Unit 4- HIV Flashcards

1
Q

What is the history of HIV?

A

Early 1980s, United States

  • Physicians in New York and California made the first observations of a new infectious disease of homosexual men.
  • Sudden appearance of rare skin cancer called Kaposi’s sarcoma
  • Atypical pneumonia caused by Pneumocystis carinii
  • CMV infections
  • Candiasis
  • Other observed opportunistic infections
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2
Q

What is (GRID) Gay-Related Immune Deficiecncy?

A

All observed individuals suffered from immune suppression.

1981: The syndrome was named GRID.
1982: The disease was renamed Acquired Immune Deficiency Syndrome (AIDS).
1983: 2,304 AIDS deaths
1985: Rock Hudson announced he had AIDS and died

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3
Q

Describe the discovery of HIV

A

Two research teams published results in the journal Science
Robert Gallo’s group, NCI, NIH, United States
Luc Montagnier’s team, Pasteur Institute, France
Both described retrovirus isolated from cultured T cells from lymph node biopsy of an AIDS patient
Upon investigation, Montagnier’s team was the first to isolate HIV.

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4
Q

What is HIV-1 and HIV-2?

A

HIV-1 isolated by Gallo and Montagnier’s teams was designated HIV-1.
Montagnier isolated another strain that is rare in the United States but endemic to Western Africa, designated HIV-2.
HIV-2 is significantly less infectious and progresses more slowly to AIDS than HIV-1.

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5
Q

Where did HIV come from?

A

House cat theory

Hunter theory (or crossing the species barrier theory)

Contaminated poliovirus vaccines theory

Colonization (or Heart of Darkness) theory

Conspiracy theory

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6
Q

What is Feline Immunodeficiency Virus (FIV)?

A

Lentivirus that affects domesticated housecats worldwide

  • causative agent of feline AIDS

RElated to HIV

  • similar proteins p24

Humans cannot be infected by FIV nor can cats be infected by HIV

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7
Q

What is the Hunter Theory?

(Most commly accpeted theroy)

A
  • HIV is a viral zoonosis.
    • Simian immunodeficiency virus (SIVcpz): virus related to HIV-1, that infects chimpanzees (native to Cameroon) thought to have crossed the species barrier.
    • Genetic sequences of SIVcpz and early HIV strains are nearly identical
    • Naturally infected chimps were killed for food (bushmeat) and eaten; their blood entered cuts or wounds on the hunter.
  • Subsequently, SIVcpz adapted to become HIV-1.
  • Plasma sample taken from a male in Congo in 1959 found to be seropositive for HIV and contain HIV genetic material
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8
Q

What is the contaiminated Vaccine Theory?

A
  • Initial spread of HIV-1 occurred in Africa during large-scale vaccination campaign
  • Multiple patients inoculated with same syringe creating potential for SIV to mutate and spread
  • Alternatively, oral polio vaccine suggested to be contaminated with SIV
  • Erroneous belief that vaccine was produced in kidney cells from SIV-infected chimpanzees
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9
Q

Where did HIV-2 Originate?

A
  • HIV-2 entered the human population as a zoonosis (like HIV-1).
  • Sooty mangabeys are native to Guinea Bissau, Gabon and Cameroon and naturally carry SIVSM.
  • SIVSM from sooty mangabeys (an Old World Monkey) likely evolved into HIV-2 when humans acquired it from hunting sooty mangabeys for food and through contaminated blood transfusions and mass vaccination efforts.
  • 10% of the general population in Guinea Bissau is HIV-2 sero-positive.
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10
Q

What ist he AIDS pandemic?

Patient Zero vs. The earilest AIDS Cases

A
  • Who was patient zero?
  • Randy Shilts book, And the Band Played On, proposed that a homosexual French-Canadian flight attendant who died of AIDS in 1984 was patient zero.
  • Unprotected sex with ~2,500 partners
  • HIV had been found in blood samples and frozen tissues older than the 1980s.
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11
Q

What is HIV transmission?

A
  • HIV is present in blood, semen, vaginal fluids, breast milk, saliva (low levels), and tears (low levels).
  • Most common ways HIV can be transmitted are:
    • Anal and vaginal intercourse
    • Sharing of contaminated needles (IV drug users)
    • Blood transfusions (using infected blood or blood products)
    • Accidental needlestick injuries
    • Congenital AIDS
    • Sharing HIV-contaminated tattoo needles, razors, acupuncture needles, ear-piercing implements
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12
Q

What are the rare routes of HIV transmission?

