Journal Article

In-vitro Immunomodulatory activity of Azadirachta indica A.Juss. Ethanol: water mixture against HIV associated chronic CD4+ T-cell activation/ exhaustion

Nakabuye, Mariam, Anywar, Godwin Upoki, Nalunga, Justine, Cham, Fatim, Olwenyi, Omalla A., Kibuuka, Hannah, Tindikahwa, Allan, Kiweewa, Francis, Asingura, Bannet, Lichter, Eliezer Z., Naluyima, Prossy, Semwogerere, Michael, Bagaya, Bernard, Fletcher, Courtney V., Podany, Anthony T., Byrareddy, Siddappa N.

2021

Overview

Background In Sub-Saharan Africa, herbal therapy continues to be utilized for HIV-1 disease management. However, the therapeutic benefits of these substances remain ambiguous. To date, little is known about the effects of these plant extracts on chronic CD4 + T-cell activation and exhaustion which is partly driven by HIV-1 associated microbial translocation. Methods Effects of Azadirachta indica, Momordica foetida and Moringa oleifera ethanol: water mixtures on cell viability were evaluated using the Guava PCA system. Then, an in-vitro cell culture model was developed to mimic CD4+ T cell exposures to antigens following HIV-1 microbial translocation. In this, peripheral blood mononuclear cells (PBMCs) isolated from HIV negative ( n  = 13), viral load < 1000 copies per mL ( n  = 10) and viral load > 1000 copies per mL ( n  = 6) study participants from rural Uganda were treated with Staphylococcus enterotoxin B (SEB). Then, the candidate plant extract ( A. indica ) was added to test the potential to inhibit corresponding CD4+ T cell activation. Following BD Facs Canto II event acquisition, variations in %CD38, %CD69, Human Leukocyte Antigen -DR (HLA-DR), Programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3), interferon gamma (IFN γ) and interleukin 2 (IL-2) CD4 + T cell expression were evaluated. Results Following exposure to SEB, only A. indica demonstrated a concentration-dependent ability to downregulate the levels of CD4 + T cell activation. At the final concentration of 0.500 μg/mL of A. indica, a significant downregulation of CD4 + CD38 + HLA-DR+ expression was observed in HIV negative ( p  < 0.0001) and both HIV infected groups ( P  = 0.0313). This plant extract also significantly lowered SEB induced % CD4+ T cell HLADR, PD-1 and Tim-3 levels. PD-1 and CD69 markers were only significantly downmodulated in only the HIV negative (( p  = 0.0001 and p  = 0.0078 respectively) and viral load< 1000 copies per ml (p = 0.0078) groups. Conclusion A. indica exhibited the in-vitro immunomodulatory potential to inhibit the continuum of SEB induced CD4+ T-cell activation/ exhaustion without impacting general T-cell specific functions such as cytokine secretion. Additional studies are needed to confirm A. indica as a source of natural products for targeting persistent immune activation and inflammation during ART.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Acetaldehyde / Acquired immune deficiency syndrome / Adolescent / Adult / AIDS / Alcohol / Alcohol, Denatured / Alternative medicine / Analysis / Antigens / Antiretroviral therapy / Apoptosis / Azadirachta / Azadirachta indica / Azadirachta indica (A. indica) ethanol: water mixture / Basic research / Biological products / Biological response modifiers / Biotechnology industry / CD38 antigen / CD4 antigen / CD4+ T cell activation/exhaustion / CD4-positive T-lymphocytes / CD4-Positive T-Lymphocytes - drug effects / CD69 antigen / Cell activation / Cell culture / Cell Culture Techniques / Cell death / Cell viability / Chiropractic Medicine / complement / Complementary & Alternative Medicine / Cytokines / Cytotoxicity / Development and progression / disease control / enterotoxins / Ethanol / Ethanol - chemistry / Evaluation / Female / Flowers & plants / guavas / Health aspects / Herbal medicine / Histocompatibility antigen HLA / Histocompatibility antigens / HIV / HIV (Viruses) / HIV Infections - drug therapy / HLA antigens / HLA histocompatibility antigens / Human immunodeficiency virus / Humans / immunoglobulins / Immunomodulation / Immunomodulators / Infections / Inflammation / Interferon / Interferon gamma / Interleukin 2 / Interleukins / Internal Medicine / Leukocytes / Leukocytes (mononuclear) / Lymphocyte Activation - drug effects / Lymphocytes / Lymphocytes T / Male / Medicine / Medicine & Public Health / Microbial translocation / Microorganisms / Middle Aged / Momordica foetida / Moringa oleifera / Mucin / mucins / Natural products / PD-1 protein / Peripheral blood mononuclear cells / Phytotherapy / Plant extracts / Plant Extracts - pharmacology / Plant sciences / Proteins / Research Article / secretion / Staphylococcal enterotoxin B / Staphylococcal enterotoxin B (SEB) / Staphylococcus / T cells / Translocation / Uganda / viral load / Water - chemistry / Young Adult