Lecture 8 CH10 Communicable Disease STI-HIV.pptx.pdf

Communicable Disease ControlSTI/HIV Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com. Learning Objectives Explain how communicable diseases are transmitted and controlled. 2. List the common sexually transmitted infections (STIs). Describe their m...

Communicable Disease ControlSTI/HIV Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com. Learning Objectives Explain how communicable diseases are transmitted and controlled. 2. List the common sexually transmitted infections (STIs). Describe their major clinical manifestations, complications, and methods of treatment. 3. Describe the symptoms of herpes infection in men and women. Explain the effects on sexual partners. Describe how herpes may affect a fetus or infant of an infected mother. 4. Understand the pathogenesis of human immunodeficiency virus infections, the groups affected, and the effects of the virus on the immune system. List the major clinical manifestations of the infection, the significance of a positive test for antibody to the virus, and methods of preventing spread of the infection. Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com 1. Communicable Diseases Endemic: Communicable disease in which a small number of cases are continually present in the population Epidemic: Communicable disease concurrently affecting large numbers of people in a population (contained to a defined geographic area) Pandemic: Global, world-wide outbreak across several countries or continents Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Communicable disease: Disease transmitted from person to person Methods of Transmission Direct transmission ▪ Direct physical contact (sex) ▪ Droplet spread (coughing, sneezing) Indirect transmission through an intermediary mechanism ▪ Contaminated food or water ▪ Insects (vector) Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Communicable disease perpetuates with continuous transmission of infectious agent from person to person by either direct or indirect methods Methods of Control ▪ Immunization – Personal vs Population ▪ Active (Vaccination) vs Passive (Plasma containing antibodies/Maternal transmission) If a large enough proportion are vaccinated, disease will die out as there are increasingly scarce opportunities for transmission (ie small pox) ▪ Identification, isolation, and treatment of infected persons ▪ Control of means of transmission (mask wearing, contact limitation) Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Reduction in number of susceptible individuals Methods of Control Identification, isolation, and treatment ▪ Use of Testing is reliant on test availability and effectiveness (specificity/sensitivity) ▪ Isolation - Promptly carried out to shorten time in which others may be infected (person-to-person transmission) will also depend on resources ▪ Isolation prevents contact with susceptible persons and stops spread If infection is not obvious, disease may not be recognized and treated; will continue to spread and be difficult to control (tuberculosis, STIs, etc.) - non specific/delayed symptoms are because these are signs of immune response and not directly cause by pathogen Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com ▪ Primary methods of control when immunization is not available ▪ Can use indicators of disease (ie fever) – not always specific ▪ Effectiveness depends on transmission capability and symptomatic disease Ebola – Fever followed by GI symptoms – transmissible when GI symptoms appear. -virus also not detectable at fever stage Methods of Control ▪ Chlorination of water supplies ▪ Effective sewage treatment facilities ▪ Standards for handling, manufacturing, and distributing commercially prepared foods ▪ Eradication and/or control of animal sources and vectors ▪ Physical barriers - nets Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Controlling indirect transmission for contaminated food or water Requirements for Effective Control During the bubonic (relating to swollen lymph nodes ) plague, known as black death (body color due to death by septicemia) – 70% death rate (10% with tx) One of the deadliest diseases (14th century - 50m) in human history (second to smallpox) ▪ People did not know the disease is carried by rodents and the bacterium (Yersinia pestis) is transmitted to people by flea bites (vector and replication host) Starts with fever, weakness and headache 1-7 days ▪ Resulted in many widespread and misguided attempts to control disease spread – you can’t quarantine a rat! ▪ Can also be spread via droplets causing a pneumonic plague, or fatal pulmonary infection At present we know the cause, have effective tests, treatment (vaccines/antibiotics) and The disease has sporadic outbreaks (500-600/year that are easily treated and controlled). Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Requires knowing cause of disease and methods of transmission ▪ Otherwise, control measures will be ineffective STIs Other Than HIV ▪ Between sexual partners Four major STIs ▪ Syphilis (Treponema pallidum) ▪ Gonorrhea (Neisseria gonorrhoeae) ▪ Herpes (herpesvirus) ▪ Chlamydia (Chlamydia trachomatis) Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Spread primarily by sexual contact Comparison of Four Major STDs Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Syphilis (Treponema pallidum) Forms a chancre: Small ulcer at site of inoculation • Location: Penis, vulva, vagina, oral cavity, or rectum • Swarming with treponemas; highly infectious • Persists for 4 to 6 weeks; heals even without treatment Even with healed chancres, treponemas are widely disseminated and continue to multiply Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Primary syphilis Penetrates mucous membranes of genital tract, oral cavity, rectal mucosa, or through break in skin; multiplies rapidly throughout body Syphilis ▪ Begins several months after chancre has healed ▪ Fever, lymphadenopathy, skin rash, shallow ulcers on mucous membranes of oral cavity and genital tract ▪ Persists for several weeks then subsides even without treatment ▪ Recurrences subside spontaneously ▪ Latent phase can last many years Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Secondary syphilis: Systemic infection with skin rash and enlarged lymph nodes (develops after 4-10 wks typically lasts 2-3 years) Syphilis ▪ Late manifestations of the disease may appear up to 20 years after initial infection; not generally communicable ▪ Organisms remain active, causing irreparable organ damage due to chronic inflammation (scarring of aortic valve; degeneration of fiber tracts in spinal cord; mental deterioration; paralysis) ▪ Neuro and ocular syphilis are common in this stage Causes major life threatening conditions Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Tertiary syphilis: Late destructive lesions in internal organs (3-15y develops in 15-40%) Syphilis blood test rely on immune system response - presence of antibodies that formed as a response - however this takes a few weeks/months so there won’t be any ▪ Serologic tests (antigen–antibody reactions): Turns positive soon after chancre appears and remains positive for years ▪ Useful for diagnosing disease in asymptomatic individuals and in cases where chancre is inaccessible or escapes detection (most cases) ▪ Some tests will remain positive forever making reinfection more complicated to detect (Use combination testing with 3 tests) and must be interpreted in combination with clinical history Even when treated for bacteria already Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Diagnostic tests ▪ Microscopic exam ▪ Detection of Treponema from fluid squeezed from chancre ▪ Establishes diagnosis several weeks before a blood test becomes positive Congenital Syphilis ▪May cause death of fetus in secondary/tertiary ▪Treatment early in the pregnancy is important because treponemas are less likely to pass through placenta during first few weeks of pregnancy Peneclinin ▪During early pregnancy, placental villi are covered by a double layer of epithelium and contain more connective tissue that is less permeable Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Transmission of disease from mother to child Gonorrhea Gonorrhea: Neisseria gonorrhoeae infection Gonorrhea in females ▪ Infects mucosa of uterine cervix and urethral mucosa ▪ May spread into the Bartholin glands, adjacent to the vaginal orifice ▪ Cervical infection: Profuse vaginal discharge ▪ Urethral involvement: Pain, burning on urination ▪ Some may be asymptomatic secrete vaginal fluid - can cause swelling and pain Easily spread Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com ▪ Primarily infects mucosal surfaces: Urethra, genital tract, pharynx, rectum ▪ Symptoms appear about a week after exposure ▪ Clinical manifestations differ between males and females Gonorrhea Gonorrhea in females, cont. Increased risk Manifestations ▪ Abdominal pain and tenderness ▪ Fever ▪ Leukocytosis Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com ▪ Infection may spread upward into fallopian tubes ▪ Tubal infection: Salpingitis (inflammation of fallopian tubes) ▪ Abscess formation in tubes ▪ Major complications: Tubal scarring and sterility ▪ Tubal scarring can impede ovum transport with pregnancy developing in fallopian tube (Ectopic pregnancy) Gonorrhea ▪ Acute inflammation of mucosa of anterior urethra ▪ Purulent urethral discharge ▪ Pain on urination ▪ Less likely to be asymptomatic in males than females Major complications ▪ Spread of infection to posterior urethra, prostate, seminal vesicles, vasa differentia, and epididymis ▪ Sterility: Infection in vas deferens and epididymis may lead to scarring, blocking the transport of sperm can be temporary Permanent if these are damaged Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Gonorrhea in males Gonorrhea ▪ Rectum: Pain and tenderness; purulent bloody mucoid discharge ▪ From either anal intercourse or contamination of rectal mucosa from infected vaginal secretions ▪ Pharynx and tonsils: Oral-genital sex acts Disseminated gonococcal infection more damage ▪ Organisms gain access into bloodstream and spread throughout body ▪ Fever; joint pain; multiple small skin abscesses; infections of the joints, tendons, heart valves, meninges Major medical emergency Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Extragenital