HIV pathogenesis Flashcards
what is AIDS? describe it
acquired immunodeficiency syndrome
following a viral infection, the immune system was wiped, allowing subsequent pathogens to harm them
anyone can get HIV/AIDS
- transmission can also occur at birth or heterosexually or with needles
describe the first documented case of AIDS
in the West, young men had a serious lung infection, pneumocystis pneumonia, which was caused by a fungus
in the East, young men had a new form of cancer, Kaposi Sarcoma, which resulted in lesions around the neck, back, and mouth
- normally seen in those in their 70s and 80s - but in this situation, was seen in young men in their 20s/30s
young men were affected because their immune system wasn’t developed… following a viral infection, the immune system was wiped, allowing subsequent pathogens to harm them
- new diseases targeting a new type of population!
where is the highest prevalence of AIDS in the world?
sub-Saharan Africa
1/4 of individuals here are infected
what “solutions” are there to AIDS?
to help people living with HIV by supplying antiretrovirals
how do antiretrovirals work?
the antiretrovirals block viral replication - doesn’t treat it because the retrovirus has been inserted into the host genome… the antiretroviral causes the virus to remain dormant but this virus can also be reactivated
e.g. if a patient is off antiretrovirals for a week
cART: combined Antiretroviral therapy, a cocktail
what is HIV?
family: retroviridae
subfamily: lentivirues
only 2 viruses from the lentivirus subfamily infect humans: HIV-1 & HIV-2
has a lipid-bilayer envelope
had a nucleocapsid
- capsid complexed with genome
how are viral structural proteins often identified?
by molecular weight or glycosylation status
what are the 3 important HIV proteins?
gp120
- viral receptor
- surface protein (SU)
gp41
- fusion protein
- transmembrane protein (TM)
p24
- capsid protein (CA)
- not nucleocapsid
- protects the genome!
describe the retroviral, or more specifically HIV life cycle
envelope glycoproteins, gp120 and gp41, interacts with host cell receptors, CD4 and it’s co-receptors, CCR5 and CXCR4
external envelope has fused with the plasma membrane, facilitating entry
- only the core in maintained and remains intact, up until the nucleus
reverse transcription occurs in the core, while the core is in the cytoplasm
the core is transported via the nuclear pore complex into the nucleus
capsid uncoats within the nucleus, exposing its genome
the genome is converted into double stranded DNA, a pre-initiation complex (PIC)
the dsDNA integrates itself into the host chromosomal
- could stay there forever
RNA is eventually produced from the dsDNA/PIC and exported into the cytoplasm
the +ssRNA will find host ribosomal machinery to make the viral proteins to be assembled
why are retroviruses so variable - why are they considered quasispecies?
they have a reverse transcriptase, a polymerase that lacks the 3’ to 5’ exonuclease function
this results in 1-10 nucleotide error per synthesis. thus, HIV is hard to control and create vaccines for
this heterogeneity in retrovirus populations results in a collection of variants/quasispecies
what are the 3 major parts of the retroviral genome and what proteins do they encode for?
note: the genome is complexed with the nucleocapsid
Gag
- makes structural proteins such as the capsid and nucleocapsid
e.g. p24 in HIV
Pol
- makes enzymes such as reverse transcriptase, protease, and integrase
Env
- makes envelope proteins
e.g. gp120 and gp41
these parts are found in this order!
describe the integration of proviral DNA into the cellular genome?
proviral DNA is integrated to cellular genome at a random site
function carried out by viral enzyme integrase, present in the core
integrase will cut proviral DNA and host DNA to attach them together
the virus/infection stays for life… so cure is extremely rare
- because retroviruses are quasispecies, they try to use multiple drugs (cocktails)
describe the origin of HIV
cases in Africa (Central)
archived samples revealed HIV existed so far back as 1959 in Zaire (Central Africa), now called Congo
- determined via sequencing
almost all sex workers in Zaire and Rwanda were HIV positive in major cities
describe the diversity/evolution of HIV-1 and HIV-2
HIV-2 hasn’t evolved has much, contrary to HIV-1
HIV-1 can be split into groups
the largest group of HIV-1 that infects humans is M (stands for major), at approximately 80% of HIV-1 cases… other groups (N, O, P) are more rare
there are more subtypes within group M; group M has more variability
note: each group represents a transfer from an animal to a host - M was its own transfer, N was its own, and etc.
describe the diversity/evolution of HIV-1 M
prevalence of subtypes in countries are due to how it was introduced to the country and maybe due to treatment methods that caused tighter isolation
out of the subtypes, C is the most prevalent in Southern Africa - and the world (most cases are in Southern Africa)
subtype B is the most prevalent in North America
subtype D results in a quicker death
CRFs (circulating recombinant forms) are mixtures of various subtypes… they’re usually sex workers that have been infected many types
a new subtype L was described somewhat recently, but not strongly established - lack of evidence
how is HIV-2 different from HIV-1
HIV-2 doesn’t progress to AIDS as quickly
it’s not as transmissible nor as deadly
not much evolution in HIV-2 = less variety in comparison
what’s the source of HIV-1 and how was this determined?
sequencing reveals that HIV-1 is very similar to another lentivirus, SIV (for simians, non-human primates)… specifically SIVcpz, SIV from chimpanzees
note: SIV in chimps (SIVcpz), transmitted by sexual SIV-positive chimps, do get AIDS and die - they don’t have vaccines
the virus was measured in fecal samples of chimp populations… because chimps don’t swim, populations are isolated (by water)
it was found that two families of chimps has SIV: pan troglodytes schweinfurthii and pan troglodytes troglodytes
but the SIV from pan troglodytes troglodytes matches HIV-1… thus, the origin of HIV-1 is from these chimps
how was SIV/HIV transmitted to chimps?
old world monkeys had a virus but they were not sick as the virus wasn’t pathogenic; their immune system was able to fend off the effects
these old world monkeys were reservoirs for this virus
e.g. SARS-CoV2 in bats
chimps are vegetarian but must have eaten infected old world monkey, receiving SIV which was later transmitted to humans
HIV-1 M and HIV-1 N was directly transmitted from a chimp, thru different transmission events
HIV-1 O is hypothesized to have been transmitted from a chimp to a gorilla intermediate and then to a human… could be without the gorilla but we are lacking evidence for either
HIV-1 P has a confirmed gorilla intermediate
describe how HIV-1 was first transmitted and the accelerators
the epicenter for HIV-1 was Kinshasa or Zaire
bushmeat hunting was a common practice, even in the 1920s. it was done via machete which was bloody - the blood of infected chimps/gorillas could infect humans
bushmeat hunting was not new to the 1920s… meaning, there were accelerators
possible accelerators:
european colonization which led to the creation of the largest sex worker industry
introduction of health care to African populations, but these lacked proper sterilization methods… instead, they boiled equipment and men undergoing circumcision were cut with the same blade which was infected with HIV
what are the methods of transmission for HIV and why?
HIV must be sexually transmitted, intravenous drug use, blood transfusions, or even at birth
only these methods, because HIV is an enveloped virus
if the envelope is destroyed, the glycoproteins are also destroyed and the virus can’t attach and transmit
what is zoonoses?
spread between animals and people
the event is called a spillover event
when the virus is first received, immune system is overwhelmed - could lead to death
what’s the reservoir of ebola? to what was it transmitted to, from the reservoir?
the reservoir of ebola, aka the actual hosts are bats
they are not infected by the virus
ebola was then transmitted to apes, monkeys, antelopes
