CD4+ Helper T-Cell Proliferation as a Way to Combat HIV
Overview of T-Cell Differentiation and Proliferation
http://www.sabiosciences.com/pathway.php?sn=CD40_Signaling
T- cell regulation and proliferation is still a very unclear subject. They know more about CD8+ T cells than CD4+ T cells due to the greater proliferative responses of the CD8+ T cells. During development, Myeloid and Lymphoid stem cells are made. These stem cells eventually will differentiate into all the mature immune cells. T cells are developed in the Thymus gland. T cells can have the phenotype of either CD8+ or CD4+, and which one they are will ultimately decide what role they actually play in the immune system. After CD4+ cells are mature, they are released into the circulatory system, waiting to come across an antigen- presenting cell. When they do, they release cytokines and interleukins which activate B cells to mature into plasma cells which produce antibodies. Naïve CD4+ T cells also undergo massive cell proliferation upon encountering these antigen-presenting cells. This does require the appropriate cytokine environment to support this proliferation. These “antigen-specific CD4+ T cells” need to be coupled with differentiation into one of several regulatory phenotypes if the wanted result is cells that can act to contain the pathogen that elicited the response, as well as memory cells that can act against that pathogen if reintroduced later. For more information, click here.
T- cell regulation and proliferation is still a very unclear subject. They know more about CD8+ T cells than CD4+ T cells due to the greater proliferative responses of the CD8+ T cells. During development, Myeloid and Lymphoid stem cells are made. These stem cells eventually will differentiate into all the mature immune cells. T cells are developed in the Thymus gland. T cells can have the phenotype of either CD8+ or CD4+, and which one they are will ultimately decide what role they actually play in the immune system. After CD4+ cells are mature, they are released into the circulatory system, waiting to come across an antigen- presenting cell. When they do, they release cytokines and interleukins which activate B cells to mature into plasma cells which produce antibodies. Naïve CD4+ T cells also undergo massive cell proliferation upon encountering these antigen-presenting cells. This does require the appropriate cytokine environment to support this proliferation. These “antigen-specific CD4+ T cells” need to be coupled with differentiation into one of several regulatory phenotypes if the wanted result is cells that can act to contain the pathogen that elicited the response, as well as memory cells that can act against that pathogen if reintroduced later. For more information, click here.
In Yamane et al., they demonstrated that CD4+ T cells can be separated into two groups. One is designated Th1, and these produce IFNγ and IL-2 as their dominant cytokines. Th2 produce IL-4 as their dominant cytokines. Depending on the infection, the naive CD4+ T cells can differentiate into either Th2 or Th1 cells. The host chooses the response that is most appropriate to the threat, depending on certain factors. If the host chooses the wrong fate of the naive CD4+ cells, this can prove to have bad consequences for the host. The factors that make a host choose a certain differentiation pathway vary in each infection, but overall depend on size of the pathogen. A quick diagram of this is shown below. The naive CD4+ T cell can also be called a T precursor cell.
In differentiation, naïve CD4+ T cells express a measurable amount of GATA3. Researchers believe GATA3 is important in CD4+ T cell differentiation in the thymus. GATA3’s expression is thought to be upregulated when stimulated under certain conditions in vitro. These conditions contain things such as exogenous IL-4 being there, and the neutralization of IFNγ and IL-12. The upregulation of GATA3 is thought to need both IL-4 and then engagement of the TCR. This is thought to imply the involvement of the pathways downstream of TCR in GATA3 upregulation. Although still not completely known how, researchers think that several pathways mediate TCR-induced GATA3 upregulation.
This process is thought to happen during the immune response, and if it is not working properly, or is sabotaged, the body cannot fight off certain pathogens, such as when HIV inhibits proliferation of CD4+ T cells. For this study in full, click here.
In differentiation, naïve CD4+ T cells express a measurable amount of GATA3. Researchers believe GATA3 is important in CD4+ T cell differentiation in the thymus. GATA3’s expression is thought to be upregulated when stimulated under certain conditions in vitro. These conditions contain things such as exogenous IL-4 being there, and the neutralization of IFNγ and IL-12. The upregulation of GATA3 is thought to need both IL-4 and then engagement of the TCR. This is thought to imply the involvement of the pathways downstream of TCR in GATA3 upregulation. Although still not completely known how, researchers think that several pathways mediate TCR-induced GATA3 upregulation.
This process is thought to happen during the immune response, and if it is not working properly, or is sabotaged, the body cannot fight off certain pathogens, such as when HIV inhibits proliferation of CD4+ T cells. For this study in full, click here.
http://www.nature.com/nature/journal/v402/n6760supp/fig_tab/402b018a0_F2.html
What is HIV?
