Related article: Effects of bacteria and viruses on their human host
Acquired Immunodeficiency Syndrome (AIDS) is a deficiency of cellular immunity brought on by infection with the human immunodeficiency virus (HIV-1) and characterized by a range of opportunistic diseases and infections. Such opportunistic infection proliferate in the absence of a robust immune response.
One of the key mechanisms that HIV fosters immune dysfunction is through completely taking over the VDRThe Vitamin D Receptor. A nuclear receptor located throughout the body that plays a key role in the innate immune response. and interfering with D-binding protein. As a result, en end-stage AIDS patients levels of 1,25-DPrimary biologically active vitamin D hormone. Activates the vitamin D nuclear receptor. Produced by hydroxylation of 25-D. Also known as 1,25-dihydroxycholecalciferol, 1,25-hydroxyvitamin D and calcitirol. approach zero.
Main article: Metabolism of vitamin D and the Vitamin D Receptor
HIV uses the VDR to recognize its own LTR promoter region in order to transcribe its own genome, thus taking over the VDR.1)
There is no evidence that supplemental vitamin D helps HIV or AIDS patients.
Vitamin D supplementation is associated with reduced immune activation levels in HIV-1-infected patients on suppressive antiretroviral therapy. 7)
Of note, we observed that patients with low vitamin D levels displayed a reduced CD4/CD8 ratio (P ¼ 0.03, Table 1), which is usually a sign of increased immune activation in HIV-infected patients receiving effective ART [16]. We also analyzed CD38 expression on the surface of memory CD8+ T cells as a robust marker of immune activation. Although there was substantial interindividual variability, patients with severe vitamin D deficiency displayed modest but statistically significant higher levels of CD38 expression, compared with individuals with normal vitamin D (P ¼ 0.04, Table 1).
We thus monitored CD4/CD8 ratio, as well as cellular activation (i.e. CD38 expression) and cell cycling (i.e. Ki67 expression) of memory CD8+ T cells in vitamin D supplemented individuals. These patients presented a higher CD4/CD8 ratio post-compared with pre-supplementation (Fig. 1b). Moreover, vitamin D increase upon supplementation was associated with a reduction in cellular immune activation levels (Fig. 1c). We also found that serum levels of vitamin D and the expression of the cellular immune activation markers were inversely correlated in this longitudinal setting (Fig. 1d). Vitamin D status appears therefore to impact on cellular immune activation levels.
Main article: Co-infections
Pathogens are able spread effectively in an immunocompromised environment. This means it's possible that AIDS patients pick up substantial pathogen loads. It is further possible that it is these Th1 pathogensThe community of bacterial pathogens which cause chronic inflammatory disease - one which almost certainly includes multiple species and bacterial forms., which kill patients. Viral co-infections (including Epstein-Barr virus, Human Herpes Virus 6, etc.) are found in all the diseases the Marshall ProtocolA curative medical treatment for chronic inflammatory disease. Based on the Marshall Pathogenesis. treats, but the viruses are not believed to bethe proximate cause of disease.
Mycobacterium avium-intracellulare infection and immunoblastic sarcoma in a fatal case of AIDS. 8)
CD38 plays a role in effective containment of mycobacteria within granulomata and polarization of Th1 immune responses against Mycobacterium avium. 9)
… Absence of CD38 rendered mice more susceptible to mycobacterial infection. This susceptibility seems to be due to ineffective Th1 differentiation and polarization, which is essential for the control of M. avium infection. In addition, absence of CD38 seems to compromise the maintenance of the granulomatous barrier, leading to dissemination and unrestrained growth of mycobacteria. …
CD38 Controls the Innate Immune ResponseThe body's first line of defense against intracellular and other pathogens. According to the Marshall Pathogenesis the innate immune system becomes disabled as patients develop chronic disease. against Listeria monocytogenes Using a murine Listeria monocytogenes infection model, we found that CD38 knockout (KO) mice were highly susceptible to infection. Enhanced susceptibility was already evident within 3 days of infection, suggesting a function of CD38 in the innate immune response. CD38 was expressed on neutrophils and inflammatory monocytes, and especially inflammatory monocytes further upregulated CD38 during infection. Absence of CD38 caused alterations of the migration pattern of both cell types to sites of infection. … In vitroA technique of performing a given procedure in a controlled environment outside of a living organism - usually a laboratory., macrophages of CD38 KO mice were less efficient in uptake of listeria but still able to kill the bacteria. Dendritic cells also displayed enhanced CD38 expression following infection. However, absence of CD38 did not impair the capacity of mice to prime CD8+ T cells against L. monocytogenes, and CD38 KO mice could efficiently control secondary listeria infection. In conclusion, our results demonstrate an essential role for CD38 in the innate immune response against L. monocytogenes.
