Acquired Immunodeficiencies Session 27 PDF

Acquired Immunodeficiencies Session 27 MICRG 1553 Lisa Kronstad, Ph.D. [email protected] October 23, 2024 Cholla D 1  Learning Objectives Describe what is known about how HIV...

Acquired Immunodeficiencies Session 27 MICRG 1553 Lisa Kronstad, Ph.D. [email protected] October 23, 2024 Cholla D 1  Learning Objectives Describe what is known about how HIV emerged into the human population Be able to explain the natural history of HIV infection in terms of viral replication, antibody production, and lymphocyte counts Describe the components of the HIV virion that relate to strategies for diagnosis and treatment of HIV infection Articulate the challenges of HIV vaccine development Draw the replication cycle of HIV and indicate the steps inhibited by current anti-retroviral medications Articulate the importance of anti-retroviral medication adherence and the the rationale for targeting multiple replication steps simultaneously 2 Lecture Outline Emergence of a new pathogen Virology HIV Diagnostics HIV Vaccine Development Highly Active Anti-Retroviral Treatment (HAART) 3 "Silent Spread" of an unknown disease Danish surgeon working in the Democratic Republic of the Congo in the 1964 and 1972-77 1974: developed diarrhea, swollen lymph nodes, weight loss, and fatigue Wikipedia - Margrethe Rask (1930-1977) Danish Physician 1977: returns to Copenhagen in respiratory distress Found to have Staphylococcus aureus, candidiasis, and pneumonia from Pneumocystis jirovecii and extremely low T cells - cause of death unexplained 4 Not so silent spread of an unknown disease Centers for Disease Control (CDC). Kaposi's sarcoma and Pneumocystis pneumonia among homosexual men--New York City and California. MMWR Morb Mortal Wkly Rep. 1981;30(25):305-308. 1981: increasing numbers of homosexual men began to die of opportunistic infections and rare malignancies Kaposi's sarcoma - rates of extremely rare Wikipedia cancer increase dramatically 1983: term Acquired ImmunoDe ciency Syndrome (AIDS) coined - cause unknown 1994: KS (but not AIDS) discovered to be caused by a herpesvirus and transmitted sexually - Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) 5 https://lloyd-derm.com/conditions/common-medical-skin-conditions/kaposis-sarcoma/ fi Timeline of early AIDS Early 1980's: blood banks dismissed calls by the CDC to use a hepatitis B test as a surrogate until a test for the cause of AIDS could be developed. 90% of hemophiliacs treated with blood-clotting factors between 1979 and 1984 became infected with HIV 1985: Ryan White, a 13-year-old hemophiliac with AIDS, is banned from school 6 Discovery of a novel retrovirus January 1983, lymph node sample from a patient in the pre-AIDS phase was brought to Pasteur Institute in France Retrovirus-like particles seen under an electron microscope Presence of reverse transcriptase detected Virus is sequenced and February 4,1983, First snapshot of the HIV-1 virus proteins characterized taken at Institut Pasteur 1985 - blood test for Human Immunode ciency Virus (HIV) licensed 7 fi Timeline of early HIV/AIDS NEJM study of 101 people living in close but non sexual contact with people with AIDS, including sharing toothbrushes, razors, clothing etc. found no evidence of transmission Now recognized to spread by sexual, percutaneous and perinatal (placenta and breast milk) routes 8 "Silent Spread" of an unknown disease 5 June 1981 - AIDS epidemic formally recognized in the US Wikipedia - Margrethe Rask (1930-1977) Danish Physican In 1987, Dr. Rask's stored blood tested positive for HIV Viral sequence from a man living in the Congo taken in 1959 also found positive - oldest known case 9 Zoonotic Origins of HIV/AIDS Human Immunode ciency virus (HIV) is a result of multiple jumps of simian immunode ciency viruses (SIVs) that infect African primates One transmission event (~1911), involving SIVcpz from chimpanzees in southeastern Cameroon, gave rise to HIV-1 group M - principal cause of AIDS pandemic Probably passed from chimpanzees to human hunters through blood- borne transmission Currently: ~40 million