Lecture 41 - Acquired Immunodeficiencies PDF

https://www.dynamed.com/approach-to/approach-to-recurrent-infections-inadults#CAUSES_OF_SECONDARY_IMMUNODEFICIENCIES_IN_ADULTS Acquired Immunodeficiencies Dr. Shannon Murray, MS PhD BMS 5308 Lecture #41 [email protected] Special Acknowledgement to Drs. Teresa Johnson & Renee Prater Lecture Obj...

https://www.dynamed.com/approach-to/approach-to-recurrent-infections-inadults#CAUSES_OF_SECONDARY_IMMUNODEFICIENCIES_IN_ADULTS Acquired Immunodeficiencies Dr. Shannon Murray, MS PhD BMS 5308 Lecture #41 [email protected] Special Acknowledgement to Drs. Teresa Johnson & Renee Prater Lecture Objectives • Differentiate between primary and secondary immunodeficiency disorders. • Relate the processes by which malnutrition results in acquired immunodeficiency. • Identify the relationship between malnutrition and compromised barrier function. • Recognize common findings and clinical signs in patients with acquired immunodeficiency due to malnutrition. • Relate the processes by which aging results in acquired immunodeficiency. • Define senescence and how it relates to immunodeficiency in the aged population. • Relate the processes by which chemotherapeutics result in acquired immunodeficiency. • Identify treatment options for reducing chemotherapy’s adverse effects on the immune system and recognize their mechanisms of action. • Relate the processes by which excessive alcohol consumption results in acquired immunodeficiency. • Recognize common findings and gender-specific clinical signs in patients with acquired immunodeficiency due to excessive alcohol consumption. • Relate the processes by which human immunodeficiency virus (HIV) results in acquired immunodeficiency. Reading References • Basic Immunology, 6th ed., Abbas, Lichtman, and Pillai – Chapter 12 – “Acquired (Secondary) Immunodeficiencies" through end of chapter • Cellular and Molecular Immunology, 10th ed., Abbas, Lichtman, and Pillai – Chapter 21 – “Secondary (Acquired) Immunodeficiencies" to end of chapter • Immunology for Medical Students, 3rd ed., Helbert – Chapter 33 – “Secondary Immunodeficiency" https://www.dynamed.com/approach-to/approach-to-recurrent-infections-in-adults#CAUSES_OF_SECONDARY_IMMUNODEFICIENCIES_IN_ADULTS Introduction to Acquired Immunodeficiencies • RECALL: Primary immunodeficiency is rare and caused by hereditary, congenital, or genetic defects in the immune system. • Secondary immunodeficiency is more common and is acquired during a person’s lifetime due to living conditions (incl. environmental), exposures, behaviors, etc. • Immunodeficiencies frequently do not present with clinical signs…. • …because of redundancies in immune system that often mask clinical signs of immune deficiency. • 1º and 2º immune deficiencies can often be acutely treated in similar ways. • 2° immunodeficiency may be reversible if underlying cause is eliminated. ‘Acquired’ or Secondary Immunodeficiencies ALCOHOLISM https://www.annallergy.org/article/S1081-1206(21)01021-8/fulltext More Focused – 2° ID Major pathogenic mechanisms • Aging • Immunosuppression as complication of another disease process, e.g., cancer, malnutrition, autoimmunity • Iatrogenic immunodeficiencies – result of immunosuppressive medication, e.g., immunotherapies • Immunodeficiency resulting from infection targeting the immune response, e.g., HIV-1 Table 21.6, Cellular and Molecular Immunology, 10th ed., 2022 Causes of 2° Immunodeficiencies in Adults Class Secondary Immunodeficiency Immunologic Dysfunction Associated Infections Malnutrition Protein-calorie malnutrition Nutrient deficiency Decreased Cell-Mediated Immunity (CMI), Weakened mucosal barriers Diarrheal diseases, Respiratory tract infections Infections HIV-1 T cell lymphopenia, Decreased CMI, Decreased humoral immunity Viruses , Fungi, Opportunistic pathogens (i.e., TB) Alcoholism Protein-calorie malnutrition Micronutrient deficiency Reduced myeloid cell phagocytosis and chemotaxis; elevated inflammatory cytokines (i.e., TNF); decreased GM-CSF* & DCs; women > inflammation than men Respiratory tract infections, TB, and pneumonia, liver disease/cirrhosis Age Advanced age Decreased CMI; Restricted T and B cell repertoire Viral and bacterial infections Hematologic malignancy (immunosuppressive chemotherapy) Leukemia Lymphoma Various immune dysfunction Dependent on immune suppression Autoimmune disease (immunosuppressive drug regimens) SLE, RA, MS, Sjogren syndrome Various immune dysfunction Dependent on immune suppression Environmental exposures Smoking, toxins, ultraviolet light, ionizing radiation, high altitude Lymphopenia, decreased CMI, non-specific immune activation, impaired innate immune function Dependent on immune suppression Tissue injury Surgery Trauma Disruption of epithelial and mucosal barriers Dependent on immune suppression and location of injury Causes of 2° Immunodeficiencies in Adults Class Secondary Immunodeficiency Immunologic Dysfunction Associated Infections Malnutrition Protein-calorie malnutrition Nutrient deficiency Decreased Cell-Mediated Immunity (CMI), Weakened mucosal barriers Diarrheal diseases, Respiratory tract infections Infections HIV-1 T cell lymphopenia, Decreased CMI, Decreased humoral immunity Viruses , Fungi, Opportunistic pathogens (O.I.s) (i.e., TB), AIDS-defining cancers O.I.s., AIDS-associated cancers HIV-1 + Antiretroviral Therapy Alcoholism Protein-calorie malnutrition Micronutrient deficiency Reduced myeloid cell phagocytosis and chemotaxis; elevated inflammatory cytokines (i.e., TNF); decreased GM-CSF* & DCs; women > inflammation than men Respiratory tract infections, TB, and pneumonia, liver disease/cirrhosis Age Advanced age Decreased CMI; Restricted T and B cell repertoire Viral and bacterial infections Hematologic malignancy (immunosuppressive chemotherapy) Leukemia Lymphoma Various immune dysfunction Dependent on immune suppression Autoimmune disease (immunosuppressive drug regimens) SLE, RA, MS, Sjogren syndrome Various immune dysfunction Dependent on immune suppression MALNUTRITION, AGING, AND IMMUNODEFICIENCY Malnutrition and Infections https://ssftmalnourishment.weebly.com/day-3.html https://www.reddit.com/r/MapPorn/comments/q0tga8/hunger_map_2021/ A Multifactorial Process • Low weight:height ratio is associated with 148% ↑ risk of diarrheal disease and 20% ↑ risk of URT. • Immune pathophysiology of malnutrition ‒ ‒ ‒ ‒ ‒ Decreased CMI and DTH Fewer lymphocytes – in numbers and responses Reduced antibody response, esp. at mucosal surfaces Impaired phagocytosis Decreased complement and cytokines • Other effects of malnutrition that further impair immunity: ‒ ‒ ‒ ‒ https://www.mdpi.com/1660-4601/8/4/1174/htm Reduced gastric acid and gastritis Reduced gut motility Decreased turnover of epithelial cells Enzyme deficiencies that are associated with digestion Clinical Manifestations • Low BMI:height ratio and altered anthropometry • Signs of protein deficiency ‒ Depigmentation of hair and poor skin quality ‒ Edema due to altered oncotic pressure in blood ‒ Reduced CD4 Th cells, so lower CD4:CD8 ratio ‒ Reduced enzyme, cytokine, and structural protein production (impaired inflammation and wound healing) • Signs of vitamin deficiency ‒ Anemia – biotin, vitamin B12 deficiency ‒ Oxidative damage – vitamin C and E deficiency ‒ Poor enzyme function – zinc, iron, vitamin B deficiency ‒ Reduced phagocyte killing – micronutrient deficiency (iron, selenium, copper, zinc) ‒ Reduced vision & mucosal immunity – vitamin A https://www.mdpi.com/1660-4601/8/4/1174/htm Aging and Disease Susceptibility • Immunity gradually deteriorates as the patient ages = “immune senescence” • Impact ‒ Elevated neoplasia to cancer due to reduced tumor surveillance ‒ Increased susceptibility to infectious disease ‒ Reduced Naïve T & B cells ‒ Also reduces magnitude of inflammatory response, e.g., 20% of adults >65 yoa do not have fever with serious bacterial infections. https://www.sciencedirect.com/science/article/pii/B9780124115965000150 Changes at multiple levels Aging and Immunity • Structural ‒ Altered DNA – telomere shortening ‒ Decreased 1° lymph organ function o Decreased stem cell proliferation (oxidative DNA damage) o Thymic involution – fewer naïve T cells o Increased memory T ‘exhausted’ cells, i.e., PD-1+, Tim3+ • Reduced innate immunity ‒ Reduced activity of APCs, phagocytes, NK cells • Reduced adaptive immunity ‒ Lower level and less diverse Ab response, reduced signaling in naïve T cells ‒ Increased susceptibility to persistent viruses, i.e., varicella-zoster virus (VZV) (chickenpox; shingles) https://www.frontiersin.org/articles/10.3389/fimmu.2020.579220/full DRUG-INDUCED OR IATROGENIC IMMUNODEFICIENCY Drugs Commonly Associated with Immunosuppression Targeted therapies – against particular sets of cells • Corticosteroids – e.g., prednisone ‒ Interferes with immune cell effector functions (cytokine production, phagocytosis, chemotaxis, induces anergy • Cytotoxic agents – e.g., methotrexate ‒ Decreases T and B cell proliferation and function (CMI, Ab production) • Immunotherapy – e.g., adalimumab, tofacitinib, tocilzumab ‒ Inhibit immune effector function, most often by interfering with cytokine binding or signaling • Chemotherapy – e.g., 5-fluorouracil, etoposide, doxorubicin, vinblastine ‒ Damages proliferating cells Non-specific effect – unintentional targeting • Cyclosporine, gold, penicilliamine, anti-epileptics ‒ Induces transient IgA deficiency Adverse Drug Reaction and IgA Deficiency • IgA deficiency is the most common primary immunodeficiency • Can also be an acquired immunodeficiency ‒ Usually an adverse drug reaction – most commonly associated with cyclosporine, gold, penicillamine, and anti-epileptics ‒ May also result from viral infection – most pronounced effects seen hepatitis C virus, Epstein-Barr virus, and congenital rubella virus infections • Clinical manifestation – recurrent respiratory or GI infections and diseases (e.g., allergies) • Immunologic deficit – low/undetectable serum or mucosal IgA while ‒ B cell numbers are normal ‒ Levels of other Ig isotypes are normal https://www.sciencedirect.com/science/article/pii/S0385814621001954 Chemotherapy and Immunity • Goal of chemotherapy is to kill rapidly dividing cells. • Cells that are affected: ‒ Tumor cells – reduces tumor size ‒ GI epithelium – causes nausea, vomiting ‒ Follicular cells – produces hair loss ‒ Hematopoietic cells – causes anemia, neutropenia, and lymphopenia, predisposing pt for infections https://www.cdc.gov/cancer/preventinfections/images/nurse-patient-vaccination-700.jpg?