HIV and AIDs/Antiviral Agents (7/`9))

Zhou Lecture 6 (Lecture 24)

What is Zika Virus? what are the signs? what diseases are associated?

enveloped, icosahedral, nonsegmented, ss + sense RNA virus of Flaviviridae

related to Yellow, dengue, and west nnile

Disease:

• microcephaly, severe brain malformations

• may cause gullain-barre syndrome

Signs: fever, rash, joint pain, conjunctivitis, muscle pain, headaches within 2 weeks of travel from an area with Zika

How do retroviruses with oncogenes replicate?

helper virus/cell transformation

how is Zika virus spread?

transmitted by daytime active Aedes mosquitoes (A aegypti, Albopictus)

mosquito bites

pregnant woman to fetus

sex with infected person

lab exposure

blood transfusion

NOT breastfeeding

how does zika affect people?

generally asymptomatic/mild symptoms

symptoms last several days-week

not sick enough to go to hospital

low fatality rate

how does Zika virus cause Gullain Barre syndrome (GBS)?

GBS: NS state where immune system damages the nerve cells(myelin sheaths), causing muscle weakness, sometimes paralysis

Strongly associated with Zika, but only small portion with ZIka get GBS

How is Zika treated?

no specific medicine or vaccine

treating symptoms:

• rest, drink enough fluids, do not take aspirin or NSAIDs

Prevention:

• destory mosquito habitats

• wear protective clothing

• avoid unsafe sex with potentially infected partners

review treatment and prevention of arboviral diseases

difficult to diagnose from symptoms and travel history

treatment: control fever, convulsions, dehydration, shock, edema

Vaccination

control: pesticide/insect repellents, protective clothing, stay indoors at night

what are the general properties of retroviruses? 3 subfamilies?

induce neoplastic diseases and AIDs in the host

many species

subfamilies:

• oncoviruses: acute, nonacute oncogenic virus

• lentiviruses: slow virus

  • neurologic, pneumonias, AIDs

• Spumaviruses: no pathological effects

Structure of retroviruses? A, B, C, D types?

spherical, 65-150nm diameter

viral genome: 2 identical RNA

Types:

• A: no nucleocapsid

• B: eccentrically located nucleocapsid

• C: centrally located nucleocapsid

• D: eccentric core, less gp

describe the structure of the retroviral genome

Gag: precursor polyprotein for capsidproteins

• Protease for processing the polyprotein

Pol: reverse transcriptase

Env: envelope protein

LTR: long terminal repeat

What is the difference between oncoviruses and oncogenes?

oncovirus:

• acutely oncogenic, usually defective

• slowly oncogenic,replication competent

  • human leukemia virus > leukemia

oncogenes:

• acute transformation

• not important for virla replicatoin

• numerous

• location variable

what is the difference between non-acute leukemia virus, acute transforming virus, and rous sarcoma virus structure?

nonacute leukemia virus: lacks an oncogene > slow cancer

acute transforming virus: contains an oncogene > rapid cancer

rous sarcoma virus structure: contains src (potent oncogene) > very rapid cancer

SEQ replication of a defective oncogenic virus

defective transforming virus defects cell

helper virus infects same cell

3 ways:
A) Cell gets both: transforming virus + helper virus

• It becomes a transformed virus-producing cell, making lots of virus.

B) Cell gets only the transforming virus

• It becomes a transformed cell (cancer-like),
  but cannot produce virus, because it lacks the helper.

C) Cell gets only the helper virus

• It becomes non-transformed, but produces helper virus only.

proto-oncogenes

normal cellular genes

highly conserved

share homology with viral oncogenes

differ in structure and activity from viral oncogenes: point mutations, truncations, constantly active

what are the 3 oncogene families?

cell surface receptors

cytoplasmic signaling intermediates

nuclear transcription factors

how are retroviruses and cancer associated?

retroviruses lead to tumor formation

oncogenes not necessary for replication

• constantly lost

• viral tumor mostly not infectious

retroviruses are tools for studying tumor formation

proto-oncogenes can be activated into oncogenes

What are AIDs? symptoms?

fatal immunodeficiency disease arising form infection of HIV and accompanied by some of the following symptoms

• opportunistic infection

• persistent fever

• unusual cancer — karposi sarcoma

• extensive wt loss

• chronic diarrhea

• neurological disorders

common symptoms: fever, loss of appetite, wt loss, extreme fatigue, englargement of lymph nodes

What are different types of AIDs?

malignancy: Kaposi’s sarcoma (skin and mucous membranes)

AID dementia complex: neurological abnormalities

pnemonia: pneumocystis carinii

encephalitis: toxoplasmia gondii

yeast infection

mononucleosis: cytomegalovirus

herpes simplex virus

What are some risk factors of HIV?

anal sex

HIV carriers in heterosexual sex

multiple sexual partners

blood transfusions and blood products

congenital and neonatal AIDs

medical and dental personnel

How does AIDs enter the body?

HIV enters through blood or sexual secretions via broken skin or mucous membranes, infects dendritic cells and macrophages under the skin, and then spreads to lymph nodes, bone marrow, and the bloodstream where it amplifies and disseminates.