Wikipedia people are living with HIV/ AIDS worldwide 10 fi fi Discovery of a novel human herpesvirus Centers for Disease Control (CDC). Kaposi's sarcoma and Pneumocystis pneumonia among homosexual men--New York City and California. MMWR Morb Mortal Wkly Rep. 1981;30(25):305-308. KS became a highly stigmatized sign of HIV infection during height of AIDS pandemic Wikipedia 1994: DNA sequences from skin biopsies from AIDS-KS patients detected a new human herpesvirus - Kaposi's sarcoma- associated herpesvirus (KSHV or HHV-8) 11 https://lloyd-derm.com/conditions/common-medical-skin-conditions/kaposis-sarcoma/ Lecture Outline Emergence of a new pathogen Virology HIV Diagnostics HIV Vaccine Development Highly Active Anti-Retroviral Treatment (HAART) 12 HIV Virology: Structure Single-stranded, positive polarity, RNA virus, enveloped Replication to produce DNA from RNA via reverse transcriptase and is thus a retrovirus (Group VI) Viral DNA integrates into host DNA 13 HIV Virology: Genome Three structural genes: Gag: encodes internal proteins such as p24 used for serology test Pol: encodes reverse transcriptase, protease and integrase Env: encodes gp120/gp41 (attachment) Six regulatory genes Tat reduces HLA class I molecules 14 HIV Virology: Tropism Glycoproteins gp120 and gp41 that interact with CD4 molecule, leading to infection of CD4+ T cells Loss of cellular immunity Development of opportunistic infections (e.g. Kaposi's sarcoma and many others) 15 HIV Virology: Antigens Gp120: highly variable envelope glycoprotein that interacts with CD4 receptor Antibodies to gp120 neutralize the infectivity of HIV Gp41 envelope glycoprotein that mediates fusion with viral envelope with cell membrane during infection P24 located in the core 16 Replication cycle of HIV 1- Entry at the cell surface beings with gp120 binding to CD4: Co-receptor: gp120 interacts with CCR5 or CXCR4 Homozygosity for a 32 base pair deletion encoding for CCR5 (CCR5∆32) leads to a non-functional protein and confers a level of HIV resistance 17 Replication cycle of HIV 2 - Replication occurs in the cytoplasm: Reverse transcription of viral RNA into dsDNA dsDNA migrates to nucleus of CD4 T cells Integrates into host DNA mediated viral integrase Transcription of viral mRNA by host polymerase 18 Replication cycle of HIV 3 - Processing Translation into viral polyprotein cleaved into functional units Mature virion then exits cell 19 Lecture Outline Emergence of a new pathogen Virology HIV Diagnostics HIV Vaccine Development Highly Active Anti-Retroviral Treatment (HAART) 20 Natural History of HIV infection Primary Infection Initial infection is in dendritic cells at mucosal site Dendritic cells carry virus to lymph node In lymph nodes, it rapidly replicates and disseminates to the rest of the body via bloodstream 2-4 weeks post infection 21 Natural History of HIV infection Acute Illness Mono-like illness includes fever, sore throat, general maculopapular rash High viral load (red line) Resolves without intervention Seroconvert 3-4 weeks Highly infectious Perform PCR or p24 antigen test on blood to diagnose before ~4 weeks https://www.cmaj.ca/content/194/45/E1541 Photographs of a 39-year-old man with acute HIV infection, showing (A) small, well- circumscribed, red maculopapular rashes (arrows) on his anterior thorax. (B) Close- 22 up image of the rash. Natural History of HIV infection Clinical Latency ~4 months, CD8 T cells and antibodies control acute phase 7-11 years in untreated asymptomatic patients Antigen/Antibody test 23 Natural History of HIV infection AIDS Opportunistic infections and malignancies CD4 T cells decline No longer stimulate B cells to produce antibodies and CTL to kill infected cells - 100% mortality Antigen/Antibody test 24 HIV Diagnostics P24 located in the core and antibodies against p24 are important diagnostically Found in blood and saliva 25 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2614444/ gure/F1 fi HIV Diagnostics ~40% of transmission occurs in people unaware of HIV+ status CDC recommends everyone 13-64 get HIV tested at least once, and if at higher risk then more