_=43766 Chemotherapy and the Immune System How do chemotherapeutics work? • Alters DNA structure – is incorporated into DNA or alters biochemical precursors in DNA synthesis • Interferes with tumor cell growth and replication • Interferes with cell trafficking • Net result → decreases tumor cell survival • Chemotherapy can impact all cells of the immune system, most commonly: ‒ Antigen presenting cells ‒ Phagocytes ‒ T and B lymphocytes and NK cells • So, chemotherapy causes marked immunosuppression. Reversing or Minimizing the Effects of Chemotherapy on the Immune System Multiple strategies • Blood transfusion to replace lost cells • Specific growth factors to repopulate red/white cells, e.g., G-CSF (filgrastim or Neupogen®, Zarxio®, Granix®) to increase neutrophil production • Hematopoietic stem cell transplantation if bone marrow stem cells were killed • Targeted delivery of chemotherapy such as isolated infusion to reduce systemic effects of chemotherapy, e.g., antibody-drug conjugates (ADCs) rather than systemic administration • Use immunotherapy rather than chemotherapeutics to fight cancer, e.g., immune checkpoint inhibitors (ICI), Ab against cancer epitopes, CAR T cells, DC-based therapies, immunostimulatory antibody-based therapies (e.g., anti-Treg or anti-IL-10) ALCOHOL-INDUCED IMMUNODEFICIENCY Substantial Alcohol Use Suppresses the Immune System • Low level alcohol exposure (1 glass of wine a day) may have health benefits, e.g., antioxidants in red wine • Higher levels impede immune function ‒ Contributes to malnutrition ‒ Reduces neutrophil chemotaxis ‒ Reduces phagocytosis by neutrophils and macrophages ‒ Impairs cytokine function, disrupting cell-cell communication in the immune system https://www.researchgate.net/profile/Samir-Zakhari/publication/7560740/figure/fig1/AS:702689675603970@1544545682521/Modulation-of-immune-cell-functions-by-alcohol.ppm Alcoholism Often Presents Like Malnutrition and its Effects on Immunity Alcoholics are often malnourished: • Inadequate protein dietary intake → like malnutrition • Micronutrient malnutrition – average alcoholic gets 50% of daily calories from alcohol = empty calories • Altered microbiome in gut and lung • Alcohol reduces intestinal absorption of consumed foods • Liver cirrhosis causes nausea, vomiting, anorexia • Liver disease also causes elevated TNF which causes loss of appetite (cachexia) • Alcoholics also have depressed IGF so their muscles waste away ‒ IGF= insulin-like growth factor, hormone that maintains muscle mass So, alcoholics’ immune status resembles malnutrition. https://pubs.niaaa.nih.gov/publications /arh40/images/molina1.gif Alcohol Affects Hormones = There are Sex-specific Differences in How Immunity is Affected by Alcohol • Alcohol stimulates hypothalamic-pituitary-adrenal (HPA) axis to inhibit immune responses • Different hormonal effects by sex https://pubs.niaaa.nih.gov/publications /arh26-4/257-263.htm Alcohol-Induced Immunosuppression Differs by Sex There are also hormonal differences in alcoholism that impact immunity • Males have higher testosterone – which is immunosuppressive ‒ Increases corticosteroids (CCS) and decreases Ab production ‒ Stimulates HPA axis to release immunosuppressive CCS ‒ CCS reduce phagocyte chemotaxis and phagocytic/killing abilities • Females have higher estrogen – which induces cytokine production • However, females have higher risk for cirrhosis from chronic inflammation ‒ Long-term – 2 drinks/day for females vs. 4 drinks/day for males ‒ Females have decreased ability to metabolize alcohol in the stomach • Mechanism for alcohol-related liver damage: ‒ Alcohol activates inflammatory responses o Causes endotoxin (lipopolysaccharide, LPS) release from GI tract which leads to endotoxemia o Endotoxins activate Kupffer cells in liver o Activated Kupffer cells produce free radicals and cytokines which destroy hepatocytes CHRONIC INFLAMMATION RESULTS IN IMPAIRED IMMUNE HEALTH Alcohol Impacts Immune Cells Differently – and is Dependent on Consumption Amount and Time Major factors in determining the impact: • Amount of drinking • Length of time of moderate/heavy drinking https://ars.els-cdn.com/content/image/1s2.0-S0278584615300385-gr1.jpg INFECTION-INDUCED IMMUNODEFICIENCY Infection-Related Chronic Immunosuppression • Generally, produces a transient suppression of immune responsiveness ‒ An Exception – the retroviruses: RNA viruses that encode reverse transcriptase (RT) that allows viral RNA to be transcribed into DNA and insert into the host genome • Most common infections known to produce immunosuppression: ‒ Human immunodeficiency virus 1 and 2 – infects and kills CD4 T cells ‒ Measles virus – sustained (weeks) decrease in T cell functionality ‒ Epstein-Barr virus* – infects and kills B cells (herpesviruses) ‒ Cytomegalovirus* – infects many cells, esp. macrophages (herpesviruses) ‒ Chronic M. tuberculosis and fungal infections – results in anergy to a number of Ags ‒ Chronic parasitic infections – e.g., Plasmodium spp. and African Burkitt’s lymphoma Herpesviruses: Ancient DNA virus family = establishes persistent infections by evading host immunity. When