Retroviruses

retroviruses

single stranded, + strand RNA viruses

what can retroviruses cause?

leukemias/sarcomas and neoplasias, wasting diseases, immunosuppressive disease

HTLV-1

human T cell leukemia virus type 1

HTLV-2

human T cell leukemia virus type 2

HIV-1

human immunodeficiency virus type 1

HIV-2

human immunodeficiency virus type 2

HFV

human foamy virus

t/f there are different clades of HIV-1, with different geographic distributions, but the clades are genetically exactly the same

false- there are ~10-20% differences in clades

what does the HIV genome have on it?

CAP and polyA tail, as well as viral genes

what is the retrovirus genome essentially?

a eukaryotic messenger RNA

tat

transcriptional transactivator (essential), can be released from infected cells, can be taken up by uninfected cells and alter gene expression in these cells, can induce programmed cell death (apoptosis) in uninfected cells

nef

membrane associated, downregulates CD4 and MHC I, enhances virion infectivity

what gene is mutated in long term non-progressors infected with HIV?

nef

does nef (-) SIV cause disease in adult rhesus maques?

no, but does in newborns

vpr

virion associated, causes apoptosis of infected cells, cell cycle arrest

vpu

influences virus release (without this the virus accumulates in cells)

vif

facilitates virus spread

rev

post-transcriptional activator (essential)

what does HIV-1 productively infect?

CD4+ T lymphocytes and macrophages

what does HIV-1 establish a low level of infection in?

dendritic, langerhan’s, and plasmacytoid dendritic cells

what is the lifecycles of a retrovirus?

receptor binding, entry, reverse transcription, nuclear entry of DNA, integration, RNA synthesis, protein synthesis, virion assembly, virion release, proteolytic maturation

what parts of the retrovirus lifecycle can be targeted by antiretroviral drugs?

receptor binding, entry, uncoating/reverse transcription, nuclear entry, integration, assembly, proteolytic maturation

what is the primary receptor and co-receptors for HIV-1?

primary: CD4

co-receptors: CCR5, CXCR4 (chemokine receptors)

which cells express CCR5?

T cells and macrophages

what cells express CXCR4?

T cells

do all HIV strains use both receptors?

no, different strains have different preferences

are there individuals who are resistant for HIV-1?

yes, they are homozygous for a deletion in CCR5

long term non-progressors express elevated levels of which chemokines and why is this important?

MIP-alpha, MIP-1beta, RANTES, they bind to CCR5

how does HIV-1 enter a cell?

fusion of the viral and target cell lipid membranes

maraviroc

inhibits binding to CC

entry can be inhibited by drugs that…

prevent fusion (T-20)

reverse transcription

ssRNA → dsDNA, major target for anti retroviral drugs, high misincorporation rate which leads to accumulations of mutations and generation of viral mutants

how do nucleoside analogs work to inhibit reverse transcription?

block by substrate competition, examples are AZT and ddl

how do non-nucleoside analogs work to inhibit reverse transcription?

bind to reverse transcriptase outside of active site and block activity, example is nevirapine

t/f most retroviruses including HIV-1 can only infect dividing cells

false- it is true that most retroviruses can infect only dividing cells, but HIV-1 and other lentiviruses can infect non-dividing cells like macrophages

how is HIV-1 DNA integrated into the target cell’s chromosome?

a virally encoded integrase

raltegarvir or elvitegravir

inhibit integration of HIV-1 DNA into the target cell chromosomes

what is HIV-1 transcribed by and why is this important?

RNA polymerase II

it is error prone and contributes to the generation of viral variants because it does not have proof reading activity

gag

MA-CA-NC

gag/pol

MA-CA-NC-PR-RT-IN

where are precursor proteins and unspliced mRNA assembled?

at the cell membrane

lenacapavir

binds CA monomers and inhibits assembly

how are HIV-1 virions released from the cells?

budding

what happens after HIV-1 virions are released?

precursor proteins are proteolytically cleaved by the viral protease (this process is a target for protease inhibitors like saquinivir and indinavir)

why are anti-retroviral drugs not a CURE for HIV infection?

HIV establishes latent infections in CD4T cells, these latently infected cells act as a reservoir that can rapidly re-establish high levels of viremia once drug treatment is stopped

HIV latency

major barrier to eradicating HIV infection, occurs in multiple cell populations in different compartments, several mechanisms lead to this

at the most basic level, what does HIV-1 do?

impairs cells function and kills cells

AIDS

>200 CD4 T cells per microliter, after HIV infection

what stage of infection is the rate of HIV-1 replication the highest?

very high at all stages, and this coupled with high mutation rate results in virus strains that are more pathogenic

evolution of HIV-1 happens from poorly replicating non-syncytium inducing strains to syncytium inducing strains are typically (more/less) pathogenic

more

what are some HIV-1 induced T cells abnormalities?

loss of response to recall antigens, impaired proliferation, impaired IL-2 receptor expression, altered cytokine production (shift from Th1 profile to Th2 profile)

what are some HIV induced macrophage abnormalities?

impaired chemotaxis, impaired phagocytosis, impaired cytokine production

how does HIV-1 kill?

direct killing- high levels of virus expression can be cytotoxic because it interferes with cellular gene expression and causes a loss of membrane integrity

syncytium formation- large, multinucleated cells generated when an uninfected CD4+ cell fuses with a virally infected cell expressing gp120

immune attack- infected cells are killed by both a CTL response and by antibody dependent cell-mediated cytotoxicity (ADCC)

apoptosis- programmed cell death, (facilitated by tat)