often, and all pregnant women Risk factors: sex, sharing needles, syringes 26 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2614444/ gure/F1 fi Lecture Outline Emergence of a new pathogen Virology HIV Diagnostics HIV Vaccine Development Highly Active Anti-Retroviral Treatment (HAART) 27 HIV Vaccine Challenges 2007 Vaccine trial using Adenovirus type 5 - gag/ pol/nef vaccine found that people in the vaccine arm displayed higher risk of HIV infection than placebo arm 28 https://www.nature.com/articles/nature07352/ gures/2 fi HIV Vaccine Challenges HIV reverse transcriptase lacks proof reading mechanisms, introducing multiple errors into each new strand during each round of replication An infected person produces 100,000,000,000 new virions and ~34 billion viral variant - Mutational escape Designing a vaccine that induces broadly neutralizing antibodies and/or T cells against so many variants has proven daunting https://www.mdpi.com/ 29 HIV Vaccine Challenges After infection and integration into CD4 host DNA, HIV persists in a pool of cells HIV reservoirs - helper T cells and others - dif cult to eliminate reservoir Vaccines prevent disease, not infection, therefore any potential vaccine may exert its immunological function too late to prevent viral integration No known correlate of protection - almost everyone who is exposed becomes infected with near 100% mortality Elite controllers have been found that maintain suppressed viral levels without HAART, although still retain a low frequency of intact integrated HIV DNA copies in T cells 30 https://www.nature.com/articles/nature.2013.13971 Lecture Outline Emergence of a new pathogen Virology HIV Diagnostics HIV-1 Vaccine Development Highly Active Anti-Retroviral Treatment (HAART) 31 HIV Anti-viral targets With proper adherence to anti-viral medication, HIV viral load is reduced to undetectable levels, decreasing risk of transmission and increasing life expectancy 32 HIV Anti-viral targets Viral Entry inhibitors: block CCR5 binding Viral integrase inhibitors: prevent insertion of HIV genome into host chromosome Reverse transcriptase inhibitors - prevents conversion of RNA genome to DNA Protease inhibitors - block viral proteins at the point of membrane insertion MUST use combination therapy to avoid emergence of resistant virus 33 HAART impact on CD4 T cells Group A: uninfected controls Group B: Untreated, HIV+ Group C: HAART- treated, HIV+ 34 https://www.nature.com/articles/mi200835/ gures/1 fi Antiretroviral therapy 35 https://ourworldindata.org/hiv-aids Importance of Adherence Strict adherence to ART is critical for viral suppression and preventing resistance. As pharmacists, you may be involved in counseling patients on the importance of taking medications regularly and address barriers to adherence, such as side effects, cost, or complexity of the regime Poor adherence can lead to: Sub-therapeutic plasma HAART concentrations Development of resistance and cross-resistance (drugs in the same class) Failure of primary regimen and loss of immune function 36 https://i-base.info/guides/art-in-pictures/drug-levels-and-adherence Take Home Messages HIV likely emerged from chimpanzees in the early 20th century and mostly spread silently before being recognized and identi ed in the 1980's Virus infects CD4 T cells, leading to a drop in CD4 T cell levels, causing patients to become susceptible to opportunistic infections Diagnostically, nucleic acid testing on blood is used in the rst few weeks post-exposure (10-33 days) while antibody/antigen tests to p24 can be used in the clinical latency or AIDS phases HIV undergoes mutational escape with no known correlates of immunological protection, thus posing a challenge to vaccine development HIV medication must be taken as combination therapy and drugs are available that target multiple steps of the replication cycle 37 fi End of Lecture One “Muddiest point” - area of confusion? SUPER happy to answer questions - Of ce is 360D Dr. D. Science Hall! Seriously talking about this stuff is my favorite thing to do in life. Will return all e-mails within 24 hr period! 38 fi