Differential Drug Resistance Acquisition in HIV-1 of Subtypes B and C

Soares, Esmeralda A.; Santos, André F.; SOUSA, T; Sprinz, Eduardo; Martínez, Ana Maria Barral de; Silveira, Jussara María; Tanuri, Amílcar; Soares, Marcelo A.

doi:10.1371/journal.pone.0000730

Cited by 57 publications

(57 citation statements)

References 34 publications

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“…51 In a study of patients from Rio Grande do Sul, Brazil, in a population infected by subtypes B and C, a lower rate of accumulation of mutations was found in subtype C than subtype B. 52 However, certain NRTI mutations such as K65R have been shown to develop more quickly in subtype C than in other subtypes. 13 NNRTI-associated mutations were found in 98.5% of patients in virologic failure.…”

Section: Hiv-1 Subtype On Drug Resistance Mutations In Nigeriamentioning

confidence: 99%

Impact of HIV Type 1 Subtype on Drug Resistance Mutations in Nigerian Patients Failing First-Line Therapy

Chaplin

Eisen

Idoko

et al. 2011

AIDS Research and Human Retroviruses

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A diverse array of non-subtype B HIV-1 viruses circulates in Africa and dominates the global pandemic. It is important to understand how drug resistance mutations in non-B subtypes may develop differently from the patterns described in subtype B. HIV-1 reverse transcriptase and protease sequences from 338 patients with treatment failure to first-line ART regimens were evaluated. Multivariate logistic regression was used to examine the effect of subtype on each mutation controlling for regimen, time on therapy, and total mutations. The distribution of HIV-1 subtypes included CRF02_AG (45.0%), G (37.9%), CRF06_cpx (4.4%), A (3.6%), and other subtypes or recombinant sequences (9.2%). The most common NRTI mutations were M184V (89.1%) and thymidine analog mutations (TAMs). The most common NNRTI mutations were Y181C (49.7%), K103N (36.4%), G190A (26.3%), and A98G (19.5%). Multivariate analysis showed that CRF02_AG was less likely to have the M41L mutation compared to other subtypes [adjusted odds ratio (AOR) ¼ 0.35; p ¼ 0.022]. Subtype A patients showed a 42.5-fold increased risk (AOR ¼ 42.5, p ¼ 0.001) for the L210W mutation. Among NNRTI mutations, subtype G patients had an increased risk for A98G (AOR ¼ 2.40, p ¼ 0.036) and V106I (AOR ¼ 6.15, p ¼ 0.010), whereas subtype CRF02_AG patients had an increased risk for V90I (AOR ¼ 3.16; p ¼ 0.003) and a decreased risk for A98G (AOR ¼ 0.48, p ¼ 0.019). Five RT mutations were found to vary significantly between different non-B West African subtypes. Further study to understand the clinical impact of subtype-specific diversity on drug resistance will be critically important to the continued success of ART scale-up in resource-limited settings.

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Section: Hiv-1 Subtype On Drug Resistance Mutations In Nigeriamentioning

confidence: 99%

Impact of HIV Type 1 Subtype on Drug Resistance Mutations in Nigerian Patients Failing First-Line Therapy

Chaplin

Eisen

Idoko

et al. 2011

AIDS Research and Human Retroviruses

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“…Brenner et al (3) have shown for subtype C that the 65R mutation occurs faster in cell culture in response to tenofovir pressure than it does in subtype B. A study from Brazil looked at 160 sequences from treatment-experienced HIV-1-infected individuals (21). It was found that subtype C viruses accumulated drug resistance mutations at a lower rate than subtype B isolates after at least 4 years of treatment.…”

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confidence: 99%

“…The same study showed that the 41L mutation was rare compared to what was expected from the subtype B data; in fact, it did not occur in this study at all. In Brazil, where subtypes B and C cocirculate in the same population, a study found that the 41L and 210W TAM mutations occurred more frequently in subtype B than in subtype C (21).…”

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confidence: 99%

Replicative Capacity Differences of Thymidine Analog Resistance Mutations in Subtype B and C Human Immunodeficiency Virus Type 1