HIV is an autoimmune disease. HIV stands for Human immunodeficiency virus. Eventually if left alone, HIV will turn into AIDS (autoimmune deficiency syndrome). HIV attacks the body’s immune system, specifically the CD4+ T cells. These CD4 cells turn it many of the other immune cells needed to fight off infections. If left alone, HIV drastically reduces the number of CD4+ T cells in the body. Over time, HIV can destroy so many of these cells that the body can’t fight off infections and disease. Once the body is open completely to these infections, it is thought that the patient has transferred to AIDS. For more information, click here.
Video about HIV
From YouTube, "How HIV Causes Disease"
The Importance of CD4+ Cells and the Immune Response
https://en.wikipedia.org/wiki/Immune_system#/media/File:Lymphocyte_activation_simple.png
Helper T cells express T cell receptors (TCR) that recognize antigen bound to Class II MHC molecules. MHC stands for major histocompatibility complex and class II molecules are found in antigen-presenting cells such as dendritic cells, B- Cells and some phagocytes. MHC class II pathway occurs by phagocytosis, and extracellular proteins are endocytosed, and digested in lysosomes.The MHC:antigen complex is also recognized by the helper cell's CD4+ co-receptor, which recruits molecules inside the T cell that are responsible for the T cell's activation. The activation of a resting helper T cell causes it to release cytokines that influence the activity of many cell types. Cytokine signals produced by helper T cells enhance the function of macrophages and the activity of killer T cells. Also, the CD4+ helper T cell activation causes an upregulation of molecules expressed on the T cell's surface which provide extra stimulatory signals typically required to activate antibody-producing B cells. This is all seen in the diagram below.
Helper T cells express T cell receptors (TCR) that recognize antigen bound to Class II MHC molecules. MHC stands for major histocompatibility complex and class II molecules are found in antigen-presenting cells such as dendritic cells, B- Cells and some phagocytes. MHC class II pathway occurs by phagocytosis, and extracellular proteins are endocytosed, and digested in lysosomes.The MHC:antigen complex is also recognized by the helper cell's CD4+ co-receptor, which recruits molecules inside the T cell that are responsible for the T cell's activation. The activation of a resting helper T cell causes it to release cytokines that influence the activity of many cell types. Cytokine signals produced by helper T cells enhance the function of macrophages and the activity of killer T cells. Also, the CD4+ helper T cell activation causes an upregulation of molecules expressed on the T cell's surface which provide extra stimulatory signals typically required to activate antibody-producing B cells. This is all seen in the diagram below.
https://en.wikipedia.org/wiki/T_helper_cell
Without CD4+ Helper- T cells, CD8+ Killer- T cells are left “blind” and cannot target infections as well. An antigen- presenting cell (APC) triggers CD4+ cells to be made and signal rest of the immune response such as interleukins and other T-cells to be made. If CD4+ cells are destroyed before they can signal anything, nothing in the immune response can be triggered right, and a small cold can turn into something life threatening.
Without CD4+ Helper- T cells, CD8+ Killer- T cells are left “blind” and cannot target infections as well. An antigen- presenting cell (APC) triggers CD4+ cells to be made and signal rest of the immune response such as interleukins and other T-cells to be made. If CD4+ cells are destroyed before they can signal anything, nothing in the immune response can be triggered right, and a small cold can turn into something life threatening.
http://www.scielo.br/img/revistas/bjmbr/v42n6/html/7678i01.htm
In the end, the CD4+ T cell is essential to the immune response, and without it working, the immune response cannot happen right, leading the body to a dangerous vulnerability as seen in HIV, when CD4+ T cells are destroyed.
In the end, the CD4+ T cell is essential to the immune response, and without it working, the immune response cannot happen right, leading the body to a dangerous vulnerability as seen in HIV, when CD4+ T cells are destroyed.
Treatment: Proliferation of CD4 Helper T- Cells To help Immune System prevail
HIV treatment has generally been to try to limit the virus’s effect, and help the body fend off infections it can longer fend off easily itself. ART is antiretroviral therapy. ART is a combination of many drugs. HIV medicines are grouped into six drug classes according to how they fight HIV. The six drug classes are:
HIV treatment has generally been to try to limit the virus’s effect, and help the body fend off infections it can longer fend off easily itself. ART is antiretroviral therapy. ART is a combination of many drugs. HIV medicines are grouped into six drug classes according to how they fight HIV. The six drug classes are:
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Nucleoside reverse transcriptase inhibitors (NRTIs)
Protease inhibitors (PIs)
Fusion inhibitors
CCR5 antagonists (CCR5s) (also called entry inhibitors)
Integrase strand transfer inhibitors (INSTIs)
These all try to either stop HIV from replicating, or stop CD4+ cells from degradating. But now, a new path of medicine research has emerged, trying to trigger CD4+ cell proliferation, in order to balance out the ones being destroyed by the virus. For more information about AIDS treatment options, click here.
