IMMUNOLOGY OF HIVINFECTION AND AIDSInteractions between HIV and the
immune system
Basic Statistics – United States In the U.S. in 2010, 1.1 million people were living
with HIV infection. About 50,000 people become infected with HIV each year in the U.S.
Through 2010, 1,129,127 acquired immunodeficiency syndrome (AIDS) cases were reported.
Of those, 619,400 have died (current death rate ~17,000 per year). (Worldwide, 25 million have died.)
Worldwide, it is estimated that over 34 million people are infected with HIV. ~2.7 million were infected with HIV in 2010, including ~390,000 children under 15.
~1.8 million died of HIV/AIDS in 2010.
http://www.cdc.gov/hiv/topics/surveillance/resources/reports/http://www.who.int/mediacentre/factsheets/fs360/en/index.html
Trends in Annual Rates of Death due to the 9 Leading Causes among Persons 25−44 Years Old, United States, 1987−2009
Note: For comparison with data for 1999 and later years, data for 1987−1998 were modified to account for ICD-10 rules instead of ICD-9 rules.
Estimated numbers of AIDS cases in children <13 years of age, by year of diagnosis, 1992–2007—50 states and the District of Columbia
Total = 47,129 new cases
Groups representing <2% of total are not shown. Source: CDC, statistics_basics_factsheet.pdf
LENTIVIRUSESVirus DiseaseHuman Immunodeficiency Virus (HIV)
Human AIDS
Simian Immunodeficiency Virus (SIV)
AIDS in monkeys
Visna/maedi Virus Neurologic disease in sheep
Equine Infectious Anemia Virus (EIAV)
Horse anemia
Caprine Arthritis/Encephalitis Virus
Goat encephalitis
HIV Proteins
Envelope (env) glycoproteins - gp160 precursor gp120, gp41
Group antigen (gag) proteins - p24 (core), p17 (scaffold)
Polymerase (pol) proteins - p66 and p51(reverse transcriptase), HIV protease, p32 (endonuclease)
Regulatory proteins - tat, rev, vif, nef
HIV Replication
Binding and Internalization Reverse transcription & DNA incorporation Transcription & translation of viral genes Assembly and budding Cell activation and its role in viral
replication
CCR5,CXCR4Coreceptors
Receptors involved in HIV Binding/Internalization
CD4 – gp120 binds to CD4 on T cells or monocyte/macrophage lineage cells, promoting removal of gp120 and internalization of virus
Chemokine receptors CCR5 and CXCR4 act as important coreceptors
The glycolipid galactosyl ceramide can also promote binding
Antibodies bound to HIV can enhance uptake of virus through binding to Fc receptors
HIV1-Bal HIV1-Bal+ CD4+17b
Dr. Jun Liu, Dept. of Pathology & Laboratory Medicine
gp120
gp41
Dr. Jun Liu
gp120 Fab 17b(binds coreceptor binding site)
CD4(solubleForm)
Chemokine Receptors that also act as HIV Coreceptors
CCR5Receptor for RANTES, Mip1α, Mip1βFound on macrophagesCoreceptor (with CD4) for Macrophage Tropic HIV32-CCR5 – 32 bp deletion mutation, decreases HIV
transmission and slows disease progression during HIV infection
CXCR4Receptor for stromal derived factor-IEnhances binding, internalization of Lymphotropic HIV
MIP-1P also affects HIV infection CCL3LI – encodes Migration Inhibition
Protein - 1αP (MIP-1αP), the major ligand for CCR5
MIP-1αP is a major inhibitor of HIV infection, may compete with HIV for CCR5 binding
Humans have varying number of CCL3LI gene duplications; individuals with low copy numbers are more susceptible to HIV infection
Science 307:1434-1440 (March 4, 2005)
Effect of activation on virus protein expression(as measured by reverse transcriptase activity)
Cell to Cell Transfer of HIV
Infected vs. Virus-Producing Cells
Autoradiographs showing grains over T cells infected with HIV (A) and those expressing HIV RNA and producing virions (B) Note that many more cells are infected than are actively producing virus particles.
Clinical Course of HIV Infection
Stage Viral Load Anti-HIV Antibodies
CD4+ Levels
Symptoms
Primary High + Variable 40-60% of patients
Asymptomatic (Stage 1)
Moderate/Low ++ Normal/High >500/µl
None
Early Symptomatic
(Stage 2)
Moderate + Low 201-499/µl
+
Late Symptomatic
(AIDS, Stage 3)
High + Very Low <200/µl
++
HIV+ people look like everyone else
HIV in body fluids
HIV-Infected Cells in Semen
Example – Maculopapular rash during early HIV Infection
http://medicalpicturesinfo.com/hiv-rash/
Viral Load during Stages of HIV Infection
Infections and malignancies that are common in AIDS
(Geha and Notarangelo,“Case Studies in Immunology”, Case 10: AIDS)
Progression to AIDS
Immune Responses AntibodyNeutralizingEnhancing
CD4+ T cellsLoss of helper, DTH, cytotoxic functionDecrease in cell numbers
CD8+ T cellsCytotoxicity - lysis/apoptosis
HIV-infected cellsUninfected CD4+ cells
Cell Antiviral Factor (CAF)
ELISA for detection of anti-gp120 antibodies
(Geha and Notarangelo,“Case Studies in Immunology”, Case 10: AIDS )
CD8 cytotoxic activity declines before decreases in CD4+ numbers
Effects of apoptosis: disruption of nucleus, organelles; DNA fragmentation
Immunotherapy and Vaccination
Immunotherapy Immune reconstitution Passive immunotherapy
VaccinationRecombinant gp160 (VaxSyn HIV-1)Recombinant live-vector vaccines (vaccinia, canarypox)Virus-Like Particles (VLPs) Peptide vaccines (V3 and CD4 binding regions) Live, attenuated HIV viruses Inactivated viruses
Vaccine target –gp120
V3 loop – most immunoprotective, but also highest variability
CD4-binding region – antibodies against this region may block binding of HIV to CD4 prevent infection of CD4+ cells
ProblemswithHIVVaccines
Animal ModelsAnimal Virus Result Used to study:Chimpanzee HIV-1 Latent Infection Vaccine efficacyMacaques SIV AIDS-like wasting
diseaseVaccine efficacy,therapy, pathogenesis
Rabbits HIV-1 Defective infection Latent infectionMice- HIV genometransgenic
-- AIDS-like illness Pathogenesis
Mice - tat transgenic -- Kaposi’s sarcoma CarcinogenesisSCID-human lymphoidcell chimera
HIV-1 AIDS-like disease Pathogenesis, therapy
Sheep Visna Chronicneurodegeneration
Lentivirus pathogenesis
Goats Caprine arthritis, encephalitis Lentivirus pathogenesisHorses EIAV hemolytic anemia Lentivirus pathogenesis
The Berlin Patient (Timothy Brown) – only person that has been ‘cured’ of HIV infection
Baylor College of Medicine, Sept. 23, 2011
Summary - Immunology of AIDS HIV-1 and HIV-2 infect CD4+ T cells, macrophages
and other cells, leading to virus production, cytolysis, or latent infection.
HIV infection progresses through primary, asymptomatic, early symptomatic, and late symptomatic (AIDS) stages.
Depletion of CD4+ T cells leads to profound defects in helper and DTH activities.
Antibody and cytotoxic lymphocyte activities combat HIV infection, but do not prevent progression.
Immunotherapy and vaccination strategies are under development.
http://www.cdc.gov/hiv/topics/surveillance/resources/guidelines/index.htm