A
  • Organ transplants
    2009: First documented case of HIV transmission from a living donor in the United States
  • Incident spurred new testing recommendations by the CDC
  • Pre-mastication (pre-chewing food)

Three cases reported in the United States
Parent or caregiver pre-masticated food for infants

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13
Q

Can Kissing and Oral SEx Transmit?

A
  • Social kissing is not high risk behavior
  • Open mouthed kissing increases risk
  • The risk increases if the infected person has canker sores or lesions in his/her mouth
  • Oral sex poses similar risks
    • HIV infected T lymphocytes from semen may enter abrasions or lesions int he mouth
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14
Q

What are the ways HIV is not transmitted?

A
  • Soap and water easily disrupts HIV.
  • HIV is highly susceptible to drying out.
  • Contact with sweat, saliva, or tears has never been shown to result in transmission.
  • Handshaking and hugging has not resulted in transmission.
  • Mosquitoes or other insects cannot transmit HIV.
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15
Q

How do you Prevent HIV?

A
  • Abstinence from sex
  • Barrier methods (condoms)
  • Microbiocides
    • Gels, creams, genetically engineered probiotics
    • Fusion and replication inhibitors
  • Pre-exposure prophylaxis (PREP) reduces risk
    • antiviral drug tenofivir (RT inhibitor)
  • Post-exposure prophylaxis (PEP reduces risk)
    • Antivirals given within 48 hours of exposure
    • 2-3 drugs given over 4 weeks
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16
Q

Talk about AIDS in Africa?

A

Africa, the world’s largest continent, has been hit harder by HIV/AIDS than any other region of the world.
Poverty, limited access to antivirals, too few healthcare workers
Majority of infected aged 15-49
Each day in Africa:
6,600 people die of AIDS.
8800 people are infected with the HIV virus.
1,400 newborns are infected with HIV virus during birth or through breastfeeding.
At least 12 million children have lost one or more parents to AIDS.

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17
Q

What are some countries in Africa Stabiliizing?

A

HIV incidence has fallen by more than 35% between 2001 and 2009 in 22 sub saharan countries.

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18
Q

What are the hotspots in worldwide HIV epidemic?

A

HIV incidence increased by more than 25% in 5 countries in Eastern Europe and Central Asia between 2001 and 2009.
Primary route of transmission is intravenous drug use.
Molecular analysis of HIV strains isolated from people in Belarus, Russia, Kazakhstan, and other former Soviet Union countries evolved from southern Ukraine.
Followed heroin trading routes

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19
Q

Describe AIDS in China

A

Estimated 740,000 people living with HIV in China
48,000 new HIV infections per year
2009: China reported that AIDS had become the country’s leading cause of death
Home to one of the largest injection drug user populations in the world
Blood product donors and recipients account for 10.7% of HIV infection (2005)
High degree of stigmatization & discrimination of people living with HIV in China

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20
Q

What is the general epidemiology?

A

HIV cases and deaths among adults adn adolescents diagnosed with AIDS declining since 1993.

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21
Q

How does AIDS/ HIV play a role in U.S. correctional faciliites?

A

Activities in preisions that pose a risk for HIV transmission

  • Homosexual activity
  • Intravenous drug use
  • Tattooing and body piercing
  • Sharing of tooth brushes and shaving equipment
  • Incidents of violence
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22
Q

How is AIDs and Seniors in the US relate?

A

11%–17% of people living with HIV are 50+ years old.
Between 1990 and 2001, cases in seniors quintupled.
24%–30% of men and women ages 60–74 report they are sexually active.
Lack of safe sex practices and disclosures of sexual history
Erectile dysfunction drugs such as Viagra, Cialis, and Levitra has been shown to be associated with higher risk of STDs, especially HIV transmission.
First in-depth study on older adults with HIV (ROAH) over age 50 was released in 2006.

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23
Q

What are the barriers to HIV Diagnosis in Seniors

A

The symptoms of chronic illnesses in older adults resembles those of AIDS:

  • Night sweats and hot flashes
  • Weight loss or fatigue
  • Respiratory problems
  • Skin rashes
  • Flulike symptoms or diarrhea
  • Chronic pain or numbness
  • Early signs of dementia

Healthcare providers rarely think to test for HIV in older adults

24
Q

What are the clinical symptoms?

