The HIV1 Envelope Gene Is A Major Exvivo Determinant Of Viral Fitness In Both Drug Sensitive And Res

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The HIV-1 Envelope Gene Is A Major Ex-vivo
Determinant Of Viral Fitness In Both Drug
Sensitive And Resistant Isolates

• Immaculate Nankya
• Department of Molecular and Microbiology

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Measuring Ex-Vivo Fitness
HIV-1 Ex-vivo fitness

• Viral fitness is defined as the ability of a
  virus to adapt to its environment in terms of
  replicative capacity.

• Implications of Fitness on individual disease
  progression and the HIV-1 Epidemic
• Long term survivors appear to harbor virus that
  is less fit than that harbored by progressors
  (Quinones-Mateu et al., J. Virol. 2000
  74(19)9222-33).
• HIV-1 fitness appears to increase during disease
  progression (Troyer et al., J Virol. 2005
  Jul79(14)9006-18.
• Subtype C isolates appear to be less fit than any
  group M isolate (Ball et al., J. Virol. 2003
  77(2)1021-38 Arts et al., IAS abstract 270
  2003, Abraha et al Unpublished data).

Quinones-Mateu et al., J. Virol. 2000
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Subtype C is less fit than other group M isolates
Fitness of Subtype C R5 isolates
Fitness of subtype C X4 isolates
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Drug resistance profile of the subtype C X4
isolates
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Mutations in the PR-RT have may have little
effect on the overall fitness of the virus
Replicative capacity using RT-PR
Drug Resistant
Drug sensitive
r 0.0633
Fitness using whole virus
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Fitness of the Chimeric viruses is comparable to
that of the Parental strains
Competitor virus wins
Competitor virus wins
Virus in competition wins
Virus in competition wins
r 0.8235
Competitor virus wins
Virus in competition wins
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Conclusions

• Ex-vivo HIV-1 fitness in untreated patients is
  likely controlled by the efficiency of host cell
  entry and maps to the HIV-1 env gene
• Even in the presence of drug resistant mutations,
  the envelope gene may be a major determinant of
  viral fitness ex-vivo
• Drug resistance mutations may have a fitness
  impact after appearance but with continued drug
  selection, the HIV-1 env gene and function may
  compensate for this defect

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• Awet Abraha
• Dawn Moore
• Yong Gao
• Michael Lobritz
• Matt Lalonde
• Ken Nelson
• Ken Henry
• Denis Tebit
• Rick Gibson
• Aslam Syed
• Vince Torre
• Lora Angelova
• Eric Arts

• Stanford University
• David Katzenstein
• Betsy Johnston

• Collaborators from University of Zimbabwe

• NIH Research grant funded by the Fogarty
  International Center.
• International AIDS Training and Research
  Program