host immunity wanes i.e., aging or HIV infections, these infections are released from host immune control = replicate to higher levels & can cause pathology Access to HIV Antiretroviral Therapy (ART) is Still an Issue: HIV and AIDS As of 2021, 75% (28.7 million) of people living with HIV (PLWH) are on antiretroviral therapy • 38.4 million people living with HIV (PLWH) worldwide as of 2021 (0.7% of global population) ‒ ‒ ‒ ‒ 1.7 million < 15 years of age Almost 60% in Africa (3.4% of WHO African Region pop’n) High risk groups: IV drug users, transgender women, sex workers, men who have sex with men (MSM) Only 85% know their HIV status (i.e., do not know they are infected until diagnosed) • 40.1 million deaths to date (2021) • 660,000 died of AIDS-related causes in 2021 • 1.5 million new HIV cases in 2021 (340K in Europe/the Americas) HIV is a retrovirus – inserts into host DNA & encodes a reverse transcriptase - with two types HIV-1 – 90% affected live in developing countries, 80% transmitted sexually HIV-2 – endemic to West Africa, less pathogenic; ↑ in US Transmitted sexually, in blood/blood products, during birth, through breast milk Not thought to be spread by saliva or mosquitoes https://www.who.int/health-topics/hiv-aids#tab=tab_1 https://www.cdc.gov/hiv/library/factsheets/index.html HIV is a Retrovirus that Infects CD4 T cells and Integrates its DNA into their Genome • RECALL – HIV life cycle: ‒ Infection of cells – CD4 T cells (blood) ‒ Infection of resident macs and DCs (mucosal surfaces) ‒ Binds to, and enters target cell ‒ Reverse transcription of viral RNA to DNA ‒ Integration into host genome, then replication, assembly, and budding of progeny virions • HIV may be latent infection for 10+ years before symptoms, but latency is HIGHLY variable between individuals • Early signs: candidiasis, lymphadenopathy, cervical cancer, herpes zoster, and peripheral neuropathy. • Late signs: life-threatening infections, cancers CCR5 Figure 21-3, Cellular and Molecular Immunology,10th ed., 2022 HIV Infections Have a Different Character in the Pre-Antiretroviral vs. Post-Antiretroviral Therapy* Eras Pre-ART Post-ART CD4 T cell counts to < 200 cells/ul (Normal Range 500-1500 cells/ul) Preserved CD4 T cell numbers HIV Viral Loads in the blood 103 - >105 copies/ml Opportunistic Infections (OIs): Bacterial: Tuberculosis (TB) - the leading cause of mortality in HIV infections Fungal: Candidiasis AIDS-defining Cancers: Non- Hodgkin Lymphoma (Epstein-Barr Virus-associated) Kaposi Sarcoma (KS Herpes Virus-associated) No Access to ART for ~25% of PLWH Ongoing Immune Ongoing Activation Immune Monocyte Activation Activation Monocyte Inflammation Activation G.I. Tract Inflammation Microbial Translocation Common ART = Antiretroviral Therapy Undetectable Virus in the Blood (<50 copies/ml) Latent Viral Reservoirs in CD4 T cells that Persist despite ART: Collectively known as HIV CURE research 65% Decrease in TB co-infections with ART Non-AIDS-defining cancers: Lung and Liver Cancers Melanoma *1987-current This is the Clinical Course of HIV/AIDS WITHOUT Antiretroviral Therapy (ART) Three phases • Acute phase ‒ In 50-70% of pts 3-6 wks postinfection ‒ Peak of viremia, but immunity controls HIV replication ‒ Symptoms – fever, headache, sore throat with pharyngitis, rash, generalized lymphadenopathy • Clinical latency – the chronic phase ‒ Virus reservoirs – CD4, lymphoid tissues ‒ Lost T cells replaced, but slowly have lower percentage of cells replaced ‒ Symptoms – none or only minor infections Latency • AIDS ‒ CD4 counts <200 cells/mL ‒ Loss of CD4, CD8, B, and innate immune function ‒ Opportunistic infections Viral ‘Blips’ The latent viral DNA reservoir = CD4 T cells with latent HIV DNA = Early ART makes it smaller Figure 21-8, Cellular and Molecular Immunology,10th ed., 2022 HIV and Immune Cells • Infection requires CD4 AND a coreceptor ‒ CCR5 – called “R5 tropic” viruses; infect macs/DCs ‒ CXCR4 – called “X4 tropic” viruses; infect CD4 cells • R5 tropic viruses generally predominate early in infection – portal of entry and route of transmission • During course of infection, virus adapts and modifies tropism to become X4 tropic • The challenge in HIV antiviral immunity – stimulation of HIV-latently infected CD4 T cells (‘the reservoir’) leads to retroviral activation – & viral replication • Result –Viral titers are increased as immune response tries to fight it = approaches to activate cells so immune cells can ‘see’ virus, or markers for latently infected CD4 T cells to therapeutically target them. Figure 21-7, Cellular and Molecular Immunology,10th ed., 2022 https://www.mdpi.com/1999-4915/12/2/127/htm HIV-Associated Opportunistic Infections VERY defined associations with specific opportunistic infections occurring only when CD4 counts fall below a specific threshold. https://wikidoc.org/images/0/00/AIDS_illnesses_CD4.jpg More Impact of HIV-Associated Immune Loss • Without a fully functional immune response, incidence of other diseases increases • Common non-HIV-related disease in HIV+ individuals ‒Wasting syndrome or cachexia – thought to be due to TNF production in combination with changes in GI tract (see notes) ‒Lymphomas (including EBV-associated B cell lymphomas) ‒HPV-related