Changes in the Human Immunodeficiency Virus p7-p1-p6
            <i>gag</i>
            Gene in Drug-Naive and Pretreated Patients

Gallego, Óscar; Mendoza, Carmen de; Corral, Angélica; Soriano, Vincent

doi:10.1128/jcm.41.3.1245-1247.2003

Cited by 32 publications

(25 citation statements)

References 18 publications

(11 reference statements)

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“…One study has shown that these insertions occurred with equal frequency in HIV-1 isolates from both drug-naive and drug-experienced patients (13), whereas other studies have shown that they are seen more frequently in HIV-1 from drug-experienced individuals (28). In the Los Alamos database (23), no insertions identical to those in the present study have been reported, although a number of other insertions have been seen.…”

Section: Discussioncontrasting

confidence: 49%

“…Although various inserts have been reported to occur around the p6 Gag's PTAP motif (13,28), their exact amino acid sequences have not been well documented, and their frequency and role have been controversial. One study has shown that these insertions occurred with equal frequency in HIV-1 isolates from both drug-naive and drug-experienced patients (13), whereas other studies have shown that they are seen more frequently in HIV-1 from drug-experienced individuals (28).…”

Section: Discussionmentioning

confidence: 99%

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Amino Acid Insertions near Gag Cleavage Sites Restore the Otherwise Compromised Replication of Human Immunodeficiency Virus Type 1 Variants Resistant to Protease Inhibitors

Tamiya

Mardy

Kavlick

et al. 2004

J Virol

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A variety of amino acid substitutions in the protease and Gag proteins have been reported to contribute to the development of human immunodeficiency virus type 1 (HIV-1) resistance to protease inhibitors. In the present study, full-length molecular infectious HIV-1 clones were generated by using HIV-1 variants isolated from heavily drug-experienced and therapy-failed AIDS patients. Of six full-length infectious clones generated, four were found to have unique insertions (TGNS, SQVN, AQQA, SRPE, APP, and/or PTAPPA) near the p17/p24 and p1/p6 Gag cleavage sites, in addition to the known resistance-related multiple amino acid substitutions within the protease. The addition of such Gag inserts mostly compromised the replication of wild-type HIV-1, whereas the primary multidrug-resistant HIV infectious clones containing inserts replicated significantly better than those modified to lack the inserts. Western blot analyses revealed that the processing of Gag proteins by wild-type protease was impaired by the presence of the inserts, whereas that by mutant protease was substantially improved. The present study represents the first report clearly demonstrating that the inserts seen in the proximity of the Gag cleavage sites in highly multi-PI resistant HIV-1 variants restore the otherwise compromised enzymatic activity of mutant protease, enabling the multi-PI-resistant HIV-1 variants to remain replication competent.

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Section: Discussioncontrasting

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Amino Acid Insertions near Gag Cleavage Sites Restore the Otherwise Compromised Replication of Human Immunodeficiency Virus Type 1 Variants Resistant to Protease Inhibitors

Tamiya

Mardy

Kavlick

et al. 2004

J Virol

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“…However, the basis for such duplications has not been clearly defined. Some groups have reported no association between the frequency of PTAP duplications and cART (43,44), whereas other studies have documented a significant increase in the frequency of PTAP duplications in patients on therapy (45)(46)(47). Tamiya et al reported that amino acid insertions near Gag cleavage sites, including PTAP duplications, increased processing by PR mutants bearing PI resistance changes; however, the role of PIs in this phenomenon was not investigated (48).…”

mentioning

confidence: 94%

Elucidation of the Molecular Mechanism Driving Duplication of the HIV-1 PTAP Late Domain

Martins

Waheed

Ablan

et al. 2016

J Virol

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HIV-1 uses cellular machinery to bud from infected cells. This cellular machinery is comprised of several multiprotein complexes known as endosomal sorting complexes required for transport (ESCRTs). A conserved late domain motif, Pro-Thr-AlaPro (PTAP), located in the p6 region of Gag (p6 Gag ), plays a central role in ESCRT recruitment to the site of virus budding. Previous studies have demonstrated that PTAP duplications are selected in HIV-1-infected patients during antiretroviral therapy; however, the consequences of these duplications for HIV-1 biology and drug resistance are unclear. To address these questions, we constructed viruses carrying a patient-derived PTAP duplication with and without drug resistance mutations in the viral protease. We evaluated the effect of the PTAP duplication on viral release efficiency, viral infectivity, replication capacity, drug susceptibility, and Gag processing. In the presence of protease inhibitors, we observed that the PTAP duplication in p6Gag significantly increased the infectivity and replication capacity of the virus compared to those of viruses bearing only resistance mutations in protease. Our biochemical analysis showed that the PTAP duplication, in combination with mutations in protease, enhances processing between the nucleocapsid and p6 domains of Gag, resulting in more complete Gag cleavage in the presence of protease inhibitors. These results demonstrate that duplication of the PTAP motif in p6Gag confers a selective advantage in viral replication by increasing Gag processing efficiency in the context of protease inhibitor treatment, thereby enhancing the drug resistance of the virus. These findings highlight the interconnected role of PTAP duplications and protease mutations in the development of resistance to antiretroviral therapy. IMPORTANCEResistance to current drug therapy limits treatment options in many HIV-1-infected patients. Duplications in a Pro-Thr-Ala-Pro (PTAP) motif in the p6 domain of Gag are frequently observed in viruses derived from patients on protease inhibitor (PI) therapy. However, the reason that these duplications arise and their consequences for virus replication remain to be established. In this study, we examined the effect of PTAP duplication on PI resistance in the context of wild-type protease or protease bearing PI resistance mutations. We observe that PTAP duplication markedly enhances resistance to a panel of PIs. Biochemical analysis reveals that the PTAP duplication reverses a Gag processing defect imposed by the PI resistance mutations in the context of PI treatment. The results provide a long-sought explanation for why PTAP duplications arise in PI-treated patients.

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“…PR genes were then resequenced to confirm mutations. To check for possible adaptation of PR cleavage sites with a particular PR genotype (4,5,16), the sites located in the gag region were amplified with primers P24INF (5Ј-GTCCAAA ATGCGAACCCAGATTGTAA-3Ј) and PNL43R (5Ј-CGCTG CCAAAGAGTGATCTGAGGGAA-3Ј). The gag fragment had 528 nucleotides and contained CA/p2, p2/NC, NC/p1, p1/TFP, and p1/p6 cleavage sites.…”

mentioning

confidence: 99%

Impact of Nelfinavir Resistance Mutations on In Vitro Phenotype, Fitness, and Replication Capacity of Human Immunodeficiency Virus Type 1 with Subtype B and C Proteases

Gonzalez

Brindeiro

Aguiar

et al. 2004

Antimicrob Agents Chemother

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Changes in the Human Immunodeficiency Virus p7-p1-p6 gag Gene in Drug-Naive and Pretreated Patients

Cited by 32 publications

References 18 publications

Amino Acid Insertions near Gag Cleavage Sites Restore the Otherwise Compromised Replication of Human Immunodeficiency Virus Type 1 Variants Resistant to Protease Inhibitors

Amino Acid Insertions near Gag Cleavage Sites Restore the Otherwise Compromised Replication of Human Immunodeficiency Virus Type 1 Variants Resistant to Protease Inhibitors

Elucidation of the Molecular Mechanism Driving Duplication of the HIV-1 PTAP Late Domain

Impact of Nelfinavir Resistance Mutations on In Vitro Phenotype, Fitness, and Replication Capacity of Human Immunodeficiency Virus Type 1 with Subtype B and C Proteases

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