A

Three Phases of HIV-1 Infection
Primary HIV-1 infection
Chronic asymptomatic phase of infection
AIDS

25
Q

What is Primary HIV- 1 Infection?

A

Period after infection but before the development of detectable antibodies against HIV-1
Illness resembles “mono” or the flu
50% are asymptomatic

26
Q

What is Chronic Asymptomatic Phase?

A

Neither signs nor symptoms of the disease present
This phase typically lasts an average of 10 years
Typical progressors
Rapid progressors (10-20%; AIDS within 5 yrs)
Slow progressors (5-15%; AIDS free for > 15 yrs)
Long-term progressors (1%; no signs of disease)
Frequency of opportunistic infections increases as CD4 T cell counts drop below 200 cells/mL

27
Q

What is AIDS?

A

Without anti-retroviral therapy, the patient will die within 2–3 years.
As T-lymphocyte counts decrease below 50 cells/µl, the number of opportunistic infections increases.
AIDS patients also suffer from malignancies such as non-Hodgkin’s lymphoma.
Wasting syndrome is also common- a loss of more than 10% of body weight due to fever or diarrhea for more than 30 days.
AIDS patients are managed with antimicrobial prophylactic regimens.

28
Q

What is the Lab diagnosis of HIV?

A

HIV isolated in 1983
First commercial antibody detection tests were available in 1985.
Today, most clinical labs screen for HIV-1 and HIV-2 using an ELISA test (specimen is a patient’s blood sample).
All classes of anti-HIV antibodies are detected with these assays.

29
Q

What is HIV ELISA test?

A
  • Requires 2 doctor visits
    • # 1. Blood drawing and pretest counseling
    • # 2. Test results and additional counseling if needed
  • Performed by healthcare worker, tests results within 5–30 minutes
    • e.g., done on women in labor before delivery to determine infection status
    • patients following an accidental needle stick injury
  • “False negative” window- 3 weeks to 6 months between time of infection and test
    • 97% of people seroconvert by 3 months after infection
  • Positive ELISA tests must be confirmed by Western blot
30
Q

What is an HIV Western Blot?

A
  • Confirmatory test to exclude false-positive results
  • Nitrocellulose membrane is probed with patient serum
  • If the patient has been exposed to HIV, + bands will be observed on the Western blot
31
Q

What is HIV home testing Sysmtems?

A
  • FDA approved first system in 1996
    • Home Access HIV-1 Test System
  • Uses simple finger prick of blood sample
    • Place on filter paper
    • Mail in for laboratory testing
  • Confidential results obtained through toll-free phone number and post-test counseling is available
32
Q

What is mandatory testing for HIV?>

A
  • ~ 1 in 4 of the 1 million Americans infected with HIV don’t know they are infected.
  • This group is most responsible for the spread of HIV.
  • CDC released voluntary testing guidelines in 2006 that would apply to every American, ages 13–64.
33
Q

What are the gentic variation groups?

A
  • HIV mutates rapidly
  • Three distinct groups of HIV-1 based on genetic similarities
    • M (Major) group
    • O (Outlier) group; W. Africa
    • N (New) group
  • M group is further divided into clades or subtypes: A, B, C, D, F, G, H and K
  • Two viruses of different subtypes can infect the same cell
  • Circulating recombinant forms (CRFs)
34
Q

What is the HIV Virus Life Cycle?

A
  • Retroviridae family
  • Lentivirus genus (from Latin word lenti, for “slow”)
  • Cause slowly progressive, inflammatory diseases
  • HIV particles are 100–200 nm icosahedron-shaped sphere surrounded by an envelope
  • Envelope contains glycoproteins gp120 and gp41 spikes
  • Matrix proteins located below the envelope
  • Two copies of genome (+) ssRNA, cellular tRNAlys bound to each genome, which acts as a primer for RT
  • Reverse transcriptase (RT; p64) and integrase (p34) bound to viral genome
  • Protease (p10) also found within nucleocapsid of virus particle
35
Q

What is HIV-1 Entry?

A
  • HIV infects CD4+ T lymphocytes and will lyse them during a productive infection.
  • HIV infects other cells but does not lyse them:
    • Natural killer cells
    • CD8+ killer T-cells
    • Macrophages
    • Cell of the nervous system (e.g., astrocytes, neurons, glial cells, and brain macrophages)
    • Dendritic cells
36
Q

What is HIV Entry?

