Antiretroviral Therapy for HIV-2 Infection: Recommendations for Management in Low-Resource Settings

Peterson, Kevin; Jallow, Sabelle; Rowland‐Jones, Sarah; Silva, Thushan I. de

doi:10.1155/2011/463704

Cited by 34 publications

(54 citation statements)

References 99 publications

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“…APV was seen in a single orientation in PR 2 and PR 1M , although the aniline group in PR 1M -APV had two alternate conformations with an occupancy ratio of 0.6/0.4, as described for the PR V82A -DRV structure. 24 Most of the PR 2 and PR 1M interactions with inhibitor were very similar to those of the major (0.7) occupancy conformation in the structure of PR 1 with APV, 18 with the exception of the interactions of the P2 0 aniline group [ Fig.…”

Section: Apv Complexes With Pr 1m Pr 1 and Prmentioning

confidence: 66%

“…Val47 had no hydrophobic interactions with the aniline of DRV in PR 2 and PR 1M , whereas two contacts were seen in PR 1 . The opposite was seen for the other subunit, where Val47 0 showed three van der Waals contacts with bis-THF in PR 2 and PR 1M and no contacts in PR 1 . Overall, the slightly longer hydrogen bond interaction of the triple mutant with DRV was the only change that could help explain the 6-fold poorer inhibition of PR 1M compared to PR 2 and PR 1 .…”

Section: Sqv Complexes With Pr 1m and Prmentioning

confidence: 81%

“…There are two major types: HIV-1 and HIV-2; the more common HIV-1 is subdivided into the four groups of M, N, O, and P as well as several subtypes. HIV-2 infections account for more than 1 million people, or about a third of the HIV prevalence in West Africa 2,3 and are spreading into other continents. 4,5 Treatment of HIV-2 infections employs the drugs developed for HIV-1, however, several drugs are less effective on HIV-2.…”

Section: Introductionmentioning

confidence: 99%

“…2,3 A further therapeutic quandary is posed by the drug resistant mutations arising in HIV-2 and co-infections of HIV-1 and HIV-2. 2,6 HIV-1 protease (PR 1 ) is a very effective drug target for AIDS treatment because its activity is essential for hydrolyzing the viral Gag and Gag-Pol precursor polyproteins during the maturation of infectious virus. 7 PR 1 inhibitors illustrate the success of structure-guided drug designs.…”

Section: Introductionmentioning

confidence: 99%

“…1). 15 In particular, the binding site for clinical inhibitors differs only in the conservative substitution of hydrophobic residues Val32, Ile47, and Val82 in PR 1 by Ile32, Val47, and Ile82 in PR 2 . Earlier studies showed that PR 1 bearing the substitutions, V32I, I47V, and V82I, altered the inhibition but not the binding mode of a tripeptide inhibitor.…”

Section: Introductionmentioning

confidence: 99%

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Critical differences in HIV‐1 and HIV‐2 protease specificity for clinical inhibitors

Tie¹,

Wang²,

Boross³

et al. 2012

Protein Science

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Clinical inhibitor amprenavir (APV) is less effective on HIV-2 protease (PR 2 ) than on HIV-1 protease (PR 1 ). We solved the crystal structure of PR 2 with APV at 1.5 Å resolution to identify structural changes associated with the lowered inhibition. Furthermore, we analyzed the PR 1 mutant (PR 1M ) with substitutions V32I, I47V, and V82I that mimic the inhibitor binding site of PR 2 . PR 1M more closely resembled PR 2 than PR 1 in catalytic efficiency on four substrate peptides and inhibition by APV, whereas few differences were seen for two other substrates and inhibition by saquinavir (SQV) and darunavir (DRV). High resolution crystal structures of PR 1M with APV, DRV, and SQV were compared with available PR 1 and PR 2 complexes. Val/Ile32 and Ile/Val47 showed compensating interactions with SQV in PR 1M and PR 1 , however, Ile82 interacted with a second SQV bound in an extension of the active site cavity of PR 1M . Residues 32 and 82 maintained similar interactions with DRV and APV in all the enzymes, whereas Val47 and Ile47 had opposing effects in the two subunits. Significantly diminished interactions were seen for the aniline of APV bound in PR 1M and PR 2 relative to the strong hydrogen bonds observed in PR 1 , consistent with 15-and 19-fold weaker inhibition, respectively. Overall, PR 1M partially replicates the specificity of PR 2 and gives insight into drug resistant mutations at residues 32, 47, and 82. Moreover, this analysis provides a structural explanation for the weaker antiviral effects of APV on HIV-2.

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Section: Apv Complexes With Pr 1m Pr 1 and Prmentioning

confidence: 66%

Section: Sqv Complexes With Pr 1m and Prmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Critical differences in HIV‐1 and HIV‐2 protease specificity for clinical inhibitors

Tie¹,

Wang²,

Boross³

et al. 2012

Protein Science

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Comparing HIV‐1 and HIV‐2 infection: Lessons for viral immunopathogenesis

Nyamweya

Hegedus

Jaye

et al. 2013

Reviews in Medical Virology

200

139

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HIV-1 and HIV-2 share many similarities including their basic gene arrangement, modes of transmission, intracellular replication pathways and clinical consequences: both result in AIDS. However, HIV-2 is characterised by lower transmissibility and reduced likelihood of progression to AIDS. The underlying mechanistic differences between these two infections illuminate broader issues of retroviral pathogenesis, which remain incompletely understood. Comparisons between these two infections from epidemiological, clinical, virologic and immunologic viewpoints provide a basis for hypothesis generation and testing in this 'natural experiment' in viral pathogenesis. In terms of epidemiology, HIV-2 remains largely confined to West Africa, whereas HIV-1 extends worldwide. Clinically, HIV-2 infected individuals seem to dichotomise, most remaining long-term non-progressors, whereas most HIV-1 infected individuals progress. When clinical progression occurs, both diseases demonstrate very similar pathological processes, although progression in HIV-2 occurs at higher CD4 counts. Plasma viral loads are consistently lower in HIV-2, as are average levels of immune activation. Significant differences exist between the two infections in all components of the immune system. For example, cellular responses to HIV-2 tend to be more polyfunctional and produce more IL-2; humoral responses appear broader with lower magnitude intratype neutralisation responses; innate responses appear more robust, possibly through differential effects of tripartite motif protein isoform 5 alpha. Overall, the immune response to HIV-2 appears more protective against disease progression suggesting that pivotal immune factors limit viral pathology. If such immune responses could be replicated or induced in HIV-1 infected patients, they might extend survival and reduce requirements for antiretroviral therapy.

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Encyclopedia of AIDS

Peterson¹

2014

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Antiretroviral Therapy for HIV-2 Infection: Recommendations for Management in Low-Resource Settings

Cited by 34 publications

References 99 publications

Critical differences in HIV‐1 and HIV‐2 protease specificity for clinical inhibitors

Critical differences in HIV‐1 and HIV‐2 protease specificity for clinical inhibitors

Comparing HIV‐1 and HIV‐2 infection: Lessons for viral immunopathogenesis

Encyclopedia of AIDS

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