MiR-222 (NFkB pathway)
Orecchini et al., in 2014, found that the HIV infection changed the expression of certain microRNAs. They found that specifically, the virus caused an overexpression of miR-222 which reduced proliferation of CD4+ Helper-T cells. The main virus protein they found to do this was called TAT.
Orecchini et al., in 2014, found that the HIV infection changed the expression of certain microRNAs. They found that specifically, the virus caused an overexpression of miR-222 which reduced proliferation of CD4+ Helper-T cells. The main virus protein they found to do this was called TAT.
Figure 1. HIV-1 infection induces miR-222 expression. Jurkat cells were infected with HIV-1 by standard spin-infection method or not infected (mock) and analyzed at day 1 and 2 post-infection (p.i.) by flow cytometry (A) and qRT-PCR (B). (A) Histograms show the fluorescence of cells labeled with PE-conjugated anti-p24 mAb. The mean fluorescence intensity (MFI) values and the percentage of p24+ cells are indicated. Dashed line represents labeled mock-infected cells. (B) qRT-PCR was used to measure endogenous miR-222 expression level. Relative miR-222 level in mock Jurkat cells was set to 1. Error bars are SD of one experiment performed in triplicate. One representative experiment out of three is shown.
For this experiment in full, click here.
http://ajpheart.physiology.org/content/304/8/H1050
While this figure is talking about the heart, it shows the same pathway that is used for CD4+ cells. miR-222 comes in and inhibits p27 and p57, which normally would make proliferation happen. When overexpression of miR-221/222 happens, more inhibition happens, inhibiting proliferation even more. From their results overall, they found that HIV-1 infected cells target miR-222, which promotes CD4+ mRNA degradation, preventing CD4+ translation. This process dramatically reduces CD4+ expression on the surface of these HIV-1 infected cells. They believe this is done because the presence of CD4+ can cause problems for the virus life cycle, such as inhibiting release of viral particles. This study also found that soon after the first infection, the early viral Nef protein downregulates CD4+ on the cell surface by increasing the rate of CD4+ internalization, and targeting these internalized molecules for degradation. At the end of the whole study, the researchers proposed that Tat induced miR-222 expression, which starts this whole process. The researchers also believed that the identification of another mechanism in which HIV-1 eliminates CD4+ showing that HIV-1 has been able to find ways to eliminate CD4+ cells at every step of the way, does prove that CD4+ can be a serious threat to HIV.
While this figure is talking about the heart, it shows the same pathway that is used for CD4+ cells. miR-222 comes in and inhibits p27 and p57, which normally would make proliferation happen. When overexpression of miR-221/222 happens, more inhibition happens, inhibiting proliferation even more. From their results overall, they found that HIV-1 infected cells target miR-222, which promotes CD4+ mRNA degradation, preventing CD4+ translation. This process dramatically reduces CD4+ expression on the surface of these HIV-1 infected cells. They believe this is done because the presence of CD4+ can cause problems for the virus life cycle, such as inhibiting release of viral particles. This study also found that soon after the first infection, the early viral Nef protein downregulates CD4+ on the cell surface by increasing the rate of CD4+ internalization, and targeting these internalized molecules for degradation. At the end of the whole study, the researchers proposed that Tat induced miR-222 expression, which starts this whole process. The researchers also believed that the identification of another mechanism in which HIV-1 eliminates CD4+ showing that HIV-1 has been able to find ways to eliminate CD4+ cells at every step of the way, does prove that CD4+ can be a serious threat to HIV.
SO WHAT?
Sehgal et al., in 2015, found that IFN-α exerts both antiproliferative and immunomodulatory effects on mature dendritic cells via miR-221 downregulation. They believed this IFN-miR-221 interaction could play an important role in HIV understanding and treatment. This opens the doors to much more research being done on downregulating certain microRNAs to allow the proliferation of immune cells to combat HIV, especially the proliferation of CD4+ Helper T cells. For more information, click here.
Sehgal et al., in 2015, found that IFN-α exerts both antiproliferative and immunomodulatory effects on mature dendritic cells via miR-221 downregulation. They believed this IFN-miR-221 interaction could play an important role in HIV understanding and treatment. This opens the doors to much more research being done on downregulating certain microRNAs to allow the proliferation of immune cells to combat HIV, especially the proliferation of CD4+ Helper T cells. For more information, click here.
http://www.nature.com/nri/journal/v14/n1/full/nri3581.html
Climent et al., in 2014, also found a link to proliferation of CD4+ and CD8+ cells helping fight HIV and a good possible vaccine focus. They concluded that using PLA-p24 nanoparticles and MVA expression HIV genes could induce HIV-1-specific-T-cell responses. These responses could kill the real antigen presenting cells, and thus could be possible candidates for an anti-HIV vaccine development.