A
  • Early course of infection: HIV infects macrophages
  • Later in the course of infection: HIV infects T lymphocytes
  • The rapid progression to AIDS is associated with a switch in co-receptor preference.
  • HIV enters cells via a cellular receptor and co-receptor
  • Major cellular receptor: CD4 present on T-lymphocytes (also present in low concentrations on macrophages)
  • Co-receptor on T lymphocytes: CXCR4 (fusion)

Co-receptor on macrophages: CCR5

37
Q

What is HIV entry and uncoating?

A
  • gp120 of the virus interacts with CD4.
  • Subsequently, HIV gp120 and gp41 undergo a conformational change, causing a co-receptor reaction.
  • The virus anchors into the membrane of the CD4+ cell.
  • HIV gp41 changes into a coiled shape, bringing the virus and cell membrane together, allowing them to fuse, resulting in entry and uncoating.
38
Q

What is Reverse transcription of HIV RNA?

A
  • HIV RT binds to tRNAlys on the viral genome and initiates DNA synthesis
  • Refer to Chapter 10 (retroviral genome replication)
  • When reverse transcription is complete, the final product is dsDNA flanked by LTRs at each end of the viral genome.
  • The viral DNA is transported to the nucleus of the cell where the viral genome may be integrated into the host cell’s chromosomal DNA.
39
Q

What is HIV Proviral Integration?

A

Proviral integration is catalyzed by the integrase (p32) protein.
p32 is packaged in the original HIV particle.
HIV can latently infect cells.
T cells in the gut
The latent reservoirs are one of the main barriers to elimination of HIV infection.
During a production infection, HIV-1 is reactivated and the completion of the life cycle occurs.

40
Q

What is HIV-1 Transcrtiption?

A

HIV-1 utilizes the host cell’s transcription and translational machinery.
The proviral DNA is transcribed from a single promoter in the 5′ LTR into a 9 kb viral RNA transcript by the cellular RNA polymerase II.
HIV-1 tat and rev regulate gene expression.

41
Q

What is HIV TAR?>

A
  • TAR is located at the 5′ end of all HIV RNAs.
  • The binding of tat to TAR increases the transcription rate from the HIV LTR at least 1000-fold.
  • rev binds to the RRE element, facilitating the export of unspliced and incompletely spliced viral RNAs from the nucleus to cytoplasm.
  • Some full-length viral mRNAs are packaged into virions following transport into the cytoplasm.
  • Other viral mRNAs are spliced within the nucleus to form mRNAs that are translated into the different viral proteins.
42
Q

What is the translation of HIV proteins?

A

Cellular ribosomes translate proviral mRNA into viral proteins.
Gag gene and the gag and pol genes together are translated into one large precursor polyprotein cleaved by a viral encoded protease.
Full-length env, gp160 is transported through the Golgi where it is glycosylated and cleaved by a cellular protease into gp120 and gp41 to form mature envelope proteins.
Mature gp120 and gp41 are targeted to the surface of the infected cell.

43
Q

What is HIV-1 Assembly?

A
  • HIV-1 virion components (e.g., the viral RNA, gag, pol, and env proteins) are assembled at budding sites located at the cellular plasma membrane.
  • The gag and gag-pol proteins are cleaved by an HIV specific protease to form mature virus particles.
44
Q

Describe the HIV Virus Life cycle overview

A
45
Q

What is HIV & Immune Evasion?

A
  • Destruction of virus-specific CD4 T helper cells
  • Antigenic escape variants
  • Hijacking of cellular complement inhibitors
  • HIV Nef downregulates expression of MHC class I
  • HIV Tat upregulates Bcl-2 in infected cells; prevents apoptosis
  • HIV can also trigger apoptosis to facilitate spread
  • New mechanisms continued to be discovered!
46
Q

What is the cellular pathogenesis?

A
  • Ultimately, HIV causes AIDS by depleting CD4+ T helper lymphocytes.
    • Weakening of the immune system
    • Body cannot stop infections or remove cancer cells
    • Opportunistic infections
  • HIV causes syncytia formation
  • AIDS dementia complex
    • Occurs in 20% of infected individuals
    • Symptoms:
    • Impairment of cognitive reasoning (e.g., short-term memory problems and concentration)
    • Behavior changes (apathy, withdrawal, irritability, depression, personality changes)
    • Motor performance (clumsiness, tremors, leg weakness)
47
Q

What is HIV Human Genetics/Resistance: The smallpox Hypothesis?

