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Recent Developments in AIDS Diagnosis & Treatment
Presented by Joyce Lee, Kobika Thiyagasothy & Stephen Yee
Overview
Introduction to AIDSDiagnosis of HIV-AIDSTreatment of HIV-AIDS Summary
Introduction to AIDS
What Is HIV/AIDS?
Human Immunodeficiency Virus (HIV) causes Acquired Immune Deficiency Syndrome (AIDS)
Origin of HIV HIV-2 from soty mangabeys HIV-1 from chimps
Viral Life Cycle
2 phases: Extracellular & Intracellular Virus targets CD4 Receptor and Co-Receptor
on T-helper cells Reverse transcription of viral genome into a
DNA copy followed by integration into host genome
New virions assembled and bud off from host
How Does HIV Spread?
Transfer of bodily fluids Hetero and homosexual sex Oral Sex Needle Sharing Transfusion of contaminated blood products Childbirth & Breastfeeding
HIV/AIDS Mechanism
Immune system battles with virus Depletion of helper T-cells Host becomes vulnerable to secondary
infections
HIV/AIDS Mechanism
3 Phases of InfectionI. Acute Phase
Initial spike in viral load Followed by host immune response
II. Chronic Phase Immune system remains highly activated Results in depletion of helper T-cells
III. AIDS Phase
AIDS as a Public Health Issue
First case in 1981 13 400 newly infected with HIV every day 8 500 die of AIDS everyday
Methods of Diagnosis
Symptom Diagnosis
Compromised immune system High vulnerability to opportunistic infections Severity of symptoms can encompass multiple
organ systems
Symptom Diagnosis
Pulmonary1. Pneumoncytis Pneumonia (PCP)2. Tuberculosis (TB)
Gastrointestinal1. Esophagitis2. Chronic Diarrhea
Salmonella, Shigella, Listeria, Campylobacter
Symptom Diagnosis
Neurological1. Taxoplasmosis2. Progressive Multifocal Leukoencephalopathy
(PML) Tumors
Epstein-Barr Virus (EBV) Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) Human Papillomavirus (HPV)
Symptom Diagnosis
Antibody Tests
Enzyme Linked Immunosorbent Assay (ELISA) High degree of sensitivity for screening
Western Blot Test Viral proteins are separated first
Rapid Antibody Test Qualitative immunoassays OraQuick, Orasure & UniGold
Antibody Tests
Enzyme Immunoassays (EIA) 3rd Generation Wells contain recombinant proteins or synthetic
peptides Also contains anti-HIV IgG and IgM antibodies Change in colour indicates presence of anti-HIV
IgG and IgM Faster detection of HIV infection than previous 2
generations
Antigen Tests
P24 antigen test for HIV specificity A capsid protein of the virus Very short window of viability
Antibody Tests
Nucleic Acid-Based Tests
Has been used to detect diseases and genetic implications
Detection of target HIV gene sequences PCR is one method used to detect diagnostic
DNA fragments
Nucleic Acid-Based Tests
Polymerase Chain Reaction (PCR) uses heat stable DNA polymerase and 2 primers to amplify a target sequence
Real-time PCR Assays: Quantitative Method to measure PCR product as it is produced Allows quantification of number of pathogens in a
sample
Nucleic Acid-Based Tests
Abbot RealTime HIV-1 Assay Nested set of hybridization probes of various
lengths▪ Fluorescein (FAM) label at the 5’ end▪ Dabcyl or BHQ 1–dT at the 3’ end
Nucleic Acid-Based Tests
• In absence of target sequence, the quencher in close proximity of FAM absorbs the fluorescent signal
In presence of target sequence, the hybridization probe binds to target sequence Quencher separates from FAM resulting in
fluorescent emission
Antibody Tests
Enzyme Immunoassays (EIA) 4th Generation Well coated with HIV antigen and P24 antibody Colour change indicates anti-HIV antibody or P24
antigen Detection of P24 allows for earlier diagnosis of HIV
infection
Algorithm Tests
Future Algorithms Testing algorithm proposed to use the most
sensitive test possible with assays that differentiate HIV-1 from HIV-2 antibodies
If reactive for Ag / Ab but negative for antibodies, then tested for HIV-1 RNA
RNA establishes diagnosis of AHI which alerts doctors for urgent care
SIMBAS
Self-Powered Integrated Microfluidic Blood Analysis System (SIMBAS) Future cell powered chip Works like pregnancy test but checks for HIV or TB Chip separates plasma from blood cells and
detects if Vitamin B7 or Biotin was present Diagnosis in a matter of minutes
Methods of Treating HIV/AIDS Patients
Treatment
Isolated to homosexuals, hemophiliacs and heroin users
No actual cure Prevention based treatment
Sexual Education Drug Awareness
Treatment
AZT Structure similar to normal nucleotide Thymidine Has a –N3 group which interrupts DNA synthesis Proved effective and halted loss of macrophages