MVA is modified vaccinia Ankara. It was developed as a vaccine for poxvirus, but now is used in research as a vector of vaccine delivery system of antigens. PLA is a type of drug delivery system, and p24 is a virus protein, and coats the drug delivery system to allow the nanoparticle to infiltrate the HIV virus. In this study, they found that getting these vesicles in, allowed proliferation of CD4+ and CD8+ cells, which in turn allow the body a fighting chance. They aren’t quite sure yet how this happens, but more research is being done.
Climent et al., in 2014, also found a link to proliferation of CD4+ and CD8+ cells helping fight HIV and a good possible vaccine focus. They concluded that using PLA-p24 nanoparticles and MVA expression HIV genes could induce HIV-1-specific-T-cell responses. These responses could kill the real antigen presenting cells, and thus could be possible candidates for an anti-HIV vaccine development.
MVA is modified vaccinia Ankara. It was developed as a vaccine for poxvirus, but now is used in research as a vector of vaccine delivery system of antigens. PLA is a type of drug delivery system, and p24 is a virus protein, and coats the drug delivery system to allow the nanoparticle to infiltrate the HIV virus. In this study, they found that getting these vesicles in, allowed proliferation of CD4+ and CD8+ cells, which in turn allow the body a fighting chance. They aren’t quite sure yet how this happens, but more research is being done.
Fig. 3.
T cell proliferation in response to autologous MDDCs pulsed with PLA-p24 without any maturation inducer added. T cell proliferation was assessed in a 6-day co-culture in triplicates using the CFSE proliferation assay. MDDCs were pulsed with PLA-p24 and soluble p24 at 1 μg/ml each. The mean % of CFSElow cells (% of proliferation) in the CD3+ CD8+ (CD8+) and CD3+ CD8− (CD4+) gates responding to MDDCs pulsed with PLA-p24 and soluble p24 is shown (n = 6), after mock subtraction. Error bars represent the SEM from the mean of 6 independent individuals. (*) p < 0.05, paired Student's t-tests. http://www.sciencedirect.com/science/article/pii/S0264410X14012493
In the end, there is much more research needed to be done on HIV treatment in general, and whether proliferation of the immune response’s elements could hurt the body in the long run when they shouldn’t be.
In the end, there is much more research needed to be done on HIV treatment in general, and whether proliferation of the immune response’s elements could hurt the body in the long run when they shouldn’t be.
References
Kumar, A., Abbas, W., & Herbein, G. (2014). HIV-1 Latency in Monocytes/Macrophages. Viruses, 6(4), 1837-1860. Retrieved March 12, 2016, from http://www.mdpi.com/journal/viruses
Orecchini, E., Doria, M., Michienzi, A., Giuliani, E., Vassena, L., Ciafrè, S. A., … Galardi, S. (2014). The HIV-1 Tat protein modulates CD4 expression in human T cells through the induction of miR-222. RNA Biology, 11(4), 334–338. http://doi.org/10.4161/rna.28372
Okoye, A. A., & Picker, L. J. (2013). CD4+ T cell depletion in HIV infection: mechanisms of immunological failure. Immunological Reviews, 254(1), 54–64. http://doi.org/10.1111/imr.12066
Raposo, R. A., Trudgian, D. C., Thomas, B., Wilgenburg, B. V., Cowley, S. A., & James, W. (2011). Protein Kinase C and NF- B-Dependent CD4 Downregulation in Macrophages Induced by T Cell-Derived Soluble Factors: Consequences for HIV-1 Infection. The Journal of Immunology, 187(2), 748-759. Retrieved March 12, 2016, from http://www.jimmunol.org/content/187/2/748.full.pdf
Sehgal Mohit, Zeremski Marija, Talal Andrew H., Ginwala Rashida, Elrod Elizabeth, Grakoui Arash, Li Qi-Ging, Philip Ramila, Khan Zafar K., and Jain Pooja. Journal of Interferon & Cytokine Research. September 2015, 35(9): 698-709. doi:10.1089/jir.2014.0211.
Sprent, J., Zhang, X., Sun, S., & Tough, D. (2000). T-cell proliferation in vivo and the role of cytokines. Philosophical Transactions of the Royal Society B: Biological Sciences, 355(1395), 317–322. from, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1692740/
Yamane, H., & Paul, W. E. (2012). Memory CD4+ T Cells: Fate Determination, Positive Feedback and Plasticity. Cellular and Molecular Life Sciences, 69(10), 1577–1583. http://doi.org/10.1007/s00018-012-0966-9, from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3391580/
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