4.38 Flashcards by sophie rosen

Retroviruses
characteristics (5)

• Positive strand RNA viruses (5000-12000 bp)
• Enveloped
• Contain reverse transcriptase enzyme
• Cause chronic disease long after infection
• HIV (human immunodeficiency virus) is a retrovirus
that causes AIDS (acquired immunodeficiency
syndrome)

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• Contain reverse transcriptase enzyme

Copies RNA into DNA

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Cause chronic disease long after infection

Due to integration of viral DNA into host

chromosome

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HIV adsorption and penetration
M tropic (initial infection):
Receptor/coreceptor:

cells of macrophage lineage

CD4 and CCR5

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HIV adsorption and penetration
T tropic (later during infection):
Receptor/coreceptor:

T cells

CD4 and CXCR4

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Viral ENV protein gp120

binds to

cellular receptor
CD4 and to coreceptor
CXCR4 or CCR5

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Coreceptor interaction

essential for

gp41 contact
and viral fusion with host
cell

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Small number of resistant people

- lack the –

-coreceptors

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HIV penetration (due to membrane fusion promoted by —)

gp41

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HIV genome replication

Part 1: synthesis of viral DNA copy (2)

Reverse transcriptase (RT) synthesizes one strand of DNA using viral RNA as
the template.
Reverse transcriptase (RT) synthesizes the other strand of DNA using the newly
created viral single DNA strand above as the template.

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RT enzyme is the major target for — drugs

anti-HIV

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RT enzyme is — prone

error
(1 error every 10000 nts!)
~1 error per genome

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Part 1: synthesis of viral DNA copy
Cellular — used as
a primer by reverse
transcriptase

tRNA

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Part 1: synthesis of viral DNA copy
Several steps are required to
create a double stranded
DNA copy of the

positivesense, single-stranded RNA

genome

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HIV genome replication
part 2: integration of viral DNA copy into host cell genome
Promoted by viral — enzyme

integrase

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HIV genome replication
part 3: transcription of integrated viral DNA copy
to create more viral RNA

Viral DNA is transcribed into RNA by host cell RNA polymerase II

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HIV protein expression

and viral assembly (2)

Viral RNA serves as mRNA
for translation
AND
Viral RNA serves as the
viral genome that is
packaged into virions

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Viral assembly occurs at

plasma membrane.

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Virions acquire their membrane by budding of

— from the plasma membrane

nucleocapsids

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Translation creates viral

—

polyproteins

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Viral polyproteins get
cleaved to final mature
sizes by viral —

protease

HIV accessory factors (2)

nef

vpu

nef

decreases expression of MHC class I molecules on the surface of an
infected cell, preventing killing by cytotoxic T cells

vpu

reduces cell surface CD4 expression and enhances viral release

Long terminal repeats (LTRs) (2)

``` Transcriptional promoter (upstream LTR) and terminator (downstream LTR) Promoter responds to host cell signals and can also be relatively dormant, creating the latent state that is an important characteristic of HIV ```

HIV entry (3)

Virus may enter through microabrasions on mucosal surfaces needle punctures (IV drug users) intact mucosal surfaces

HIV entry | Virus may enter as (2)

part of an infected cell (macrophage, lymphocyte, spermatozoa) free virus

HIV replication during the --- phase of infection | after burst of viral replication that occurs during --- infection

chronic | initial

HIV replication during the chronic phase of infection | after burst of viral replication that occurs during initial infection (2)

``` Note initial contact is with macrophage lineage cells. Infect/stick to dendritic cells transport to lymph node - contact with CD4 T cells DTH ```

