Antiretroviral Drug Resistance in Human Immunodeficiency Virus Type 2

Ntemgwa, Michel; Toni, Thomas; Brenner, Bluma G.; Camacho, Ricardo Jorge; Wainberg, Mark A.

doi:10.1128/aac.00154-09

Cited by 72 publications

(61 citation statements)

References 89 publications

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“…A rapid emergence of mutations potentially associated with drug resistance has been reported for HIV-2 ϩ patients under ART (25,29,41). We confirmed the presence of mutations in the reverse transcriptase and protease in our ART-treated HIV-2 cohort (Table 4).…”

Section: Relationship Of Plasma and Cell-associated Viral Load With Csupporting

confidence: 74%

Cell-Associated Viral Burden Provides Evidence of Ongoing Viral Replication in Aviremic HIV-2-Infected Patients

Soares¹,

Tendeiro

Foxall

et al. 2011

J Virol

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Viremia is significantly lower in HIV-2 than in HIV-1 infection, irrespective of disease stage. Nevertheless, the comparable proviral DNA burdens observed for these two infections indicate similar numbers of infected cells. Here we investigated this apparent paradox by assessing cell-associated viral replication. We found that untreated HIV-1-positive (HIV-1 ؉ ) and HIV-2 ؉ individuals, matched for CD4 T cell depletion, exhibited similar gag mRNA levels, indicating that significant viral transcription is occurring in untreated HIV-2 ؉ patients, despite the reduced viremia (undetectable to 2.6 ؋ 10 4 RNA copies/ml). However, tat mRNA transcripts were observed at significantly lower levels in HIV-2 ؉ patients, suggesting that the rate of de novo infection is decreased in these patients. Our data also reveal a direct relationship of gag and tat transcripts with CD4 and CD8 T cell activation, respectively. Antiretroviral therapy (ART)-treated HIV-2 ؉ patients showed persistent viral replication, irrespective of plasma viremia, possibly contributing to the emergence of drug resistance mutations, persistent hyperimmune activation, and poor CD4 T cell recovery that we observed with these individuals. In conclusion, we provide here evidence of significant ongoing viral replication in HIV-2 ؉ patients, further emphasizing the dichotomy between amount of plasma virus and cell-associated viral burden and stressing the need for antiretroviral trials and the definition of therapeutic guidelines for HIV-2 infection.

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Section: Relationship Of Plasma and Cell-associated Viral Load With Csupporting

confidence: 74%

Cell-Associated Viral Burden Provides Evidence of Ongoing Viral Replication in Aviremic HIV-2-Infected Patients

Soares¹,

Tendeiro

Foxall

et al. 2011

J Virol

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“…Related drug resistance mutations were assigned according to the IAS-USA 2011 consensus. HIV-2 genotypic analysis was done at the Virology laboratory from the University Hospital of Bordeaux using primers previously described for amplification of Reverse transcriptase and Protease regions [12]. The obtained fragments were sequenced on both strands using the ABI BDV3.…”

Section: Genotypic Analysismentioning

confidence: 99%

Multiclass Primary Antiretroviral Drug Resistance in a Patient Presenting HIV-1/2 Dual Infection

Castro

Recordon-Pinson²,

Cavassini

et al. 2011

Antiviral Therapy

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“…Previous studies demonstrated that HIV-1 and HIV-2 have different evolutionary histories and share only 50% genetic similarity (9,10). Unfortunately, all currently available antiretroviral drugs were specifically developed to inhibit HIV-1 entry and replication, and consequently some drugs in clinical use have limited or no activity on HIV-2, including all nonnucleoside reverse transcriptase inhibitors, some protease inhibitors, and the fusion inhibitor T20 (enfuvirtide; Fuzeon) (11)(12)(13)(14). T20, a 36-mer linear peptide derived from the native gp41 C-terminal heptad repeat (CHR) sequence of the HIV-1 LAI isolate, was approved as the first and, so far, only HIV-1 fusion inhibitor for clinical use (15)(16)(17).…”

mentioning

confidence: 99%

A Helical Short-Peptide Fusion Inhibitor with Highly Potent Activity against Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus

Xiong

Borrego

Ding

et al. 2017

J Virol

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Human immunodeficiency virus type 2 (HIV-2) has already spread to different regions worldwide, and currently about 1 to 2 million people have been infected, calling for new antiviral agents that are effective on both HIV-1 and HIV-2 isolates. T20 (enfuvirtide), a 36-mer peptide derived from the C-terminal heptad repeat region (CHR) of gp41, is the only clinically approved HIV-1 fusion inhibitor, but it easily induces drug resistance and is not active on HIV-2. In this study, we first demonstrated that the M-T hook structure was also vital to enhancing the binding stability and inhibitory activity of diverse CHR-based peptide inhibitors. We then designed a novel short peptide (23-mer), termed 2P23, by introducing the M-T hook structure, HIV-2 sequences, and salt bridge-forming residues. Promisingly, 2P23 was a highly stable helical peptide with high binding to the surrogate targets derived from HIV-1, HIV-2, and simian immunodeficiency virus (SIV). Consistent with this, 2P23 exhibited potent activity in inhibiting diverse subtypes of HIV-1 isolates, T20-resistant HIV-1 mutants, and a panel of primary HIV-2 isolates, HIV-2 mutants, and SIV isolates. Therefore, we conclude that 2P23 has high potential to be further developed for clinical use, and it is also an ideal tool for exploring the mechanisms of HIV-1/2- and SIV-mediated membrane fusion. IMPORTANCE The peptide drug T20 is the only approved HIV-1 fusion inhibitor, but it is not active on HIV-2 isolates, which have currently infected 1 to 2 million people and continue to spread worldwide. Recent studies have demonstrated that the M-T hook structure can greatly enhance the binding and antiviral activities of gp41 CHR-derived inhibitors, especially for short peptides that are otherwise inactive. By combining the hook structure, HIV-2 sequence, and salt bridge-based strategies, the short peptide 2P23 has been successfully designed. 2P23 exhibits prominent advantages over many other peptide fusion inhibitors, including its potent and broad activity on HIV-1, HIV-2, and even SIV isolates, its stability as a helical, oligomeric peptide, and its high binding to diverse targets. The small size of 2P23 would benefit its synthesis and significantly reduce production cost. Therefore, 2P23 is an ideal candidate for further development, and it also provides a novel tool for studying HIV-1/2- and SIV-mediated cell fusion.

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Antiretroviral Drug Resistance in Human Immunodeficiency Virus Type 2

Cited by 72 publications

References 89 publications

Cell-Associated Viral Burden Provides Evidence of Ongoing Viral Replication in Aviremic HIV-2-Infected Patients

Cell-Associated Viral Burden Provides Evidence of Ongoing Viral Replication in Aviremic HIV-2-Infected Patients

Multiclass Primary Antiretroviral Drug Resistance in a Patient Presenting HIV-1/2 Dual Infection

A Helical Short-Peptide Fusion Inhibitor with Highly Potent Activity against Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus

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