diseases – common warts, genital warts, and cervical carcinoma ‒HIV-associated neurocognitive disorder or HAND ‒Reactivation of latent viral infections – esp. CMV, but also EBV, VZV, HSV-1/2, HHV-6/7 The Impact of HIV on Immunity and Health • With impaired CD4 Th cell numbers and function, other components of immune system do not function properly (see suppl. slides) • Reduced immune functions include: ‒ Loss of CD4 T helper cells and the cytokines they produce ‒ Loss of cell-mediated immunity – CD8 CTL, macs, NK cells ‒ Dysregulated B cell function and Ab secretion ‒ Reduced numbers of PMNs and levels of C’ proteins • Don’t die of AIDS, but of AIDs-related illnesses they are unable to fight off https://i0.wp.com/post.healthline.com/wp-content/uploads/2021/05/551063-TheEffects-of-HIV-on-the-Body-1296x2127-Body-1296x2125.png?w=1155&h=4466 HIV Infections Have a Different Character in the Pre-Antiretroviral vs. Post-Antiretroviral Therapy* Eras Pre-ART Post-ART CD4 T cell counts to < 200 cells/ul (Normal Range 500-1500 cells/ul) Preserved CD4 T cell numbers HIV Viral Loads in the blood 103 - >105 copies/ml Opportunistic Infections (OIs): Bacterial: Tuberculosis (TB) - the leading cause of mortality in HIV infections Fungal: Candidiasis AIDS-defining Cancers: Non- Hodgkin Lymphoma (Epstein-Barr Virus-associated) Kaposi Sarcoma (KS Herpes Virus-associated) No Access to ART for >25% of PLWH Ongoing Immune Ongoing Activation Immune Monocyte Activation Activation Monocyte Inflammation Activation G.I. Tract Inflammation Microbial Translocation Common ART = Antiretroviral Therapy Undetectable Virus in the Blood (<50 copies/ml) Latent Viral Reservoirs in CD4 T cells that Persist despite ART: Collectively known as HIV CURE research 65% Decrease in TB co-infections with ART Non-AIDS-defining cancers: Lung and Liver Cancers Melanoma *1987-current Long-Term Non-Progressors Preserve CD4 T cells and have Varied but Lower Viral Loads • Characteristics of this patient population ‒ High CD4+ and CD8+ T cell counts ‒ May have persistent viremia for at least 10-15 yrs with no symptomatic disease ‒ Do not require treatment to maintain T cell counts or asymptomatic disease • Can be divided into 2 subsets ‒ Long-term non-progressors (LTNP) – viral load ~5,000 copies/mL blood ‒ LTNP elite controllers (LTNP-EC) – viral load ≤50 copies/mL • Basis for ability to control ‒ Role for MHC Class I – specific HLA Class I loci associated with non-progression in genetic association studies ‒ CD8 CTL response – some elite controllers generate strong CTL responses specific for highly conserved peptides in HIV gag that cannot mutate without losing infectivity https://clinicalinfo.hiv.gov/sites/default/files/glossaries/images/Long-Term-Nonprogressor-800.jpg HIV Drug Therapies Keys in treatment • Interfering with virus replication reduces CD4 T cell killing, increasing immunocompetence • Targeting multiple points of replication simultaneously • Pre-exposure Prophylaxis (PrEP) HIV Replication Cycle and Major Viral Proteins https://www.mdpi.com/2073-4409/8/10/1155/htm This is the Clinical Course of HIV/AIDS WITH Antiretroviral Therapy (ART) After ART, HIV is undetectable in blood, but latent HIV reservoirs are present. When PLWH interrupt treatment, the virus rebounds. Early ART makes the latent reservoir smaller The problem is: LATENT HIV reservoirs = CD4 T cells that harbor HIV DNA and when not suppressed, produce HIV virus https://i-base.info/guides/art-in-pictures/the-natural-history-of-hiv-in-detail https://www.sciencedirect.com/science/article/pii/S2055664020304908 Antiretroviral Therapy does not CURE HIV infections as HIV Latently Infected Cells and an ‘Active Reservoir’ Persists Therapeutic Approaches: Therapies to Purge the Latent HIV Reservoir Early ART Modified From Margolis et al., 2017.Nat Immun Timothy Ray Brown aka “The Berlin Patient” was ‘Cured’ of HIV infection HIV infected, early ART-treated, presented with leukemia This approach was found to work for 5-10 people who were PLWH and had a bone marrow transplants from CCR5!32 donors. Later post-mortem studies of TRB’s tissues showed low levels of HIV in some tissues. Matched by his physician, with a Bone Marrow Transplant from a donor with a mutation in a HIV co-receptor mutation CCR5!32 unable to be infected by most HIV strains, proposed by his physician, Dr. Gero Hutter, who had read the scientific literature. No latent virus, no viral reservoirs found for >15 years (w.o ART) Dr. Gero Hütter Timothy Ray Brown In Memoriam, 2020 I hope my basic immunology & research background will help you think about these topics & your work as physicians – with insight about the research. HIV Infections Have a Different Character in the Pre-Antiretroviral vs. Post-Antiretroviral Therapy* Eras Pre-ART Post-ART CD4 T cell counts to < 200 cells/ul (Normal Range 500-1500 cells/ul) Preserved CD4 T cell numbers HIV Viral Loads in the blood 103 - >105 copies/ml Opportunistic Infections (OIs): Bacterial: Tuberculosis (TB) - the leading cause of mortality in HIV infections Fungal: Candidiasis AIDS-defining Cancers: Non- Hodgkin Lymphoma (Epstein-Barr Virus-associated) Kaposi Sarcoma (KS Herpes Virus-associated) No Access to ART for ~25% of PLWH Ongoing