gonorrhea Gonorrhea ▪ Culture swab ▪ Suspected sites: Urethra, cervix, rectum, pharynx ▪ Blood in disseminated infections ▪ Nucleic acid amplification test: Based on identification of nucleic acids in organism Treatment: Antibiotics - ceftriaxone ▪ Penicillin-resistant strains due to penicillinase enzyme Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Diagnosis and treatment Herpes Two types are not restricted in distribution can cross infect but rare • less severe disease and flare ups (geared towards own compartment) ▪ Type 1: Infects oral mucous membrane ▪ Causes blisters; usually infected in childhood, most adults have antibodies to virus ▪ May cause genital infections ▪ Type 2: Infects genital tract ▪ Infections usually occur after puberty ▪ Causes 80% of infections – higher rate of recurrence ▪ 20% from type 1 due to oral-genital sexual practices ▪ May infect oropharyngeal mucous membranes Cold sores Most people are asymptomatic • hard to test for Goes in dormant phase in neuro-ganglia • reemerges and causes infection Once you have herpes it is there forever • no vaccine, etc. Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Herpes: Herpes simplex virus infection Herpes Vesicles and shallow ulcers following sexual exposure Women: Extensive involvement ▪ Vulva: Usually painful ▪ Vagina, cervix: Little discomfort Not as well noticed Vesicles: Small, painful blisters on external genitalia and genital tract; rupture and form shallow ulcers that coalesce ▪ Contain large quantities of virus and are infectious to sexual partners If you can catch it at active phase, you can swab lesions Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Men: Glans or shaft of penis Herpes swelling Regional lymph nodes are enlarged and tender Diagnosis ▪ Intranuclear inclusions in infected cells ▪ Viral cultures from vesicles or ulcers most reliable diagnostic test ▪ Serologic tests in some cases Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Virus persists in infected tissues, causing recurrent infections Herpes Symptomatic treatments ▪ Antiviral drug shortens course and reduces severity, but does not eradicate virus (orally, per IV, or topically) ▪ Cold compress and pain relievers Major complication: Spread from infected mother to infant through active herpetic lesions in mother’s genital tract Delivery should be by cesarean section in presence of active lesions Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Treatment Chlamydia Chlamydia trachomatis infection; most common STD Clinical manifestations: Similar to gonorrhea (infection can spread to fallopian tubes to have similar effects) -many are asymptomatic Women: Cervicitis and urethritis ▪ Involves uterine cervix, urethra; moderate vaginal discharge Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Rise in cases ▪ 3 to 4 million cases per year ▪ Increased recognition due to availability of new diagnostic tests (testing bias?) Chlamydia Major complications: Sterility in women; epididymitis in men Tests for diagnosis ▪ Detection of chlamydial antigens in cervical or urethral secretions ▪ Fluorescence microscopy ▪ Cultures (swabs) ▪ Nucleic acid amplification tests: based on chlamydial nucleic acids Treatment: Antibiotics (azithromycin/doxycycline) Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Men: Nongonococcal urethritis, an acute urethral inflammation with frequency and burning on urination Other STDs ▪ Condylomata: Anal and genital warts - HPV ▪ Trichomonal vaginitis: Trichomonas vaginalis infection (protozoan parasite) ▪ Scabies and crabs (microscopic mites) important public health emergency • most are vaccinated against this now Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Other common but less serious STDs HIV virus • Human Immunodeficiency Virus •Attacks the immune system, specifically destroys CD4 T cells. •As the disease progresses immune functions are progressively suppressed. •Immune functional deficits occur in both infected and uninfected cells. http://www.coll-outao.qc.ca/bio/Imagebiologie/imagemicrobiologie/vih.jpg Source: Santé Canada Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com •Leads to the development of Acquired Immuno Deficiency Syndrome (AIDS). •Increased susceptibility to pathogens and opportunistic infections. ▪ 9 kb Genome Only 9 proteins 1 transcript, multiple genes, over 40 different mRNA can be produced - alternative splicing ▪ ssRNA retrovirus (+ve) (we have over 20 000) ▪ 2 structural proteins, Gag and Env ▪ 1 enzymatic protein (Pol) ▪ 6 regulatory proteins, Tat, Rev, Nef, Vif, Vpr and Vpu Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com ▪ codes for 9 proteins Core surrounded by a double-layered lipid envelope acquired from the cell membrane of infected cell when virus buds out from cell Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com all have dual functions and affect the immune system and viral function HIV Transmission Transmission by blood and blood products ▪ Direct inoculation: Intimate sexual contact, linked to mucosal trauma from rectal intercourse ▪ Transfusion: Contaminated blood or blood products, lessened by routine testing of all blood products ▪ Sharing of contaminated injection needles ▪ Transplacental or postpartum transmission via cervical or blood contact at delivery and in breast milk • survey to rule out anything that increases risk of transmission Not transmitted by casual household or social contacts Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com HIV virus may enter body by any of several routes ▪ Sexual contact ▪ Blood and body fluids (seminal, vaginal) ▪ Mother to infant Quickly dies if it hits air • once it gets hold —> good at staying there Steps of Infection • HIV cannot multiply alone. It must be inside a cell before it can make copies of itself. • In the host cell, HIV makes copies of itself. • These newly created virus particles can then go infect other cells. Without treatment, it is estimated that HIV can make up to 10 billion virus particles every DAY. http://membres.lycos.fr/microzoo/vih.jpg Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com • When HIV infects a cell, it hijacks it’s machinery. HIV life cycle Retrovirus • needs access to nucleus ▪ the virus binds to CD4 and enters the cell ▪ extremely error-prone and it is during this step that mutations may occur. ▪ This DNA is then transported into the nucleus ▪ The integration of the viral DNA into the host cell's genome by integrase Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com ▪ reverse transcriptase converts (+)RNA into DNA HIV life cycle continued Once it is in cell’s genome, it will stay there as long as cell is alive ▪ After integration, virus can remain dormant in the cellular genome as provirus ▪ Viral proteins are translated and cleaved by protease ▪ Viral particles are assembled at the membrane where virions are released (viral envelope composed from host lipid bi layer) ▪ Activation of T cells supports infection and production of virus ▪ patients with other ongoing infections/ inflammation have increased susceptibility to HIV infection and viral production ▪ In vitro, only activated T cells can be infected Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com ▪ Upon cellular activation, genes are transcribed and viral RNA is transported to cytoplasm HIV replication and Genetic Variability N=96 N=193 ▪ High mutation (1/cycle) rate combined with recombination events (2-20/cycle) ▪ no fidelity for RT in eukaryotes no fidelity mechanisms for HIV since it takes DNA and turns it into RNA ▪ many variants of HIV in a single infected patient in the course of one day. ▪ Over time a single patient will accumulate several variants of HIV virus ▪ rapid mutational changes in HIV and large numbers of viruses being produced provides an adaptive advantage to HIV Hard to produce vaccine for it ▪ 8-10% changes in host virus over the course of the infection N=23 Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com ▪ fast replication cycle, (generation of trillions of virus particles every day). Transmission: HIV present as both free virus particles and virus within infected immune cells. recoginizes MHC2 • can’t make antibodies that block it Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com HIV primarily infects CD4+ T cells, macrophages through interaction with CD4 receptors on the cell surface and GP120 “spikes” on the virus ▪ CD4 is the primary interaction with HIV, but CD4 alone is insufficient for virus entry into the cell Anchors HIV ▪ CXCR4 highly expressed on T cells (SDF1-chemokine receptor) ▪ Both are required to effect conformational change in gp120/41 and initiates virus:membrane fusion won’t work without both co-receptors ▪ Patients with CCR5 mutants are immune to infection with HIV Gene is predominant in nordic countries Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com ▪ CCR5 highly expressed on macrophages HIV also uses other “non-classical” receptors and routes of entry CD4 T cells main TARGET of HIV Perpetuates the disease Progressive CD4 T cell infection and eventual depletion of CD4 T cells is a marker of disease progression. Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com CD4 T cells are the most predominantly infected and replicate the highest amount of virus Tend to become reservoirs • tolerate the infection quite well Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com 90% of Viral load CD4 T cell abnormalities: Depletion/cell death, reduced proliferation /regeneration Can destroy or incapacitate neighbouring cells •Direct/ indirect destruction by viral proteins •Immune activation •Anti-cellular effect of CTLs Since less than 1% of cells are infected during at any point over the course of infection, indirect effects play an important role in the development of immune pathology and progression to AIDS. Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com •Direct destruction by infection From HIV to AIDS When does an HIV infection become AIDS? A healthy individual has between 800 and 1500 CD4T cells in 1 µL of blood. Immune deficits start to emerge below 500 mild problems below 400 Once this number drops below 200, the individual is described as having AIDS. They are then susceptible to dying from any infection or cancers, many of which we are constantly exposed to, and easily deal with. By a healthy immune system Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Blue: CD4 T-cells Red: Virus HIV infection of mucosal tissues Massive depletion/death of mucosal and memory CD4 T cells Days Weeks Infection spreads throughout body (High viral load) Immune response partially controls viral CD8 cells do a good job at repressing the virus - but Replication (viral load decreased) eventually it is defeated Months Years Clinical Latency, steady and gradual: •increase in Viral load •decrease in immune functions •decrease in CD4 cell counts Quicker progression •AIDS •Loss of immune function •Susceptibility to opportunistic infections/cancer •Death Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Infection becomes established in Lymph nodes (spreads to activated T cells) Infected and uninfected ▪ Cell- cell fusion get stuck together - affect their function ▪ Accumulation of unintegrated viral DNA ▪ Alteration of cell permeability/ lipids ▪ Apoptosis ▪ Release of toxic cytokines by infected cells ▪ Direct cellular toxicity of HIV and viral proteins ▪ Destruction of immune responses ▪ Inhibition of growth factors ▪ Degradation of cellular mRNA, reduction in protein synthesis Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Infected Cytopathic effects of HIV Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Extra secretion factors affect other cells not enough alone to combat infection Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com CD4 T cells are targeted by the HIV virus for destruction by a variety of direct and indirect mechanisms ▪ We use CD4 T cell counts to mark disease progression ▪ CD4 T cells are the “directors” of the immune response ▪ Does decreased CD4 T cell amounts account for the loss of viral control seen in HIV disease? ▪ How effective are CD4 T Cells in combating HIV infection? CD8 T Cells- the Effectors of Cell Mediated Immunity ▪ Important to combat intracellular pathogens (like HIV), controlling infection and 1. Cell to cell contact 2. Secreted factors to: destroy infected cells. (Perforin/Granzyme A, B) Inhibit virus production/ promote immune activation (IFNγ,TNFα, IL-2, MIP1α/β, RANTES) www.rockefeller.edu Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com destroying infected cells using: Cytotoxic T Cells and HIV •Cytokine/ receptor dysregulation •Direct effect of HIV soluble factors •Cell death/ apoptosis •Other immune cell dysfunction •Anergy If if CD4 is not infected, the secretion of these factors take their toll on these cells ▪ Progressive loss of CD8 T-cell mediated immunity. direct death by proteins secreted by specific cells ▪ Viral-specific CD8 T-cells remain present in the circulation at relatively normal frequencies even in patients with advanced disease. ▪ Unresponsive, fail to proliferate, express Perforin or demonstrate cytolytic activity in response to antigens. Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com CTL dysfunction can be caused by numerous factors: Loss of CD8 antiviral activity precedes CD4 T cell depletion Levy, J 1993, AIDS 7:1401-1410 In vitro model: effect of CD8 T cells on viral control in co-cultures also supports the role of CD8 T cells in control of HIV infection Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com As soon as CD8 stop functioning properly, the virus takes off Strong Anti-HIV CTL (CD8) activity is associated with LTNP/ Elite controllers, degree of control of HIV infection and in turn slower disease progression Elite control: never progress to AIDS • can maintain T-cell function efficiently Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com others keep very low viral loads Early and Late Manifestations of HIV Infection ▪ Asymptomatic ▪ Mild febrile illness Late ▪ Generalized lymph node enlargement ▪ Nonspecific symptoms ▪ Fever, weakness, chronic fatigue, weight loss, thrombocytopenia ▪ AIDS Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Early Antibody Response to HIV Antibody response to HIV Intracellular virus and antibodies do not go through cells Signs and symptoms of AIDS ▪ After a high-risk exposure and inoculation, infected person usually experiences a mononucleosis-like syndrome that may be attributed to flu or another virus ▪ Infected person may remain asymptomatic for years ▪ At early stage, only sign of HIV infection is laboratory evidence of seroconversion rely on serelogy • won’t see anything in first two moths Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com ▪ Antibodies are formed within 1 to 6 months ▪ Detection of antibodies provides evidence of HIV infection ▪ Antibodies do not eradicate virus ▪ Virus is detectable by laboratory tests (viral RNA) HIV ▪ Persistent generalized lymphadenopathy caused by impaired function of CD4 cells ▪ Nonspecific symptoms: Weight loss, fatigue, night sweats, fevers related to altered function of immune system ▪ Immunodeficiency ▪ Infection of other CD4 antigen-bearing cells (macrophages) ▪ Neurologic symptoms resulting from HIV encephalopathy and infection of neuroglial cells As virus becomes systemic delerium and dementia Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Symptoms take many forms Sequence of Events Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com t Index of Disease Viral replication: Measure amount of viral RNA in blood ▪ Virus replicates in lymph nodes, but amount of viral RNA in blood reflects extent of viral replication in lymphoid tissue Damage to immune system: Measure number of CD4 lymphocytes in blood watch them recover to see if patient is responding to treatmen ▪ Normal level: 800 to 1,200 ▪ Number declines progressively as disease advances ▪ Below 500: Risk of opportunistic infections ▪ Below 200: Risk of major HIV complication wait to put patients on treatment • the more delayed the treatment is the smaller the rebound Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Measurement of viral RNA and CD4 lymphocytes Complications of AIDS Progress much faster and are much more deadly Malignant tumors in AIDS patients ▪ Kaposi sarcoma: Human herpesvirus 8 ▪ Malignant tumors of B lymphocytes ▪ Cancers of oral cavity, rectum, uterine cervix Blood cancer is very common as well as skin cancers Re-emergence of dormant infections like: TB, CMV, EBV, HSV Body already formed defence against these Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Opportunistic infections from organisms not normally pathogenic or of limited pathogenicity ▪ Pneumocystis carinii pneumonia ▪ Mycobacterium avium complex ▪ Parasitic infections: Toxoplasmosis; cryptosporidiosis ▪ Rapidly progressive tuberculosis or histoplasmosis Treatment of HIV Infections/AIDS Primary therapy includes use of various combinations of different types of antiretroviral agents to maximally inhibit HIV viral replication with fewest adverse reactions Treatment schedules are revised as new drugs are developed and as advantages and side effects of various drug combinations are recognized Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com There is no cure for AIDS Treatment of HIV Infections/AIDS Main groups ▪ Nonnucleoside reverse transcriptase inhibitors ▪ Nucleoside reverse transcriptase inhibitors (nucleoside analogs) ▪ Protease inhibitors ▪ integrase inhibitors Main treatment • low toxicity, very effective Additional treatment ▪ Supportive therapy, nutritional support, psychological support, Social (housing) These aspects cannot be ignored especially when it comes to devestating diseases with stigma Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Anti-viral drugs given in combination to target different phases of the virus life cycle Treatment of HIV Infections/AIDS Reverse-transcriptase inhibitors interfere with copying of viral RNA into DNA by the enzyme reverse transcriptase ▪ Drugs substitute a nucleoside analog that resembles normal nucleosides used by virus to construct DNA ▪ Virus cannot distinguish between analog and normal nucleoside, interrupting viral DNA synthesis People take drug regularly so that they do not get the virus - effective PrEP – Treatment as prevention PEP - prophalaxis within 72 h - 28 course of tx Barriers: coverage varies in provinces , perception of risk Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Protease inhibitors: Block action of viral protease in viral replication; cut viral protein into short segments to assemble around viral RNA to form infectious particles ▪ Drugs reduce number of new virus particles produced NNRTI NRTI Various stages of the Life cycle of HIV are targeted and inhibited during therapy to suppress viral replication Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com COMMON IN TREATMENT ▪Financial-number of federal and provincial financial assistance programs (varies province to province) Ontario Drug Benefit (ODB), Trillium Drug program ▪Constant treatment required ▪Social : Stigma ▪Mental and Physical Health 10% struggle with care and not on effective treatment in CANADA Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Costs of treatment HIV Pathogenesis Summary: •HIV enters T cells and Macrophages through primary interaction with CD4 and secondary interactions with coreceptors (CXCR4/CCR5) which are required for virus:membrane fusion. •Although different cell types can be infected or “carry” HIV, over 90% of virus in the body is produced by actively infected CD4 T cells. •In the early stage of infection, HIV destroys large numbers of T cells at mucosal sites, which are never fully restored. •CD4 depletion is an indicator of disease progression but is not in itself responsible for all aspects of HIV dependent immune deficiency •An initial strong immune response to the virus wanes over time (5-10y) until the immune system fails, leading to disease progression and development of AIDS. •This transition period to AIDS is marked by increased virus production, lack of CD8 T cell anti viral responses and rapid CD4 T cell depletion and susceptibility to opportunistic infections and cancers •Destruction of CD4 T cells, and functional deficits in CD8 T cells are mediated by direct and indirect effects from both viral (whole virus and secreted viral proteins) and host factors. •Although treatments are available that can suppress HIV infection, there is no cure Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com •HIV then integrates into the host genome where it can actively produce more virions or remain dormant for years as provirus, until reactivated by various stimuli.