L5 Flashcards
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)
1986: HIV-2 discovered in West Africa. HIV-2 RNA is
sequence similar (40%) to HIV-1. HIV-2 is mostly a heterosexual disease.
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.
Retroviruses Have a unique
replication cycle
Retroviruses are
Ubiquitous in vertebrates
Retroviruses - Many are
benign, causing little to no impact on the host cell or host animal
Retroviruses can have significant
pathogenicity causing disease and cancer
retroviruses Spumaviruses do not cause
human disease
Retroviruses make
Make “foamy” structures insidethe cell
Retroviridae: two subfamilies
Orthoretroviridae
Spumaviridae
Retrovirus genome
Genome: (+)ssRNA
Diploid, identical copies
Retrovirus Virion:
enveloped
Historically, retroviruses were characterized by
nucleocapsid structure & location in the particle
Retrovirus Genome contents now used to classify retroviruses as
simple or complex
Simple retroviruses only encode the
Gag, Pro, Pol, and Env genes
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
Reverse transcription Defining feature of
retroviruses
RT Initiates once nucleocapsid is in
cytoplasm
RT needs higher levels of
NTPs present
Low NTP levels prevent reverse transcription
RT Occurs within a
large complex similar to nucleocapsid
Infection cannot progress
if reverse transcription does not occur
Reverse transcription is
promiscuous between genome copies
Silent” when copies are identical
Many different recombinations when different genomes are in the
virion
Retrovirus Integration
Must access the nucleus
Access during mitosis – requires dividing cells
Importation (mechanism unknown) – can infect non-dividing cells
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