Immune Ongoing Activation Immune Monocyte Activation Activation Monocyte Inflammation Activation G.I. Tract Inflammation Microbial Translocation Undetectable Virus in the Blood (<50 copies/ml) Latent Viral Reservoirs in CD4 T cells that Persist despite ART: Collectively known as HIV CURE research 65% Decrease in TB co-infections with ART Non-AIDS-defining cancers: Lung and Liver Cancers Melanoma Common Innate Immune Dysregulation with and without ART ART = Antiretroviral Therapy *1987-current Impaired Innate Immunity & GI Tract Dysregulation in HIV Infections • Neutrophils ‒ Neutropenia develops in 10% of pt in early stages of HIV infection and in 60% of pt with AIDS ‒ Reduced numbers may be due to ↓ PMN production or ↑ use and death ‒ Remaining cells may be dysfunctional with reduced chemotaxis, phagocytosis, and killing ability o This may reflect decreased cytokine help from macs (e.g., IL-15) and CD4 that are compromised ‒ Associated with severe infections, prolonged hospitalizations, and death o Bacterial – streptococci, enterobacteria, pseudomonads, enterococci o Fungal – aspergillus, candida • Complement ‒ Reduced levels of many C’ proteins – due to ↓ synthesis or ↑ use/destruction in binding and clearing of HIV Ag-Ab complexes ‒ End result – ↑ infections with pyogenic organisms and Neisseria spp. Another Aspect of HIV Pathogenesis is GI Tract Dysregulation: Does LPS Give Mixed Signals to Dendritic Cells in HIV Infections? + Dendritic Cell PLWH LPS HIV-uninfected LPS Endotoxemia Profound Decrease in CD4 T cells HIV-infected Recall: Similar GI tract pathology in Alcoholism (see slide 25) Increase in G.I. tract Permeability Decrease in Intestinal Barrier Function Possible Translocation of the Microbiota Across the G.I. tract Epithelial Cell Barrier Summary I • What is the difference between primary and secondary immunodeficiencies, and what is the most common of each? – Primary – genetic alteration; most common – selective IgA deficiency, but IgA deficiency can also be acquired – Secondary or acquired – due to “events” of life such as aging, drugs, infection; most common is protein malnutrition • How does malnutrition result in acquired immunodeficiency ? What immune mediators are compromised? What are common clinical presentations? – Loss of protein and vitamins results in decreased #s and function of T cells and Ab, decreased phagocytosis, and lower levels of C’ and cytokines – Low protein presents with loss of hair & skin pigment, decreased CD4, impaired wound healing and inflammatory response – Vitamin deficiency presents with reduced phagocytic killing, anemia, and poor enzyme function • How does aging result in acquired immunodeficiency? What immune mediators are compromised? What are common clinical presentations? – Immunosenescence – due to altered DNA (e.g., telomeres), decreased stem cells, thymic involution, increased T ’exhausted’ cells – Have loss of APC, phagocyte, & NK function; lower magnitude & diversity of Abs, fewer naïve T cells – Presents with increased susceptibility to infection, increased cancers, reduced inflammatory response (e.g., fever) • How do drug treatments result in acquired immunodeficiency? What are groups of drugs associated with immunosuppression, and how does each work? How can the effects of drugs on immune function be reversed or minimized? – Varies with class of drug; can inhibit signaling, proliferation, or effector function or can cause death of cell; targeted and nontargeted drugs – Corticosteroids, chemotherapy agents, cytotoxic drugs, immunotherapies – Stimulate production of new blood cells or mediators that are lost; replace cells by transfusion; minimize by targeted delivery (e.g., ADCs) or use of more targeted therapies (e.g., immunotherapies) instead of more broadly acting therapies (e.g., chemo) Summary II • How does alcohol use result in acquired immunodeficiency? What immune mediators are compromised? What are factors that affect development and progression? – – – – Result of protein and micronutrient deficiencies (i.e., malnutrition), altered microbiome, altered/reduced liver function Reduces phagocytic killing, PMN chemotaxis, and cytokine production More severe impact with greater level of EtOH consumption; chronic use leads to increased TNF & inflammation; altered Ig production Sex differences – due to HPA and hormonal differences between sexes (i.e., testosterone, estrogen) and how EtOH impacts them and to reduced metabolism of EtOH in women • What are common examples of infections that result in acquired immunodeficiency? What immune mediators are compromised? – HIV – impacts CD4 T cells; CMV infects monocytes; EBV – targets B cells • What are phases (how classified) and common clinical presentations of HIV infection? What opportunistic infections are commonly seen in these patients, and what allows these infections to present? – Acute, chronic or latent, and AIDS – based on viral titers, CD4 counts, and symptoms – Common opportunistic infections – candidiasis (thrush, esophagitis), Kaposi’s sarcoma, pneumocystis, PML, cryptococcus, cryptosporidium toxo, histo, CMV retinitis, MAC – which one when determined by CD4 counts – Other common presentations – increased cancers (a variety), wasting