A
  • Individuals who are homozygous for a defective CCR32 gene are virtually resistant to HIV infection.
  • two defective copies are inherited, one from each parent
  • Individuals who are heterozygous for the defective CCR532 gene progress more slowly to AIDS
  • only one defective copy inherited
48
Q

What is CCR5(delta)32?

A
  • CCR5 gene is missing 32 base pairs.
  • Codes for a truncated protein that is not detected on the cell surface
  • HIV gp120/gp41 cannot attach to it to infect cells
49
Q

What are the HIV resistance: Population Statistics?

A
  • European populations
  • 5%–14% heterozygous CCR532
  • 1% homozygous in some populations such as Caucasian North Americans
  • The CCR532 allele is almost absent in African, Asian, Native American Indian, and Middle Eastern populations.
50
Q

Where did the resistance allele come from?

A
  • Chemokine receptors play a central role in the immune response against many pathogens.
  • Time is needed for natural selection to increase the frequency of a rare allele.
  • People with CCR532 survive without immune system problems because other chemokines compensate for CCR5 (e.g., CXCR4 or CCR2).
  • Major infectious diseases in history (selective pressures)
    • Bubonic plague
    • Smallpox
    • Syphilis
    • Tuberculosis
51
Q

What is the Popular Theory?

A
  • CCR532 led to increased survival during smallpox outbreaks that occurred in 14th century Europe.
  • During this time, smallpox outbreaks were ongoing, allowing for continuous natural selection.
  • The CCR532 genetic variant was an unintended but welcomed consequence of smallpox.
52
Q

What is involved in managing HIV Patients with Antiviral Therapy?

A
  • CD4+ T Lymphocyte Counts
    • Less than 200 per µl plasma
  • Virus load monitoring
    • Used to make recommendations for antiviral treatment of patients
    • Measure HIV-1 RNA copies per ml of plasma
    • 100,000 copies per ml of plasma = clinical AIDS
    • An absence of detectable RNA copies suggests a slower progression to AIDS
  • Viral set point: viral load of person infected with HIV, which stabilizes after acute infection
    • Reached after immune system has developed HIV antibodies
    • The higher the set point, the faster the progression to AIDS
    • The lower the set point, the longer the disease remains in clinical latency
53
Q

What is HIV antiviral Therapy?

A
  • Zidovudine (AZT), a thymine analog, RT inhibitor first approved HIV-1 treatment
  • Drug resistance to AZT emerged
  • 1996: David Ho
  • HAART, Highly Active Retroviral Therapy—use of at least 3 compounds simultaneously to block HIV RT, protease, entry/fusion, integrase, etc.
54
Q

What are the Five Classes of HIV patients: Antiviral Therapy?

A
  1. Non-nucleoside (RTNNI) or nucleoside reverse transcriptase (RTNI) inhibitors of HIV RT; addition of faulty nucleotides; competitive substrate inhibitors
  2. Protease inhibitors that inhibit HIV maturation by blocking an HIV-specific protease, resulting in noninfectious virus
  3. Fusion inhibitors that block HIV fusion of viral gp41 protein and the host cell membrane
  4. Integrase inhibitors block HIV p32 activity, abolishing integration of the proviral DNA copy of HIV into the host cell chromosome
  5. CCR5 blocking inhibitor block viral attachment
55
Q

What is the progression of HIV infection based on T-cell Counts and viral loads?

A
  • Set point= viral load which stabilizes after acute HIV infection
  • Reached after development of antibodies
  • Higher the set point, the faster the progression to AIDS
56
Q

Is an HIV Vaccine Possible?

A
  • Still no HIV vaccine
  • An AIDS patient harbors 100 million genetically distinct variants of HIV.
  • HIV variants can escape both antibody and T-cell immune responses.
  • Will a vaccine be able to cope with this variability?
57
Q

How is the HIV Virion more complicated?

A
  • HIV particles carry numerous host-derived proteins within the HIV envelope.
  • Many serum proteins are bound to the HIV particle.
  • Many of the original gp120 spikes have been lost.
  • This interferes with host antibody responses toward the virus.