Comparative biochemical analysis of HIV-1 subtype B and C integrase enzymes

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Abstract

Background

Integrase inhibitors are currently being incorporated into highly active antiretroviral therapy (HAART). Due to high HIV variability, integrase inhibitor efficacy must be evaluated against a range of integrase enzymes from different subtypes.

Methods

This study compares the enzymatic activities of HIV-1 integrase from subtypes B and C as well as susceptibility to various integrase inhibitors in vitro. The catalytic activities of both enzymes were analyzed in regard to each of 3' processing and strand transfer activities both in the presence and absence of the integrase inhibitors raltegravir (RAL), elvitegravir (EVG), and MK-2048.

Results

Our results show that integrase function is similar with enzymes of either subtype and that the various integrase strand transfer inhibitors (INSTIs) that were employed possessed similar inhibitory activity against both enzymes.

Conclusion

This suggests that the use of integrase inhibitors against HIV-1 subtype C will result in comparable outcomes to those obtained against subtype B infections.

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Most cited references 22

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Global and regional distribution of HIV-1 genetic subtypes and recombinants in 2004.

Joris Hemelaar, Eleanor Gouws, Peter D. Ghys … (2006)

To estimate the global and regional distribution of HIV-1 subtypes and recombinants in 2004. A study was conducted in which molecular epidemiological data on HIV-1 subtype distribution in individual countries were combined with country-specific estimates of the number of people living with HIV. HIV-1 subtype data were collected for 23 874 HIV-1 samples from 70 countries, which together accounted for 89% of all people living with HIV worldwide in 2004. The proportions of HIV-1 infections due to various subtypes detected in each country were combined with the number of HIV infected people in the respective countries to generate regional and global HIV-1 subtype distribution estimates. Subtype C accounted for 50% of all infections worldwide in 2004. Subtypes A, B, D and G accounted for 12%, 10%, 3% and 6%, respectively. The subtypes F, H, J and K together accounted for 0.94% of infections. The circulating recombinant forms CRF01_AE and CRF02_AG each were responsible for 5% of cases, and CRF03_AB for 0.1%. Other recombinants accounted for the remaining 8% of infections. All recombinant forms taken together were responsible for 18% of infections worldwide. Combining data on HIV-1 subtype distribution in individual countries with country-specific estimates of the number of people living with HIV provided a good method to generate estimates of the global and regional HIV-1 genetic diversity in 2004. The results could serve as an important resource for HIV scientists, public health officials and HIV vaccine developers.

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Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection.

Daria J. Hazuda, David Cooper, Christine Katlama … (2008)

We evaluated the efficacy of raltegravir and the development of viral resistance in two identical trials involving patients who were infected with human immunodeficiency virus type 1 (HIV-1) with triple-class drug resistance and in whom antiretroviral therapy had failed. We conducted subgroup analyses of the data from week 48 in both studies according to baseline prognostic factors. Genotyping of the integrase gene was performed in raltegravir recipients who had virologic failure. Virologic responses to raltegravir were consistently superior to responses to placebo, regardless of the baseline values of HIV-1 RNA level; CD4 cell count; genotypic or phenotypic sensitivity score; use or nonuse of darunavir, enfuvirtide, or both in optimized background therapy; or demographic characteristics. Among patients in the two studies combined who were using both enfuvirtide and darunavir for the first time, HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 89% of raltegravir recipients and 68% of placebo recipients. HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 69% and 80% of the raltegravir recipients and in 47% and 57% of the placebo recipients using either darunavir or enfuvirtide for the first time, respectively. At 48 weeks, 105 of the 462 raltegravir recipients (23%) had virologic failure. Genotyping was performed in 94 raltegravir recipients with virologic failure. Integrase mutations known to be associated with phenotypic resistance to raltegravir arose during treatment in 64 patients (68%). Forty-eight of these 64 patients (75%) had two or more resistance-associated mutations. When combined with an optimized background regimen in both studies, a consistently favorable treatment effect of raltegravir over placebo was shown in clinically relevant subgroups of patients, including those with baseline characteristics that typically predict a poor response to antiretroviral therapy: a high HIV-1 RNA level, low CD4 cell count, and low genotypic or phenotypic sensitivity score. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.) 2008 Massachusetts Medical Society

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Integrase inhibitors to treat HIV/AIDS.

Eric Johnson, Christophe H. Marchand, Yves Pommier (2005)

HIV integrase is a rational target for treating HIV infection and preventing AIDS. It took approximately 12 years to develop clinically usable inhibitors of integrase, and Phase I clinical trials of integrase inhibitors have just begun. This review focuses on the molecular basis and rationale for developing integrase inhibitors. The main classes of lead compounds are also described, as well as the concept of interfacial inhibitors of protein-nucleic-acid interactions that might apply to the clinically used strand-transfer inhibitors.

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Author and article information

Journal

Journal ID (nlm-ta): Retrovirology

Title: Retrovirology

Publisher: BioMed Central

ISSN (Electronic): 1742-4690

Publication date Collection: 2009

Publication date (Electronic): 11 November 2009

Volume: 6

Page: 103

Affiliations

[1 ]McGill University AIDS Centre, Lady Davis Institute-Jewish General Hospital, Montreal, Quebec, Canada

[2 ]Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A 2T5, Canada

[3 ]Division of Experimental Medicine, McGill University, Montreal, Quebec H3A 2T5, Canada

Article

Publisher ID: 1742-4690-6-103

DOI: 10.1186/1742-4690-6-103

PMC ID: 2779801

PubMed ID: 19906306

SO-VID: 37c35005-299f-4655-b525-1b1faab1c3d2

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Comparative biochemical analysis of HIV-1 subtype B and C integrase enzymes

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Abstract

Background

Methods

Results

Conclusion

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Most cited references 22

Global and regional distribution of HIV-1 genetic subtypes and recombinants in 2004.

Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection.

Integrase inhibitors to treat HIV/AIDS.

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