ICL 1.14: Retroviruses Flashcards
what are the subfamilies and genus of the retroviridae family?
subfamily = orthoretrovirinae
genus = lentivirus (HIV-1 and HIV-2)
genus = deltaretrovirus (HTLV-1 and HTLV-2)
what are the characteristics of the retrovirus genome?
enveloped, (+) ssRNA genome
it uses a reverse transcriptase!!!
there are also LTRs = long terminal repeats wheich are promoters/regulatory sequences
what type of capsid does the retrovirus have?
HIV = truncated cone
HTLV = icosahedral
what are the VAP on the retrovirus envelope?
gp41 and gp120
gp120 = docking glycoprotein
gp41 = transmembrane glycoprotein
is the retrovirus genome infectious?
no
even though it’s a postive sense RNA virus, it’s not infectious
what are the steps of the retrovirus replication cycle?
- fusion of virion to the host cell surface – gp120 binds to CD4 host cell receptor
there’s also CCR5 and CXCR4 co-receptors that must be present
- RNA, reverse transcriptase, integrase, and other viral proteins enter the host cell
- viral DNA is formed by reverse transcription
- viral DNA is transported across the nucleus and integrates into the host DNA
- new viral RNA is used as genomic RNA and to make viral proteins
- new viral RNA and proteins are moved to the cell surface and a new, immature virion forms
- the virus matures by protease releasing individual virion proteins
what leads to retrovirus genetic variation?
reverse transcriptases, as other RNA polymerases, are error prone, with mutation rates in the order of 10-5 substitutions per nucleotide and round of replication
these high mutation rates promote rapid evolution and the generation of drug-resistant and antibody-escape mutants
drug-resistance and antibody escape can be often accomplished by single-nucleotide substitutions
high variability also poses problems for diagnosis and treatment.
HIV vingette
A 27-year-old man presented to an ambulatory care clinic with complaints of fever, headache, sore throat, and malaise for over a week and a rash for the past 2 days. He admitted to having unprotected sex with other men. His last encounter was 3 weeks earlier. He denied prior transfusions or intravenous drug use.
- fever
- headache
- sore throad
- malaise > 1 week
- unprotected sex with other men
where is HIV 2 more common?
africa
it’s also less virulent
how is HIV transmitted?
- STD (vaginal and anal intercourse)
- intrauterine/peripartum (nevirapine!)
- breastfeeding
- blood products
**not by casual contact
what does AIDS stand for?
acquired immune deficiency syndrome
what does ARC stand for?
AIDS-related complex
what are some of the symptoms of HIV?
2-4 weeks after HIV exposure:
- mild influenza-like or mononucleosis-like symptoms
- rash
- generalized lymphadenopathy
- fever
eventually there’s dramatic immunosuppression due to loss of CD4+ cells
immunosuppression leads to wasting syndrome (weight loss/chronic diarrhea) and opportunistic infections that are usually on leads to HIV the ultimate cause of death
what is usually the ultimate cause of death in HIV patients?
opportunistic infections
what are the common infections seen in HIV+ patients?
- Candida albicans (oral candidiasis)
- Pneumocystis carinii (pneumonia, PCP)
- Mycobacterium
- Pseudomonas
- Salmonella septicemia
- CMV (especially retinitis)
- KSHV (KS)
- JC virus (PML)
many other viral, bacterial, and fungal pathogens…
how do you diagnose HIV?
- patient medical history
- initially an ELSA after 3 weeks
- but then you need confirmatory tests like western blot and PCR
- if seropositive, CD4 counts are helpful to identify the extent of the disease
what are some of the reasons that lead to HIV misdiagnosis?
