Medical-biological groundwork of HIV’s resistance

having claimed more than 35 million lives so far. In

2015, 1.1 (940 000–1.3 million) million people died from HIV-related causes globally.
There is no cure for HIV infection. However, effective antiretroviral (ARV) drugs can control the virus and help prevent transmission so that people with HIV, and those at substantial risk, can enjoy healthy, long and productive lives.

Key facts:

WHO. HIV/AIDS.Fact sheet.Updated November 2016

and prevention of HIV infection. They fight HIV by stopping

or interfering with the reproduction of the virus in the body, reducing the amount of virus in the body.

Integrase Inhibitor

of virus
Integrase
gag-pol
polyprotein
1
2
3
4
5
6
Deliverance of viruses
Ингибиторы протеаз


NRTIs

NNRTIs
Nucleus
DNA of the cell
CCR5
or
CXCR4
Co-receptor
HIV virions
Inhibirots of

Attachmenet

Adapted:Levy JA. HIV and the Pathogenesis of AIDS. 2nd ed. Washington, DC: American Society for Microbiology; 1998:9-11
.

errors (1 in 104)
HIV-1 genome is 10 000 (104) bases

long, therefore 1 error each time the genome is replicated
Production of virus = 109 to 1010 virions per day  quasispecies
Every possible mutation present in quasispecies before ARV therapy

reference sequence
Biological definition: change in nucleic acid sequence that results

in a change in structure or function of the nucleic acid or a resulting protein

Lys
(K)

Asp
(D)

Ser
(S)

Lys
(K)

Asn
(N)

Ser
(S)

AAA GAC AGT

AAA AAC AGT

AAA GAC AGT

AAA AAC AGC

Biological causes

1-99 amino acids
RT: 1-540 amino acids
G48V
L10L/I (mix of wt and

mutant)
V82A/F (mix of 2 mutants)

sequence of a protein

Changes in structure/function of the protein (e.g.

PR or RT)

Changes in ability of drug to inhibit target enzyme (resistance)

can influence susceptibility)
“Primary” mutations
Directly affect drug binding, present near active

site
Appear first in pathway to resistance
Not present in virus not exposed to drug pressure
“Secondary” mutations
Compensate for fitness defects
Do not usually confer resistance on their own but modulate susceptibility
May include polymorphisms that are found more frequently in resistant viruses

of ART, influenced by:
Ability of regimens to suppress replication completely
Adherence

and tolerability of regimens
"Genetic barrier" to resistance
Relative fitness of resistant variant(s)
Pharmacokinetics (IQ)
Availability/continuity of drug supply
Removal of barriers to access to care
Therefore, efforts to minimize HIVDR should be focused on these factors

of drugs
Adding one drug to a failing regimen
Interruption of treatment

(even for a few days)
Prolonging a failing regimen

low turnover
Supervision and monitoring
Adequate lab services
Drug supply and delivery

systems

regimen
Avoiding interruption of treatment, even if only a few days
Regular

follow-up (going to clinic)
Staying on uninterrupted first-line ART as long as possible

to patient
Distance patient must travel to get treatment
Supply interruptions
Availability of

second-line regimens for patients whose first-line regimens fail
Timing of use of second-line regimens