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