The ARF has no clinical experience with AIDS patients yet. However, we do believe it due time that 'post-HIV wasting disease', and many of the other post-HIV disease are found to be Th1 in pathogenesis.
We would argue that it would make sense for an AIDS patient to strengthen his or her immune response and that the only way to do this is to kill the Th1 pathogens which dysregulate it.
A therapeutic probeA brief trial of the Marshall Protocol to see if it will generate an immunopathological response. The "gold standard" for testing whether a patient is a good candidate for the MP. will confirm the potential efficacy of this treatment.
In mice, CD38 was shown to be required for immunity against S. pneumoniae, as its absence rendered mice more susceptible to infection by this pathogen. This increased susceptibility was associated with a diminished neutrophil chemotaxis in response to peptides of bacterial origin. In humans, CD38 was proposed to have a protective role in HIV infection. However, the mechanisms by which this protection is achieved are, at this point, unclear. As CD38 appears to be important in viral infections and is able to modulate immune responses, namely at the level of Th1 cytokineAny of various protein molecules secreted by cells of the immune system that serve to regulate the immune system. secretion, it is conceivable that it could also play a role in immunity against intracellular pathogens, such as mycobacteria.
CD38 (cluster of differentiation 38), also known as cyclic ADP ribose hydrolase is a glycoprotein[5] found on the surface of many immune cells (white blood cells), including CD4+, CD8+, B lymphocytes and natural killer cells. CD38 also functions in cell adhesion, signal transduction and calcium signaling. … The loss of CD38 function is associated with impaired immune responses, metabolic disturbances, and behavioral modifications including social amnesia possibly related to autism.
The CD38 protein is a marker of cell activation. It has been connected to HIV infection, leukemias, myelomas, solid tumors, type II diabetes mellitus and bone metabolism, as well as some genetically determined conditions.
CD38 produces an enzyme which regulates the release of oxytocin within the central nervous system.
Daratumumab which targets CD38 has been used in treating multiple myeloma.
The role of CD38 as a signaling molecule is suggested by the observation that CD38 triggering is involved in T cell costimulation, B cell maturation, and induction of cytokine production by several cell types (Table 1). These signals are not a prerogative of a single cell lineage but are shared by B, T, and myeloid cells. CD38 signaling inhibits the growth of immature B cells in the bone marrow microenvironment, suggesting that it represents a novel regulatory mechanism of B lymphopoiesis .
In mature germinal center B cells, CD38 delivers rescue signals that protect cells from apoptosis and upregulate Bcl-2 (a molecule associated with antiapoptotic effects) in a manner similar to that observed with triggering of CD40, which is known to deliver costimulatory signals to the B cell . In purified T cells, CD38 signaling induces production of high levels of interleukin (IL) 6, granulocyte-macrophage colony-stimulating factor, interferon γ, and IL-10 and low levels of IL-4 and IL-2 (i.e., a cytokine profile shared by T helper 1 and 2 cells) .
CD38 expression in HIV-1-infected individuals: As in most viral infections, HIV-1 infection causes activation of B and T cells (both CD4 and CD8 cells), which consequently upregulates the surface expression of CD38 and other activation markers. CD38 upregulation can be detected on uninfected cells, indicating that this expression is not caused by direct infection.
An observational study of children vertically infected with human immunodeficiency virus type 1 (HIV-1) was performed to determine the role of CD38 expression in CD8+ T cells as prognostic marker of virological failure in children receiving HAART.
We studied 42 children who were receiving antiretroviral therapy and who had an undetectable virus load (uVL), and we found a negative correlation between CD38 expression in CD8+ T cells and the duration of uVL. We selected 17 HIV-1–infected children with CD38 values close to the baseline level (i.e., the first uVL achieved), and we distributed the children into 2 groups on the basis of median CD38 value in CD8+ T cells.
Children with CD38 values in CD8+ T cells that were higher than the median had a higher incidence and relative risk of virological failure than did those with values lower than the median. In conclusion, we demonstrate for the first time that CD8+CD38+ T cell count is a good prognostic marker of therapeutic failure in HIV-1–infected children.