DTH=delayed-type hypersensitivity (Type IV hyper.) -important for controlling (2) DTH is mediated by

fungal and intracellular pathogens (bacterial and viral) CD4 T cells

HIV Neurological symptoms basis is not well understood (2)

``` - possibly due to viral infection of neurons - possibly release of substances by other cells that promote inflammation in brain ```

<--- CD4 T-cell/mm3 is the | criterion for AIDS.

200 Patients with higher CD4 Tcell counts are also considered to have AIDS if they display AIDS indicator conditions (see next slide).

AIDS-Indicator Conditions (Centers for Disease Control) (7)

Candidiasis of the bronchi, trachea, or lungs Candidiasis, esophageal Kaposi sarcoma Mycobacterium avium complex (MAC) or Mycobacterium kansasii, disseminated or extrapulmonary Mycobacterium tuberculosis, pulmonary or extrapulmonary Mycobacterium, other species or unidentified species, disseminated or extrapulmonary Pneumocystis jiroveci (formerly carinii) pneumonia (PCP)

HIV | Transmission occurs by

direct exposure of persons bloodstream to body fluid containing virus. HIV is found in the blood, semen, or vaginal fluid of someone who is infected with the virus.

HIV is not transmitted by

``` casual contact (touching, etc.) (or even kissing, sneezing, bug bites, etc.) ```

HIV There is a risk for health care workers but

transmission even through needlestick is poor (less than 1% of exposures show seroconversion)

``` AIDS characteristics (2) ```

• progressive destruction of CD4+ cells leads to collapse of immune system • patient susceptible to opportunistic infections

Central nervous system disease also | associated with AIDS

dementia

AIDS-related cancers

• Kaposis sarcoma | – caused by human herpesvirus 8

HIV treatment involves: – antiviral agents (3)

* nucleoside analogue reverse transcriptase (RT) inhibitors * nonnucleoside RT inhibitors * protease inhibitors * Fusion-penetration inhibitors (target gp41)

HIV | Prevention and control

• search for vaccine is ongoing

A recombinant virus assay was used to characterize in detail neutralizing antibody responses directed at circulating autologous HIV in plasma. Examining serial plasma specimens in a matrix format, most patients with primary HIV infection rapidly generated significant neutralizing antibody responses to early (0-39 months) viruses, Plasma virus continually and rapidly evolved to escape neutralization, indicating that neutralizing antibody exerts a level of selective pressure that has been under-appreciated based on earlier, less comprehensive characterizations. These data argue that

neutralizing antibody responses account for the extensive variation in the envelope gene that is observed in the early months after primary HIV infection.

Plasmid for producing HIV virions from within cultured cells (only the part of the plasmid encoding HIV is shown) (4)

1. HIV DNA on plasmid is transcribed into HIV RNA. 2. HIV RNA is translated into HIV proteins, which assemble into nucleocapsids. 3. HIV RNA is also packaged into the nucleocapsids. 4. HIV virions are created when the nucleocapsids bud through the cell membrane.

The HIV DNA on the plasmid lacks the envelope gene (env), which has been replaced with a luciferase gene. 1. This allows for HIV env genes from the patient serum samples to be used for creation of ---. The patient env genes are expressed from a second plasmid in the cells. Because the virions contain separately supplied env proteins they are called ---.

HIV virons | pseudovirions

2. The --- present within HIV is used to detect subsequent infection by the --- produced in this study. If cells become infected they will express ---, which is easily detected using a light-based assay

luciferase pseudovirions luciferase

Pseudovirions created | in a

producer cell

Mixing pseudovirions with patient | serum samples:

different combinations of each were used, representing virus and antibodies present at different times in the study

Pseudovirions unaffected by the antibody incubation will infect test cells. Infection is monitored by

luciferase | activity.

Pseudovirions are artificial virions containing ---. In this case the envelope proteins (2) come from viral envelope genes amplified from patient serum samples. A collection of pseudovirions was generated that represented the HIV population present in each of the monthly serum samples taken during the 39 month study.

altered envelope proteins | gp41 and gp120

HTLV

human T-cell lymphotropic viruses (HTLVs) -I, -II, -III, and -IV

HTLV-I

causes adult T-cell leukemia and lymphoma

HTLV-II, -III, and –IV

no known diseases associated with these viruses