What are some misconceptions of AIDs?

transmission by: inhalation, hand shaking, sharing public facilities, food, swimming

insect bites

no transmission among family members when blood transfer is not involved

HIV Life Cycle

Entry and integration

• HIV binds and fuses with host cell membrane

• viral ssRNA enters the cell

• reverse transcriptase converst ssRNA > ssDNA > dsDNA

• viral dsDNA moves into nucleus, viral DNA inserted into host chromosomes

Latent Period:

• provirus sits silently inside host DNA months-yrs

• immune system is triggered, provirus reactivated and produce viral mRNA

Assembly and Release

• viral mRNA translated into capsid proteins, enzymes and envelope proteins

• viral RNA and proteins assemble into new HIV particles

• bud off > kill lyses the host cell

How do virus levels, antibody levels, and CD4 T-cell counts change over the course of HIV infection?

HIV levels spike early, then drop and stay low for years before rising again in AIDS

antibodies appear after a few weeks and stay high

CD4 T-cells stay near normal for years but gradually decline and fall below 200 cells/µL in AIDS.

What are the primary effects of HIV infection?

destruction of T4 lymphocygtes

infection of brain tissues leads to inflammation

What are the Secondary Effects of HIV Infection

opportunistic infections:

• fungus infections: pneumocystis carinii pneumonia (PCP), widespread, usually harmless

• Protozoan infections: toxoplasmosis

• herpes infection, bacteria infections — tuberculosis

Cancers: kaposi sarcoma, herpesvirus-8 (KSHV)

Other: neurological problems, fatigue, wt loss

AIDs Test

detecting anti-HIV antibodies

• ELISA — false positive

• Western blot

  • false engative retest

• ID HIV: research phase

AIDs Therapy

no cure

control opportunistic and HIV infections

PCP: pentamidine, sulfamethoxazole-trimethoprim

CMV: ganciclovia, foscarnet

Fungal infection: fluconazole

kaposi sarcoma: alpha inferferon and chorionic gonadotropin

HIV: combination

supportive care

Anti-HIV Drugs

most effective drugs target HIV reverse transcriptase: AZT, ddI, 3TC, d4T

protease inhibitors, block maturation of HIV

combination therapy:

• drug resistance for single drug therapy

• HAARRT

• Other drugs: integrase inhibitors, viral fusion inhibitors, interferons

What is HAART?

highly active anti-retroviral therapy

Use two RT inhibitors and one protease inhibitors

significant reduction of death rate

HIV+ but healthy possible

high cost and toxic fx

HIV Drug Classes

non-nucleoside reverse transcriptase inhibitors (NNRTIs)

nucleoside reverse transcriptase inhibitors

Protease inhibitors (PIs)

fusion inhibitors

CCR5 antagonists (CCR5s — entry inhibitors)

integrase stand transfer inhibitors (INSTIs)

AIDS Prevention

sexual history of life style

monogamous, safe sex, no anal sex, no drugs, clean needles, nor needle sharing

AID testing: critical for control

What is the target of Remdesivir?

Remdesivir targets the viral RNA-dependent RNA polymerase (RdRP), which is essential for viral RNA replication.

What kind of nucleic acid do retroviruses contain?

Retroviruses contain RNA genomes, specifically two identical RNA molecules.

How many RNAs does each retrovirus have?

Each retrovirus carries 2 identical RNA strands in its virion.

What are the three basic genes the retroviral genome encodes?

Retroviruses encode gag (capsid proteins), pol (reverse transcriptase), and env (envelope proteins).

What is provirus?

A provirus is double-stranded viral DNA integrated into the host chromosome, remaining latent until activated.

retroviral DNA integrated from their RNA genome

What enzyme makes retroviral DNA from their RNA genome?

Retroviruses use reverse transcriptase to convert their RNA genome into DNA.

What is the unique aspect of retroviral replication compared with other viruses?

Retroviral replication is unique because the virus converts RNA into DNA and integrates into the host genome before producing new virus.

retroviruses make DNA from their RNA genome and integrate the viral DNA into host DNA

What is a retroviral LTR?

LTRs (long terminal repeats) are regulatory sequences at both ends of the retroviral genome used for integration and transcription.

transcription promoter that is crucial for viral replication

Are retroviral oncogenes required for viral replication?

No—retroviral oncogenes are not required for viral replication and are often lost because they do not contribute to viral fitness.

Where do viral oncogenes come from?

Viral oncogenes originate from host proto-oncogenes that retroviruses capture and modify during infection

host DNA

do non-acutely oncogenic viruses have oncogenes?

no, they do not cause cell transformation and tumor in a short period of time. They can cause tumor after a long latent period

What does aids stand for? What is the key problem in AIDs?

Acquired Immuno Deficiency Syndrome

immune deficiency, T4 lymphocyte depletion

What causes AIDs? Why are they non-progressors

Acquired Immuno Deficiency Syndrome
lack of the cytokine receptor and infection by a weakened mutant

Stages of HIV infection and disease

initial infeciton: vague, mononucelosis like symptoms

first antibodies detected 2 months after infection

asymptomatic incubation period: 2-15 yrs

disease: fever, swollen lymph glands, fatigue, diarrhea, wt loss, neurological syndromes, opportunistic infection and cancer

Is HIV an RNA or DNA virus?

RNA

What is AZT?

• A nucleoside reverse transcriptase inhibitor (NRTI)

• Inhibits HIV reverse transcriptase activity

What is HAART?

Highly Active Antiretroviral Therapy

• Uses two reverse transcriptase inhibitors

• Plus one protease inhibitor

How can AIDS transmission be prevented?

• Blood screening

• Clean needles

• Safe sex practices