Insertions in the Human Immunodeficiency Virus Type 1 Protease and Reverse Transcriptase Genes: Clinical Impact and Molecular Mechanisms

Winters, Mark A.; Merigan, Thomas C.

doi:10.1128/aac.49.7.2575-2582.2005

Cited by 41 publications

(38 citation statements)

References 66 publications

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“…Interestingly, the insertions alone without background PR mutations confer very little resistance to any of the tested PIs, and their contribution to the total resistant phenotype could be observed only in combination with multiple other mutations in PR. This is consistent with the lack of reports on the emergence of therapy-induced mutant HIV variants that would contain the sequence insertions alone in the absence of any other mutations (19).…”

supporting

confidence: 75%

GS-8374, a Prototype Phosphonate-Containing Inhibitor of HIV-1 Protease, Effectively Inhibits Protease Mutants with Amino Acid Insertions

Šašková

Kožíšek

Stray

et al. 2014

J Virol

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e Insertions in the protease (PR) region of human immunodeficiency virus (HIV) represent an interesting mechanism of antiviral resistance against HIV PR inhibitors (PIs). Here, we demonstrate the improved ability of a phosphonate-containing experimental HIV PI, GS-8374, relative to that of other PIs, to effectively inhibit patient-derived recombinant HIV strains bearing PR insertions and numerous other mutations. We correlate enzyme inhibition with the catalytic activities of corresponding recombinant PRs in vitro and provide a biochemical and structural analysis of the PR-inhibitor complex.

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supporting

confidence: 75%

GS-8374, a Prototype Phosphonate-Containing Inhibitor of HIV-1 Protease, Effectively Inhibits Protease Mutants with Amino Acid Insertions

Šašková

Kožíšek

Stray

et al. 2014

J Virol

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“…Nonhomologous recombination leads to HIV-1 length variation and is the likely mechanism of oncogene transduction by animal retroviruses (307,345). Nonhomologous recombination can generate HIV-1 genetic variation that is important on the population level when it provides a selective advantage.…”

Section: Nonhomologous Recombinationmentioning

confidence: 99%

“…Length variation-sequence insertions or deletions-is surprisingly common in lentiviruses and associated with some forms of immune evasion, drug resistance, and long-term nonprogression (59,167,201,262). For example, insertions in HIV-1 RT, sometimes but not always the result of local sequence duplication, can contribute to drug resistance (141,345). Length variation is common in env, where an alternating occurrence of insertions and deletions of variable region length has been observed during patient-to-patient passage (57,193,223,363) and may contribute to immune evasion or coreceptor switch (238,283).…”

Section: Nonhomologous Recombinationmentioning

confidence: 99%

The Remarkable Frequency of Human Immunodeficiency Virus Type 1 Genetic Recombination

Onafuwa-Nuga

Telesnitsky

2009

Microbiol Mol Biol Rev

147

172

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SUMMARY The genetic diversity of human immunodeficiency virus type 1 (HIV-1) results from a combination of point mutations and genetic recombination, and rates of both processes are unusually high. This review focuses on the mechanisms and outcomes of HIV-1 genetic recombination and on the parameters that make recombination so remarkably frequent. Experimental work has demonstrated that the process that leads to recombination—a copy choice mechanism involving the migration of reverse transcriptase between viral RNA templates—occurs several times on average during every round of HIV-1 DNA synthesis. Key biological factors that lead to high recombination rates for all retroviruses are the recombination-prone nature of their reverse transcription machinery and their pseudodiploid RNA genomes. However, HIV-1 genes recombine even more frequently than do those of many other retroviruses. This reflects the way in which HIV-1 selects genomic RNAs for coencapsidation as well as cell-to-cell transmission properties that lead to unusually frequent associations between distinct viral genotypes. HIV-1 faces strong and changeable selective conditions during replication within patients. The mode of HIV-1 persistence as integrated proviruses and strong selection for defective proviruses in vivo provide conditions for archiving alleles, which can be resuscitated years after initial provirus establishment. Recombination can facilitate drug resistance and may allow superinfecting HIV-1 strains to evade preexisting immune responses, thus adding to challenges in vaccine development. These properties converge to provide HIV-1 with the means, motive, and opportunity to recombine its genetic material at an unprecedented high rate and to allow genetic recombination to serve as one of the highest barriers to HIV-1 eradication.

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“…These insertions have been reported mainly in codons 17, 18, 22 to 25, 31 to 31, 35 to 38, 70, 71, 95 and 96 6 .…”

Section: Introductionmentioning

confidence: 99%

A first case of protease codon 35 amino acid insertion in a HIV-1 subtype B sequence detected in the Bauru region, state of São Paulo, Brazil: case report

Grotto

Corvino

Munhoz

et al. 2011

Rev. Soc. Bras. Med. Trop.

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Amino acid insertions in the protease have rarely been described in HIVinfected patients. One of these insertions has recently been described in codon 35, although its impact on resistance remains unknown. This study presents a case of an HIV variant with an insertion in codon 35 of the protease, described for the first time in Bauru, State of Sao Paulo, Brazil, circulating in a 38-year-old caucasian male with asymptomatic HIV infection since 1997. The variant isolated showed a codon 35 insertion of two amino acids in the protease: a threonine and an aspartic acid, resulting in the amino acid sequence E35E_TD.

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Insertions in the Human Immunodeficiency Virus Type 1 Protease and Reverse Transcriptase Genes: Clinical Impact and Molecular Mechanisms

Cited by 41 publications

References 66 publications

GS-8374, a Prototype Phosphonate-Containing Inhibitor of HIV-1 Protease, Effectively Inhibits Protease Mutants with Amino Acid Insertions

GS-8374, a Prototype Phosphonate-Containing Inhibitor of HIV-1 Protease, Effectively Inhibits Protease Mutants with Amino Acid Insertions

The Remarkable Frequency of Human Immunodeficiency Virus Type 1 Genetic Recombination

A first case of protease codon 35 amino acid insertion in a HIV-1 subtype B sequence detected in the Bauru region, state of São Paulo, Brazil: case report

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