Drug Susceptibility of Subtypes A, B, C, D, and E Human Immunodeficiency Virus Type 1 Primary Isolates

Palmer, Sarah; Alaeus, Annette; Albert, Jan; Cox, Susan

doi:10.1089/aid.1998.14.157

Cited by 96 publications

(61 citation statements)

References 35 publications

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“…1B, right panel). These data were consistent with the observation that the different subtypes of major group (group M) HIV-1 (19) exhibited similar susceptibilities to AZT or ddI when the viruses were from individuals receiving no antiviral drugs (27). Furthermore, the phenotypic change in the NH2 viruses was very similar to that seen in HIV-1 strains circulating in Europe and North America, supporting the notion (4, 25, 31) that AZT-ddI combination therapy often selects AZT-resistant variants lacking ddI resistance.…”

supporting

confidence: 90%

“…These data and the predominance of AZT-sensitive strains in subtype E (Fig. 1) (27) suggest that the subtype E RT protein generally has a structure sensitive to the RT inhibitors. On the other hand, the above-mentioned data indicate that subtype E RT inherits amino acids that are distinct from those of subtype B RT and may cause local modifications in p66 subdomains.…”

mentioning

confidence: 83%

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Convergent Evolution of Reverse Transcriptase (RT) Genes of Human Immunodeficiency Virus Type 1 Subtypes E and B following Nucleoside Analogue RT Inhibitor Therapies

Sato

Tomita

Shibamura

et al. 2000

J Virol

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Changes in the drug susceptibility, gene lineage, and deduced amino acid sequences of the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) subtype E following 3-azido-3-deoxythymidine (AZT) monotherapy or AZT-2,3-dideoxyinosine combination therapy were examined with sequential virus isolates from a single family. The changes were compared to those reported for HIV-1 subtype B, revealing striking similarities in selected phenotype and amino acids independent of differences in the RT backbone sequences that constantly distinguish the two subtypes. Particularly, identical amino acid substitutions were present simultaneously at four different positions (D67N, K70R, T215F, and K219Q) for high-level AZT resistance. These data suggest that HIV-1 subtypes E and B evolve convergently at the phenotypic and amino acid levels when the nucleoside analogue RT inhibitors act as selective forces.

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supporting

confidence: 90%

mentioning

confidence: 83%

Convergent Evolution of Reverse Transcriptase (RT) Genes of Human Immunodeficiency Virus Type 1 Subtypes E and B following Nucleoside Analogue RT Inhibitor Therapies

Sato

Tomita

Shibamura

et al. 2000

J Virol

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“…At the protease level the studies presented here support those observations. On the other hand, the few existing studies reporting susceptibility of clinical isolates from different HIV-1 subtypes to existing protease inhibitors have shown no difference or only small differences among subtypes (27,28). Drugresistance mutations in non-B HIV-1 subtypes are only beginning to be reported (24), and the effects arising from the combination of these mutations with the already existing polymorphisms in non-B subtypes are not yet known.…”

Section: Discussionmentioning

confidence: 99%

Catalytic efficiency and vitality of HIV-1 proteases from African viral subtypes

Velázquez‐Campoy

Todd

Vega

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

139

105

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The vast majority of HIV-1 infections in Africa are caused by the A and C viral subtypes rather than the B subtype prevalent in the United States and Western Europe. Genomic differences between subtypes give rise to sequence variations in the encoded proteins, including the HIV-1 protease. Because some amino acid polymorphisms occur at sites that have been associated with drug resistance in the B subtype, it is important to assess the effectiveness of protease inhibitors that have been developed against different subtypes. Here we report the enzymatic characterization of HIV-1 proteases with sequences found in drug-naïve Ugandan adults. The A protease used in these studies differs in seven positions (I13V͞E35D͞M36I͞R41K͞R57K͞H69K͞L89M) in relation to the consensus B subtype protease. Another protease containing a subset of these amino acid polymorphisms (M36I͞R41K͞H69K͞L89M), which are found in subtype C and other HIV subtypes, also was studied. Both proteases were found to have similar catalytic constants, kcat, as the B subtype. The C subtype protease displayed lower Km values against two different substrates resulting in a higher (2.4-fold) catalytic efficiency than the B subtype protease. Indinavir, ritonavir, saquinavir, and nelfinavir inhibit the A and C subtype proteases with 2.5-7-fold and 2-4.5-fold weaker Kis than the B subtype. When all factors are taken into consideration it is found that the C subtype protease has the highest vitality (4 -11 higher than the B subtype) whereas the A subtype protease exhibits values ranging between 1.5 and 5. These results point to a higher biochemical fitness of the A and C proteases in the presence of existing inhibitors.