syndrome, reactivation of latent infections • KNOW HOW ANTIRETROVIRAL THERAPY (ART) PROTECTS IMMUNE FUNCTION and how the HIV clinical course is altered with ART. – CD4 T cells are more preserved, and plasma viral load is decreased to below detection, however latent viral reservoirs remain. TB remains an associated opportunistic infection (OI), but instead of AIDS-defining cancers, other cancers are elevated in risk (lung, liver). Starting ART early post-infection is associated with smaller reservoir size. • Know the main barriers to curing HIV infections and define latent viral reservoirs in ART-treated People Living With HIV (PLWH). • Explain how bone marrow stem cell transplant (HSCT) was used to functionally cure HIV in some cancer-presenting individuals. – The CCR5 delta 32 mutation was screened for in donors and used for transplantation to inhibit HIV infection of donor CD4 T cells. Summary III Class Secondary Immunodeficiency Immunologic Dysfunction Associated Infections Malnutrition Protein-calorie malnutrition Nutrient deficiency Decreased Cell-Mediated Immunity (CMI), Weakened mucosal barriers Diarrheal diseases, Respiratory tract infections Infections HIV-1 T cell lymphopenia, Decreased CMI, Decreased humoral immunity Viruses , Fungi, Opportunistic pathogens (O.I.s) (i.e., TB), AIDS-defining cancers O.I.s., AIDS-associated cancers, reservoirs HIV-1 + Antiretroviral Therapy Alcoholism Protein-calorie malnutrition Micronutrient deficiency Reduced myeloid cell phagocytosis and chemotaxis; elevated inflammatory cytokines (i.e., TNF); decreased GM-CSF* & DCs; women > inflammation than men Respiratory tract infections, TB, and pneumonia, liver disease/cirrhosis Age Advanced age Immune senescence Decreased CMI; thymic loss; decreased stem cell proliferation & inflammatory response; increased PD1+, T ‘exhausted’ cells • Restricted T and B cell repertoire Viral and bacterial infections Hematologic malignancy (immunosuppressive chemotherapy) Leukemia Lymphoma Various immune dysfunction Dependent on immune suppression Autoimmune disease (immunosuppressive drug regimens) SLE, RA, MS, Sjogren syndrome Various immune dysfunction Dependent on immune suppression References • Basic Immunology, Abbas, Lichtman, and Pillai; 6th ed., 2020 • Immunology for Medical Students, Helbert, 3rd ed., 2017 • Cellular and Molecular Immunology, Abbas, Lichtman, and Pillai, 10th ed., 2022 • Journal articles and publications as noted at images on each slide • ComBank question bank at www.truelearn.com Dr. Prater’s Top 10 Take-Aways 1. Primary immune deficiency is rare. Secondary or acquired immune deficiency is more common. 2. Both may present similarly or may be subclinical because of redundancies in the immune system. 3. The most common acquired immune deficiency is malnutrition and may be due to a macronutrient (protein) or micronutrient (vitamin or mineral) deficiency and is most prevalent in underserved areas. 4. Signs of malnutrition include gastrointestinal and respiratory disease and dysfunction, skin and hair changes, edema, anemia, oxidative damage, poor enzyme function, and decreased CMI, humoral immunity, innate immunity. 5. Aging or immune senescence results from decreased stem cell proliferation and thymic atrophy and causes decreased CMI, humoral, and innate immune functions, leading to increased risk of infectious disease and cancer. 6. Chemotherapeutic agents cause immune suppression as well as GI epithelial, follicular cell, and hematopoietic cell targeting, and work by altering DNA, cell survival, cell growth and replication and cell trafficking. 7. Adverse drug reactions can also lead to immunosuppression, particularly IgA deficiency, leading to increased risk of GI or respiratory disease. 8. Excessive alcohol impairs immune function and may mimic malnutrition due to inadequate protein intake, micronutrient deficiency, increased inflammatory cytokine profile, and liver damage. Alcohol affects genders differently (males: increased corticosteroids; females: increased inflammation). 9. There are also infectious causes of immune deficiency – Epstein-Barr virus, HIV. 10. Key points with HIV: HIV-1 is more prevalent than HIV-2; CD4 cell targeting (<200/ul is diagnostic, although all immune cells are eventually targeted); increased opportunistic infections and disorders occur when the CD4 T cell count reaches <200/ul, including a variety of bacterial, viral, fungal, parasitic, and neoplastic conditions; long-term non-progressors have MHC Class I genetic factor and increased gag-specific CD8 CTL. SUPPLEMENTAL SLIDES Causes of 2° Immunodeficiencies in Adults I Class Secondary Immunodeficiency Immunologic Dysfunction Associated Infections Malnutrition Protein-calorie malnutrition Nutrient deficiency Decreased CMI Weakened mucosal barriers Diarrheal diseases Respiratory tract infections Infections HIV-1 T cell lymphopenia Decreased CMI Decreased humoral immunity Viruses Fungi Opportunistic pathogens EBV, CMV, Measles, Parvo B19 Transient hypogammaglobinemia May not be clinically relevant to patients with recurrent infections Corticosteroids Lymphopenia, hypogammaglobinemia, decreased cytokine production, impaired chemotaxis Bacterial and opportunistic infections Calcineurin inhibitors