L5 Flashcards by Tyler Brown

4H club” risk group retrovirus

Homosexual men, heroine addicts, Haitians, and hemophiliacs (“4H club” risk group) began dying of normally-benign opportunistic infections in U.S., defining a new disease, “acquired immune deficiency syndrome” (AIDS)

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1986: HIV-2 discovered in West Africa. HIV-2 RNA is

sequence similar (40%) to HIV-1. HIV-2 is mostly a heterosexual disease.

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HIV appears to have evolved (genetic evidence) from

simian virus in Africa (SIV) and spread through the rest of the world due to an increasingly mobile population and aberrant sexual behaviors. Theory: SIV > HIV-2 > HIV-1 with initial human infection ~ 1930.

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Retroviruses Have a unique

replication cycle

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Retroviruses are

Ubiquitous in vertebrates

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Retroviruses - Many are

benign, causing little to no impact on the host cell or host animal

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Retroviruses can have significant

pathogenicity causing disease and cancer

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retroviruses Spumaviruses do not cause

human disease

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Retroviruses make

Make “foamy” structures insidethe cell

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Retroviridae: two subfamilies

Orthoretroviridae

Spumaviridae

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Retrovirus genome

Genome: (+)ssRNA

Diploid, identical copies

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Retrovirus Virion:

enveloped

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Historically, retroviruses were characterized by

nucleocapsid structure & location in the particle

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Retrovirus Genome contents now used to classify retroviruses as

simple or complex

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Simple retroviruses only encode the

Gag, Pro, Pol, and Env genes

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Retrovirus Replication Cycle

Attachment
Entry
Reverse transcription
ssRNA genome to dsDNA
Integration
Virus dsDNA into host  making provirus
Transcription from provirus
Translation
Assembly
Release
Maturation – protease activity

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Reverse transcription Defining feature of

retroviruses

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RT Initiates once nucleocapsid is in

cytoplasm

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RT needs higher levels of

NTPs present

Low NTP levels prevent reverse transcription

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RT Occurs within a

large complex similar to nucleocapsid

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Infection cannot progress

if reverse transcription does not occur

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Reverse transcription is

promiscuous between genome copies

Silent” when copies are identical

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Many different recombinations when different genomes are in the

virion

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Retrovirus Integration

Must access the nucleus
Access during mitosis – requires dividing cells
Importation (mechanism unknown) – can infect non-dividing cells

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Retroviruses have 3’ end

processing of dsDNA

Retrovirus Attack

target DNA, nick created | Host repair

Integration of virus DNA is

permanent, no mechanism to remove it

If integrated into the germ-line then

provirus is inherited and is called “endogenous”

Integration may disrupt

host genes causing disease such as cancer

Integration identified oncogenes

Transcription factors Secreted growth factors Growth factor receptors Cell signal transduction pathways

Many defective viruses are made during

replication

Defective viruses are missing at least one of

gag, pol, or env

Retrovirus Require complementary infection to make

progeny

Can carry host genes,

tumorigenic when they carry oncogenes

Many retrovirus infections are

benign

Retroviruses usually

Usually not cytopathic

Retroviruses usually have

Little impact to cell replication & physiology

Chronic infections exert small demand on

cell and host resources (few percent of cell RNA and protein)

Retroviruses Do cause

viremia and elicit an immune response, but host animals can live normal lives for many months or years

Viruses are never eliminated by the

host response

Slow retroviruses (e.g., leukemia viruses)

Effect is like high-level mutagenesis | Eventually results in tumorigenesis

Cytopathic retroviruses

Minority of retroviruses carry cytopathic genes | Cause tissue damage directly

Acute transforming viruses

Induce rapid tumor formation Carry host genes – mitogenic or antiapoptotic Often replication defective because host gene replaces an essential gene

Human T-Cell Leukemia Virus Four distinct types (1, 2, 3, 4)

HLTV-1 most often associated with humans

HTLV

Deltaretrovirus

HTLV First isolatedin patient with

cutaneous T-cell lymphomain the late 1970s

HTLV-1 Transmission - person to person

Mother-child via breastfeeding (endemic areas) Sharing needles for drug users Blood transfusions Sexual transmission (less efficient)

HTLV-1 transmission Within the host

Highly cell associated | Primary mode for spreadis contact between infected and naïve cells

HTLV- 1 Adult T-Cell Lymphoma/Leukemia (ATLL)

Following mucosal exposure

HTLV-1 disease occurs

Occurs in 2-4% of cases

HTLV-1 latent period

30-50 years

HTLV-1 infects

Infects memory T-cells

HTLV-1 Antigen activation triggers

transcription of provirus

HTLV-1 Virus Tax protein & othersstimulate

cell proliferation

HTLV-1 Cells become transformed

generating tumors | With or without virusprotein expression

HTLV-1 Associated Myelopathy / Tropical Spastic Paraparesis (HAM/TSP)

Two disease now shown to be the same | Occurs in 1-2% of cases

HTLV-1 disease occurs

Following transfusions

Infected T-cells enter the

central nervous system Activate astrocytes, microglial cells Recruit inflammatory cells causes further tissue damage

HTLV-1 HAM/TSP Symptoms

Onset typically 3 years after infection Starts with bladder control issues Progress to lower back pain, leg weakness or stiffness in hips or knees Men suffer impotence or erectile dysfunction

HTLV-1 prevention

Eliminate breastfeeding for HTLV-1 positive mothers | Increased screening for blood products

HTLV-1 Treatment is specific to the disease

ATLL – treat the lymphoma/leukemia with chemotherapy regardless of HTLV infection HAM/TSP – corticosteriods, interferon yield temporary relief of symptoms

Human Immunodeficiency Virus type

Lentivirus Virus identified in 1984

HIV Identified due to immune deficiency occurring in previously healthy

young gay men

HIV Specific populations were

most at risk | Homosexuals, injection drug users, hemophiliacs, transfusion recipients

HIV Impact

Highest in sub-Saharan Africa

HIV transmission Sexual transmission

primary route)

HIV transmission Parenteral

Transfusion – 95% | Needle sharing – 1:150

Mother to infant HIV transmission

No AZT – 1:4 | AZT – less than 1:10

Aids latent periord

6 mths to 25 yrs

HIV Infection begins virus

containing blood or body fluidto a mucosal surface or blood

HIV targets

memory T-cells (CD4+)

HIV Initial acute infection

usually 2 weeks afterinfection | Mucocutaneous ulcerationand weight loss more indicative of HIV infection

HIV Gut Associated Lymphoid Tissue (GALT) seeded as a result of

acute infection (reservoir)

Chronic infection established

Ongoing virus replication & T-cell depletion

HIV: Opportunistic infections

``` increase Common infections Candida Coccidioidomycosis Cryptococcus Cytomegalovirus Kaposi sarcoma Tuberculosis Toxoplasmosis Wasting due to HIV infection ```

HIV Prevention

Sexual behavior and protection | Blood screening

HIV Treatment

No vaccine Antiviral treatments Nuceloside reverse transcriptase inhibitors (NRTI) – e.g., azidothymidine (AZT) Protease inhibitors – e.g., Ritonavir Non-nucleoside RT inhibitor (NNRTI) – e.g., Efavirenz Highly Active Antiretroviral Therapy (HAART) – combines three of the treatment options