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“…The majority of patients with heterosexual behavior carried nonsubtype-B HIV-1 isolates. An increasing prevalence of nonsubtype-B HIV-1 isolates in these subjects has already been described (16), and previous reports showed that these clades might be less susceptible in vitro to antiretroviral drugs (1,17).…”

Section: Discussionmentioning

confidence: 74%

High Prevalence of M184 Mutation among Patients with Viroimmunologic Discordant Responses to Highly Active Antiretroviral Therapy and Outcomes after Change of Therapy Guided by Genotypic Analysis

Nicastri

Sarmati

d’Ettorre³

et al. 2003

J Clin Microbiol

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Whether highly active antiretroviral therapy (HAART) should be modified in patients with persistent increases in CD4؉ T cells despite detectable viral loads is an unresolved question. Forty-three heavily pretreated human immunodeficiency virus (HIV)-infected patients with virologic failure during HAART were studied before a change of therapy guided by genotypic analysis and during follow-up. Patients with an increase in CD4 ؉ cell count (>100 cells/ml) over pre-HAART values were considered to be discordant patients (20 individuals), whereas patients with a lower increase or no increase in CD4 ؉ cell count were considered failing patients (23 individuals). Based on univariate analysis, a high CD4 ؉ cell count before antiretroviral treatment, homosexual behavior as a risk factor for HIV infection, reduced drug exposure to nonnucleoside reverse transcriptase inhibitors, low replicative capacity of HIV isolates, and more frequent detection of HIV isolates with a non-B subtype, an R5 biological phenotype, and M184V and T215Y/F mutations were factors associated with a discordant response to HAART. Based on multivariate analysis, only the M184V mutation remained significantly associated with a viroimmunologic discordant response (odds ratio, 25.48; 95% confidence interval, 1.43 to 453.93). No difference in lamivudine exposure was found between discordant (95%) and failing (91%) patients. Twelve months after the genotypic analysis-guided change of therapy, 3 discordant (15%) and 6 failing patients (26%) achieved undetectable viral loads (<50 copies/ml), whereas in patients with HIV RNA loads of >500 copies/ml, discordant responses were observed in 5 out of 15 discordant patients and in 4 out of 16 failing patients. A relationship between the M184V mutation and a viroimmunologic discordant response to HAART was found. After the genotypic analysis-driven change of therapy, similar rates of virologic suppression were detected in the two groups.The goal of highly active antiretroviral therapy (HAART) in patients with human immunodeficiency virus (HIV) infection is the complete suppression of viral replication. After initiation of HAART, the plasma viral load decreases to below the level of detection in many HIV-infected patients (3, 9, 13). On the other hand, in clinical practice, 40 to 70% of patients show virologic failure, generally defined as persistently detectable HIV RNA levels in plasma (5, 12).To date, the clinical significance of virologic failure remains unclear, but during partially suppressive therapy, the presence of circulating infectious-competent HIV type 1 (HIV-1) implies ongoing viral replication with the likely selection of drugresistant virus (6). A special subset of patients includes those exhibiting a sustained increase in CD4ϩ -T-cell count over 1 year of HAART, despite persistently high viral loads (10,18,20). This subset of viroimmunologically discordant patients accounts for approximately 30% of individuals receiving HAART; among them, during an 18-month follow-up period, the incidence of death or...

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Drug Susceptibility of Subtypes A, B, C, D, and E Human Immunodeficiency Virus Type 1 Primary Isolates

Cited by 96 publications

References 35 publications

Convergent Evolution of Reverse Transcriptase (RT) Genes of Human Immunodeficiency Virus Type 1 Subtypes E and B following Nucleoside Analogue RT Inhibitor Therapies

Convergent Evolution of Reverse Transcriptase (RT) Genes of Human Immunodeficiency Virus Type 1 Subtypes E and B following Nucleoside Analogue RT Inhibitor Therapies

Catalytic efficiency and vitality of HIV-1 proteases from African viral subtypes

High Prevalence of M184 Mutation among Patients with Viroimmunologic Discordant Responses to Highly Active Antiretroviral Therapy and Outcomes after Change of Therapy Guided by Genotypic Analysis

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