Decreased CMI Resp. tract and skin infections Cytotoxic agents Lymphopenia, decreased CMI and humoral immunity, neutropenia Staphylococci, Enterobacteriaceae, Gram-neg. rods, invasive mold/yeast, opportunistic pathogens Biologics Suppression of targeted mediator or pathway Infections dependent on targeted immune suppression Anti-epileptic therapies Hypogammaglobinemia, esp. IgA Resp. bacterial infections Gold, sulphasalazine, penicillamine, hydroxycolooquine IgA deficiency Resp. bacterial infections Medications Causes of 2° Immunodeficiencies in Adults II Class Secondary Immunodeficiency Immunologic Dysfunction Associated Infections Genetic and metabolic disorders Trisomy 21 Decreased humoral and cellular immunity Skin abscesses, periodontitis Upper resp. tract infections Turner syndrome Agammaglobinemia Resp. tract infections Cystic fibrosis Impaired airway clearance Resp. tract infections Diabetes mellitus Decreased lymphoproliferation, defective phagocytosis, impaired chemotaxis Skin infections, bacterial and fungal resp. infections, system viral disease Chronic uremia, nephrotic syndromes Decreased CMI, defective memory Ab response, impaired chemotaxis Invasive bacterial infections Protein-losing enteropathy Hypogammaglobinemia Recurrent bacterial infections Environmental exposures Smoking, toxins, ultraviolet light, ionizing radiation, high altitude Lymphopenia, decreased CMI, nonspecific immune activation, impaired innate immune function Dependent on immune suppression Hematologic malignancy (and immunosuppressive chemotherapy) Leukemia Lymphoma Various immune dysfunction Dependent on immune suppression Autoimmune disease (and immunosuppressive drug regimens) SLE, RA, MS, Sjogren syndrome Various immune dysfunction Dependent on immune suppression Causes of 2° Immunodeficiencies in Adults III Class Secondary Immunodeficiency Immunologic Dysfunction Associated Infections Age Advanced age • Decreased CMI • Restricted T and B cell repertoire Viral and bacterial infections Tissue injury Surgery Trauma Disruption of epithelial and mucosal barriers Dependent on immune suppression and location of injury Asplenia • Physical absence either congenitally or via surgical resection • Functional deficit such as in patients with sickle cell disease • Hypogammaglobinemia • Inability to filter circulating pathogens • Encapsulated bacteria • Babesia https://www.dynamed.com/approach-to/approach-to-recurrent-infections-in-adults#CAUSES_OF_SECONDARY_IMMUNODEFICIENCIES_IN_ADULTS Impaired Cell-Mediated Immunity in People Living with HIV • With loss of CD4 T cells, have loss of CD4 T helper cytokine production • Results in broad impact on effectors in cell-mediated immunity: ‒ CD8 CTL – limited proliferation and killing (reduced IL-2 and IFN-γ) o Reactivated latent viral infections (e.g., HSV-1/2, CMV, EBV, VZV) o Lack of control of viral infections (e.g., HPV) and cancer (e.g., EBV-related lymphomas) ‒ Macs o Dysregulated APC, so reduced activation of adaptive immune responses o Decreased phagocytosis, intracellular killing, and cytokine production o Result – reactivated TB and ↑ incidence of histo, crypto, and toxo – intracellular mac infections ‒ NK cells o Reduced ability to recognize and kill target cells – both infected and neoplastic tumor cells o Evidenced by uncontrolled new viral infections, reactivated latent infections, and cancers Impaired Humoral Immunity in People Living with HIV • Begins early in HIV infection and continues throughout life • Alterations in humoral immune responses ‒ Excessive B cell proliferation by HIV gp41 and gp120 (notes) ‒ Production of abnormal/ineffective immunoglobulins ‒ Follicular hyperplasia of lymph nodes ‒ Infections associated with IgG deficiency https://ars.els-cdn.com/content/image/1-s2.0-S2211124719303481-fx1.jpg o Encapsulated organisms (e.g., S. pneumoniae, H. influenzae) o Pneumocystis jirovecii o Giardia duodenalis o Cryptosporidium parvum https://pubs.rsc.org/en/Content/Image/GA/D1AY00072A Impaired Innate Immunity in People Living with HIV • Neutrophils ‒ Neutropenia develops in 10% of pt in early stages of HIV infection and in 60% of pt with AIDS ‒ Reduced numbers may be due to ↓ PMN production or ↑ use and death ‒ Remaining cells may be dysfunctional with reduced chemotaxis, phagocytosis, and killing ability o This may reflect decreased cytokine help from macs (e.g., IL-15) and CD4 that are compromised ‒ Associated with severe infections, prolonged hospitalizations, and death o Bacterial – streptococci, enterobacteria, pseudomonads, enterococci o Fungal – aspergillus, candida • Complement ‒ Reduced levels of many C’ proteins – due to ↓ synthesis or ↑ use/destruction in binding and clearing of HIV Ag-Ab complexes ‒ End result - ↑ infections with pyogenic organisms and Neisseria spp. Figure 4-2 – Immunology for Medical Students, 3rd ed., 2017 Viral Titers and CD4 Counts in LTNP https://www.semanticscholar.org/paper/Human-immunodeficiency-virus-type-1-long-term-the-Poropatich-Sullivan/6f60a212eb28a0487d41469d50dee9d76377ad62 Factors which may contribute to LTNP control of HIV-1 https://www.semanticscholar.org/paper/Human-immunodeficiency-virus-type-1-long-term-the-Poropatich-Sullivan/6f60a212eb28a0487d41469d50dee9d76377ad62