MicrobiologyTier 2Medical Sciences concept

Retrovirus replication - reverse transcriptase function

Core concept

```

Reverse transcriptase = RNA-dependent DNA polymerase

viral (+)ssRNA (two copies, diploid genome)
-> single-stranded cDNA (RT polymerase activity)
-> RNase H degrades the RNA template
-> double-stranded proviral DNA
-> integrase inserts it into host chromosomal DNA -> PROVIRUS, permanent
-> host RNA polymerase II transcribes it as if it were a host gene
-> Gag-Pol polyprotein -> cleaved by viral PROTEASE during maturation

```

RT has NO 3'-5' proofreading exonuclease
- -> error rate ~1 in 10^4-10^5 bases, roughly one mutation per genome per replication cycle
- -> quasispecies, rapid drug resistance, and immune escape - and the reason combination therapy is mandatory
Integration is why HIV cannot be cured - the latent reservoir in resting memory CD4 cells is invisible to drugs and to the immune system

Genome and enzymes

gag - matrix, capsid (p24, the antigen in 4th-generation assays), nucleocapsid
pol - reverse transcriptase, protease, integrase
env - gp160 -> gp120 (receptor binding) + gp41 (fusion)
Regulatory/accessory: tat, rev, nef, vif, vpr, vpu

Drug classes mapped to the cycle

Step	Class	Examples
Attachment/entry	CCR5 antagonist, fusion inhibitor, post-attachment mAb	Maraviroc, enfuvirtide, ibalizumab
Reverse transcription	NRTI - chain terminators lacking a 3'-OH	Tenofovir (TDF/TAF), emtricitabine, lamivudine, abacavir, zidovudine
Reverse transcription	NNRTI - allosteric, non-competitive	Efavirenz, rilpivirine, doravirine
Integration	INSTI	Dolutegravir, bictegravir, raltegravir, cabotegravir
Maturation	Protease inhibitor	Darunavir/ritonavir, atazanavir
Capsid	Capsid inhibitor	Lenacapavir (6-monthly SC)

Standard first-line ART is an INSTI-based triple or dual regimen - e.g. bictegravir/emtricitabine/TAF, or dolutegravir + lamivudine
Other retroviruses: HTLV-1 - adult T-cell leukaemia/lymphoma and HAM/tropical spastic paraparesis; endemic in central Australia
Hepatitis B is a DNA virus that also uses reverse transcriptase - which is why tenofovir and entecavir work against both HBV and (tenofovir) HIV, and why lamivudine monotherapy in an undiagnosed HIV co-infection selects HIV resistance

Test for HIV before treating hepatitis B with a nucleos(t)ide - a partly active regimen creates resistance
Never use monotherapy or a two-drug regimen with a low genetic barrier - the mutation rate guarantees escape
- Low barrier: lamivudine/emtricitabine (M184V), NNRTIs (K103N), raltegravir
- High barrier: boosted darunavir, dolutegravir/bictegravir
- M184V confers lamivudine resistance but reduces viral fitness and re-sensitises to zidovudine and tenofovir - it is often deliberately retained
Resistance testing (genotype) before starting ART and at any virological failure
Occupational and non-occupational PEP - a 3-drug regimen (tenofovir/emtricitabine + dolutegravir or raltegravir) started as soon as possible, ideally within hours, for 28 days
PrEP - daily tenofovir/emtricitabine, or long-acting injectable cabotegravir/lenacapavir
U=U: sustained undetectable viral load means untransmittable

3 more sections, plus exam facts

Premium unlocks every note across every specialty, and the full exam fact library behind it.