Armstrong¹,

Lee²,

Essex³

2009

J Virol

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In order to understand the impact of zidovudine resistance and thymidine analog mutations (TAMs) on subtype C human immunodeficiency virus type 1, we created mutants in subtype C reverse transcriptase (RT). The subtype B RT was placed in a subtype C backbone to act as a control. Mutants and wild-type (WT) virus were competed in a head-to-head competition assay to determine how different clones grew in the same culture. Different viruses were distinguished by sequence tags in nef and a quantitative-PCR assay. The 67N and 70R accessory mutations gave an advantage over the WT in subtype C, but these mutations in subtype B had replication capacities similar to that of the WT. Of the triple mutants examined, the TAM-1 types, 41L210W215Y, were the most fit in both subtypes, but only in subtype C was the replication capacity the same as that of the WT. The TAM-2 mutants, 67N70R215F, had the slowest replication in both clones. The mixed TAM pathway mutant, 67N70R215Y, in subtype C had a significant advantage over the TAM-2 mutant, but this was not seen in subtype B. When the WT viruses were competed with each other, the subtype B RT had enhanced replication relative to subtype C. The increased capacities of the 67N and 70R mutations may indicate that there will be greater transmitted resistance and persistence in a subtype C setting than what is known for subtype B.Human immunodeficiency virus type 1 (HIV-1) remains a leading cause of morbidity and mortality worldwide. With the advent of highly active antiretroviral therapy (HAART), the life expectancy for those on treatment has increased dramatically. Given HIV-1's ability to replicate and mutate quickly, drug resistance has been a significant problem since treatment began. While drug resistance has been studied extensively in the developed world, HIV-1 subtypes that affect developing countries are rarely targeted for drug resistance research (9).Sub-Saharan Africa continues to bear the bulk of the burden of the HIV-1 epidemic, with 22.5 million infections out of the 33.2 million global infections (22). However, the developed world has begun to take notice by contributing unprecedented amounts of money and expertise to combat the epidemic. Much of the support for developing countries has gone toward drug treatment programs for those in need, making research into drug resistance of paramount importance. As more and more people get the treatment they require, drug resistance will increasingly play a major role in the epidemic in these hard-hit areas, where expertise and laboratory tests for clinical monitoring are often not available.Some in vivo data point to different patterns of resistance between subtypes. Brenner et al. (3) have shown for subtype C that the 65R mutation occurs faster in cell culture in response to tenofovir pressure than it does in subtype B. A study from Brazil looked at 160 sequences from treatment-experienced HIV-1-infected individuals (21). It was found that subtype C viruses accumulated drug resistance mutations at a lower rate than subtype B i...

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“…Of these, group M, which is responsible for the majority of infections worldwide, is further subdivided into 9 subtypes or clades (subtypes A to K) (63). Previous reports (46,(64)(65)(66) suggested that there are differences between subtypes B and C in the accessory genes, leading to specific differences in their abilities to carry out a particular function. Hence, we were interested to see if there is any such difference with respect to inhibition of whole-cell ubiquitination by Vpr.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Vpr Redirects Host Ubiquitination Pathway

Arora

Verma

Banerjea

2014

J Virol

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HIV-1 modulates key host cellular pathways for successful replication and pathogenesis through viral proteins. By evaluating the hijacking of the host ubiquitination pathway by HIV-1 at the whole-cell level, we now show major perturbations in the ubiquitinated pool of the host proteins post-HIV-1 infection. Our overexpression-and infection-based studies of T cells with wildtype and mutant HIV-1 proviral constructs showed that Vpr is necessary and sufficient for reducing whole-cell ubiquitination. Mutagenic analysis revealed that the three leucine-rich helical regions of Vpr are critical for this novel function of Vpr, which was independent of its other known cellular functions. We also validated that this effect of Vpr was conserved among different subtypes (subtypes B and C) and circulating recombinants from Northern India. Finally, we establish that this phenomenon is involved in HIV-1-mediated diversion of host ubiquitination machinery specifically toward the degradation of various restriction factors during viral pathogenesis. IMPORTANCEHIV-1 is known to rely heavily on modulation of the host ubiquitin pathway, particularly for counteraction of antiretroviral restriction factors, i.e., APOBEC3G, UNG2, and BST-2, etc.; viral assembly; and release. Reports to date have focused on the molecular hijacking of the ubiquitin machinery by HIV-1 at the level of E3 ligases. Interaction of a viral protein with an E3 ligase alters its specificity to bring about selective protein ubiquitination. However, in the case of infection, multiple viral proteins can interact with this multienzyme pathway at various levels, making it much more complicated. Here, we have addressed the manipulation of ubiquitination at the whole-cell level post-HIV-1 infection. Our results show that HIV-1 Vpr is necessary and sufficient to bring about the redirection of the host ubiquitin pathway toward HIV-1-specific outcomes. We also show that the three leucinerich helical regions of Vpr are critical for this effect and that this ability of Vpr is conserved across circulating recombinants. Our work, the first of its kind, provides novel insight into the regulation of the ubiquitin system at the whole-cell level by HIV-1.

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Differential Drug Resistance Acquisition in HIV-1 of Subtypes B and C

Cited by 57 publications

References 34 publications

Impact of HIV Type 1 Subtype on Drug Resistance Mutations in Nigerian Patients Failing First-Line Therapy

Impact of HIV Type 1 Subtype on Drug Resistance Mutations in Nigerian Patients Failing First-Line Therapy

Replicative Capacity Differences of Thymidine Analog Resistance Mutations in Subtype B and C Human Immunodeficiency Virus Type 1

HIV-1 Vpr Redirects Host Ubiquitination Pathway

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