and T-cells In 1989 patients stopped responding Mutations were located in active sites of reverse
transcriptase
Antiretrovirals
Delay onset of infections Lifetime commitment drug plan Determined necessity by CD4 test Goal is to keep HIV in the body at a low level
Antiretrovirals
5 Major ClassesI. Protease InhibitorsII. Fusion or Entry InhibitorsIII. Integrase InhibitorsIV. Nucleoside/Nucleotide RT InhibitorsV. Non-Nucleoside RT Inhibitors
Combination Therapy
AIDS is virus with high fidelity Capable of developing resistance quickly
Cross Resistance Salvage Treatment
Side-Effects
Drug Specific Side-Effects Efavirenz causes psychiatric symptoms Protease inhibitors raise cholesterol and
triglyceride levels High Blood Pressure Susceptibility to Hepatitis infections
Side-Effects
Common antiretroviral symptoms Diarrhea Nausea & Vomiting Rashes Lipidystrophy with Loss or Gain of Fat Lipid Abnormalities
Maturation Inhibitors
Immature HIV particles composed of Gag precursor proteins
Mature infectious particle contains dense nucleoprotein Nucleocapsid and RNA
Bevirimat delays or blocks mature infectious particles from forming
Maturation Inhibitors
Maturation Inhibitors
Integrase Inhibitors
Raltegravir Dolutegravir Successful HIV replication requires 3 enzymes
Reverse Transcriptase, Integrase & Protease Inhibiting integrase blocks integration of HIV-1
DNA to host genome Prevents HIV replication and infection of new
cells
Treatments
CCR5 ∆32/ ∆32 Stem Cell Transplantation Patient remains without any sign of HIV infection
after successful transplantation Size of viral reservoir was reduced over time Cells of persons homozygous for the CCR5 gene
variant ∆32 are naturally resistant to R5 HIV strain
Treatments
Immunotherapy HIV infection results in CD4+ T-cell deficiency Correlation between a low CD4+ T cell count with
higher morbidity Helps maintain high level of CD4+ T-helper cells
Treatments
The Thai Trial $105 million, 6 year trial in Thailand Experimental Vaccine 31% effective in preventing
HIV infection RV144 a combination of ALVAC and AIDSVAX Study group includes low-risk heterosexual adults
Time to Go Home
Conclusion
Permanent cure unlikely because of rapidly reproductive nature of HIV
New combinatorial drug therapies are on the horizon
Still an importance on preventative measures
References
“AIDS & HIV Information from AVERT.org” AIDS & HIV Information. 10 January 2011. AVERT. 12 January 2011 http://www.avert.org/.
Nettleman, Mary. “HIV/AIDS Symptom, Treatment, History, Transmission, Diagnosis, Prevention” eMedicineHealth. 02 January 2011. eMedicineHealth. 12 January 2011 <http://www.emedicinehealth.com/hivaids/article_em.htm>.
Harrell, Eben. "Trial: AIDS Vaccine Reduces Risk of HIV Infection - TIME." TIME Magazine. 25 Sep 2009: n. page. Web. 29 Jan. 2012. <http://www.time.com/time/health/article/0,8599,1925957,00.html
Levy, Yves, Christine Lacabaratz, Laurence Weiss, Jean-Paul Viard, Cecile Goujard, Jean-Daniel Lelièvre, François Boué, Jean-Michel Molina, et al. "Enhanced T cell recovery in HIV-1–infected adults through IL-7 treatment." American Society for Clinical Investigation. 119:4 (2009): pp 997-1007.
Bernard M, Branson. "The Future of HIV Testing." Journal of Acquired Immune Deficiency Syndromes. 55. (2010): pp 102-105. Print.
Evering, Teresa H., and Martin Markowitz. "HIV-1 Integrase Inhibitors." PRN Notebook. 13. (2008): pp 1-9.
Yang, Sarah. "New blood analysis chip could lead to disease diagnosis in minutes." UC Berkeley News Center. N.p., 16 Mar 2011. Web. 15 Jan 2012. <http://newscenter.berkeley.edu/2011/03/16/standalone-lab-on-a-chip/>.
Freeman, Scott, and Jon Herron. Evolutionary Analysis . 4th. Upper Saddle Riber: Pearson Education, 2007. 3-37. Print.
Huang, Shihai, John Salituro, Ning Tang, Ka-Cheung Luk, John Jr Hackett, Priscilla Swanson, Gavin Cloherty, Wai-Bing Mak, John Robinson, and Klara Abravaya. "Thermodynamically modulated partially double-stranded linear DNA probe design for homogeneous real-time PCR." Nucleic Acids Research. 35.16 (2007): 1-12. Print.
NIAID. "Classes of HIV/AIDS Antiretroviral Drugs." 26 03 2009: n. page. Web. 29 Jan. 2012. <http://www.niaid.nih.gov/TOPICS/HIVAIDS/UNDERSTANDING/TREATMENT/Pages/arvDrugClasses.asp&xgt;.
Salzwedel, Karl, David Martin, and Michael Sakalian. "Maturation Inhibitors: a New Therapeutic Class Targets the Virus Structure." AIDS. 9. (2007): 162-72. Print.
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