Update on HIV Pathogenesis: Latency, Viral Reservoirs and Drug Resistance

1

Update on HIV Pathogenesis Latency, Viral
Reservoirs and Drug Resistance
Robert F. Siliciano, MDProfessor of
Medicine Johns Hopkins University School of
Medicine
The International AIDS SocietyUSA
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Sources of plasma virus

• Cells infected/day d T cV/2N 3V

• A new mutation arises in every third newly
  infected cell.

• Therefore, mutations/day V

• Genome is 10kb. Thus 30,000 mutations are
  possible.

• At V 30,000 copies/ml, every possible mutation
  arises once a day somewhere in the body!

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Sources of plasma virus
Plasma HIV-1 RNA (copies/ml)
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Establishment and maintenance of a latent
reservoir
Naive
Generation of latently infected cells



Ag
HIV



Reactivation of latent HIV
Ag

Memory
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Frequency of Latently Infected CD4 T Cells as a
Function of Time on HAART
10000
1000
100
10
Frequency (per 106 resting CD4 cells)
1
0.1
0.01
0.001
0.0001
0
1
2
3
4
5
6
7
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Time on HAART (years)
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Persistence of archival wild type and drug
resistant viruses in the latent reservoir
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HIV Evolution
Survival of the fittest.
Darwin
HIV
Survival of all major forms, active replication
of the viral variants that are the fittest under
current conditions.
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Comparing latently infected and uninfected
resting memory CD4 T cells
Relative Frequency 1,000,000 Molecules HIV
Protein 0 Molecules HIV RNA 0 Base pairs DNA
6 x 109 Survival of cell decades
and progeny
Uninfected Resting Memory CD4T Cell
Relative Frequency 1 Molecules HIV
Protein 0? Molecules HIV RNA
0? Base pairs DNA 6.000001 x 109 Survival
of cell decades and progeny
HIV-infected Resting Memory CD4T Cell
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The nature of blips
Start HAART
1000000
100000
10000
Limit of Detection (50 c/ml)
1000
Plasma HIV-1 RNA (copies/ml)
100
10
1
0.1
0.01
0.001
0
1
2
3
Time on HAART (years)
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Conclusions

• In patients with active viral replication,
  viruses are continuously deposited in a latent
  reservoir in resting CD4 T cells.
• The latent reservoir is extremely stable, and
  viruses in the reservoir can reemerge at later
  times.
• Drug resistant viruses that arise due to mistakes
  in therapy can be stored in this reservoir.
  Therefore, resistance is permanent.
• As a result of the existence of this stable
  reservoir, HIV infection is intrinsically
  incurable with antiretroviral therapy alone.
• Ongoing replication and virus release from stable
  reservoirs both contribute to viremia in infected
  individuals.

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Conclusions

• HAART largely stops ongoing replication. The low
  level viremia that continues despite HAART, and
  the blips that many patients have, do not require
  the development of new drug resistance mutations
  and may largely reflect release from stable
  reservoirs
• There can be viremia without viral evolution, and
  therefore life long control of viral replication
  is possible.
• Most blips may represent normal biological and
  statistical variation around mean viral loads of
  below 50 copies/ml rather than clinically
  significant elevations in viremia.
• Blips that are gt200 copies/ml, or reproducible on
  independent or sequential testing are more of a
  cause for concern