- genetic variation
- preexisting immunodeficiency
- maternal antibodies in newborns
- sampling early in infection, before antibody production is sufficient
what western blot result would mean a positive HIV1?
the presence of any two proteins of p24, gp41 or gp120/gp160 is considered positive for HIV-1
what is the pathogenesis of HIV?
during sexual transmission infection starts with binding of the virus to Langerhans or dendritic cells
blood transmission can take place by inoculation of virions or of virus-infected cells
macrophages undergo persistent infection, with low levels of virus production, while T-cells are killed (cytolytic infection) and produce large numbers of viral progeny
as the virus infects and lyses T-helper cells AIDS develops
the production of antibodies during infection is, at least in early stages, massive
however, the antibodies are not always neutralizing and may favor virus uptake by some cells
in addition, high mutation rates and extensive replication favor the development of resistance
what is the reason that HIV causes disease?
it’s the result of extensive loss of CD4 helper T-cells and the concomitant debilitation of helper function, which promotes secondary infection of herpesvirus reactivation
what is prophylaxis?
prevention
how do you prevent HIV?
you can’t, there’s no vaccines
the best control measure is to educate the public
the single, most important recommendation is the practice of safe sex by limiting the number of partners and using condoms
also, needles should never be reused or shared
blood screening is routinely done in developed countries, and surgical instruments should be properly disinfected
how do we treat HIV?
there are several antiviral drugs that inhibit HIV replication:
types of inhibitors:
1. entry (gp120)
- reverse transcription (RT)
- Nucleoside analogs (NRTI, DNA chain termination)
- Non-nucleoside analog (NNRTI, target enzyme) - polyprotein proteolysis
- integrase
what is HAART?
HAART = highly active antiretroviral therapy
use of single inhibitor inevitably leads to early selection of resistant mutants and loss of effectiveness
but the use of combinations of 3-4 drugs leads to
combinations that include drugs with many different mechanisms of action as possible
what are some complications that can happen with HIV?
- malignancies
tumor development is not the direct result of HIV infection, but of KSHV reactivation
- neurological damage
dementia can be the result of opportunistic infection, but can also be due to HIV infection of glial cells
what is HTLV-1?
HTLV-1 is a non-cytolytic virus that infects T cells
it’s an oncogenic virus
what is the Tax protein?
part of the HTLV-1 virus
Tax protein functions as an oncogene by regulating viral and cellular gene expression
how is HTLV1 transmitted?
- breastfeeding
- sexual contact
- blood contact
same as HIV
where is HTLV1 most common?
high prevalence in Japan, the Caribbean and Central Africa
what are the clinical features of HTLV1?
Adult T-cell leukemia/lymphoma (ATLL):
1. develops in 3-5% of HTLV carriers
- aggressive and fatal disease, death within year of diagnosis
- skin lesions may be present
Infective dermatitis associated with HTLV-1 (IDH):
1. chronic recurrent eczema
- children vertically infected
Tropical spastic paraparesis:
1. neurological damage in the peripheral nervous system
- weakness, muscle spasms, and paraparesis (weakness in legs)
3 most common in tropical regions
how do you diagnose HTLV1?
ELISA
PCR
what is HTLV pathogenesis?
HTLV infection results in a long latency period such that disease only develops many decades after exposure
ATLL is considered the result of oncogene activation in CD4+ helper cells
little is known regarding the mechanisms of neurological damage, but it may be the result of immune-mediated neuronal killing and demyelination, not of virus-induced cytopathology
how do you prevent HTLV?
no vaccine
how do you treat HTLV?
antivirals are mostly ineffective
supportive care
how do you prevent HTLV?
same ways as HIV
the best control measure is to educate the public
the single, most important recommendation is the practice of safe sex by limiting the number of partners and using condoms
also, needles should never be reused or shared
blood screening is routinely done in developed countries, and surgical instruments should be properly disinfected
what does HERV stand for?
Human Endogenous Retroviruses
what are HERVs?
HERV = Human Endogenous Retroviruses
they are the result of the integration of ancient retroviruses into the germ-line cells’ genomes
they are defective and usually inactive
HERVs together with other retroelements (SINES and LINES) make up about 30% of the human genome
HERVs are suspected of involvement in some autoimmune diseases, in particular with multiple sclerosis
one HERV is activated during pregnancy in placental tissue and thought to be involved in placental function
what are porcine endogenous retroviruses?
with the current (and, likely, future) shortage of organs for transplantation, pigs are considered good candidates for xenotransplantation
one of the main hurdles to using pig organs is the potential for porcine endogenous retroviruses to cause harm in humans
