with profiles of individuals suffering from certain autoimmune diseases with the goal of developing a restriction factor-based HIV vaccine target.
Other studies involve the characterization of latent HIV reservoirs in chronically HIV-infected individuals and the effects of innate immune mechanisms on the HIV-1 reservoir size in different T cell subpopulations in these patients.
In addition, our lab investigates the expression of anti-viral host restriction factors during HTLV-1 infection and Strongyloidiasis/HTLV-1 co-infection, and aims at identifying biomarkers for HTLV-1-associated leukemia.
The failure of antiviral vaccines is often caused by rapid viral escape from antigen-specific immune responses. Our work on human endogenous retroviruses (HERVs) is focused on an alternative approach to identify stable non-HIV-1 epitopes that are exclusively expressed on HIV-1–infected cells. HERVs are remnants of “fossil” retroviruses that are stably integrated into our genome and generally replication incompetent due to mutations acquired over time. Studies in collaboration with the Ostrowski lab at the University of Toronto have shown that during HIV-1 infection, infected individuals express both mRNA and fully functional HERV-K proteins on the cell surface of HIV-infected CD4 T cells and HERV-K-specific CD8 T cells are capable of eliminating cells infected with genetically diverse HIV-1 isolates in vitro (Jones RB et al., J Clin Invest, 2012). Furthermore, we were able to show that an anti-HERV-K antibody can bind specifically to HIV-1-infected cells and kill them through antibody-dependent cellular cytotoxicity in vitro. The titers of these antibodies are increased in HIV elite controllers compared to uninfected persons and HIV-infected adults on antiretroviral therapy (Michaud HA et al., J Immunol, 2014; Michaud HA et al., Retrovirology, 2014).
Thus, antibodies against non-HIV epitopes specifically expressed on HIV-infected cells may constitute valid therapeutic targets and we aim to employ these for the development of a HERV-based HIV vaccine.
We are continuing our studies by analyzing the differential expression of HERVs and other genomic retroelements in clinical samples from healthy individuals and HIV patients. In addition, we are currently exploring novel biological delivery mechanisms for anti-HIV antibodies.
An additional interest of our laboratory is the development of protocols to analyze HIV and biomarkers of other infectious diseases using low-cost and non-invasive methods, such as blood spots on paper, saliva and urine samples, at field sites or in other resource-limited settings.