HIV-1 genetic diversity and drug resistance among treatment naïve patients from Southern Brazil: An association of HIV-1 subtypes with exposure categories

Gräf, Tiago; Passaes, Caroline; Ferreira, Luis G.E.; Grisard, Edmundo C.; Morgado, Mariza G.; Bello, Gonzalo; Pinto, Aguinaldo Roberto

doi:10.1016/j.jcv.2011.04.011

Cited by 37 publications

(42 citation statements)

References 37 publications

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“…In terms of molecular diversity, our results corroborate previous studies that also reported a large dominance of subtype C (ϳ65%) in SC state (30)(31)(32)(33) and a more diverse epidemic in RS state, mainly because of the high prevalence of BC mosaic forms in the latter (ϳ25%) (34)(35)(36). In both states, a low prevalence of subtype F1 and BF1 recombinants (ϳ3%) was observed, while this frequency can reach up to 20% in northern regions of Brazil (37,38) and 40% in Argentina (39).…”

Section: Discussionsupporting

confidence: 91%

“…In SC, we observed an association between the het- erosexual group and HIV-1C, and the same association was previously reported in the state capital city of Florianópolis (30). The lower prevalence of BC mosaic strains in SC might be a consequence of the segregation of HIV-1C and -B in separate transmission chains, a scenario that was not observed in our sampling from RS state, where a higher number of mosaic strains was observed.…”

Section: Discussionsupporting

confidence: 90%

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Comprehensive Characterization of HIV-1 Molecular Epidemiology and Demographic History in the Brazilian Region Most Heavily Affected by AIDS

Gräf

Fritsch

Medeiros

et al. 2016

J Virol

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The high incidence of AIDS cases and the dominance of HIV-1 subtype C infections are two features that distinguish the HIV-1 epidemic in the two southernmost Brazilian states (Rio Grande do Sul [RS] and Santa Catarina [SC]) from the epidemic in other parts of the country. Nevertheless, previous studies on HIV molecular epidemiology were conducted mainly in capital cities, and a more comprehensive understanding of factors driving this unique epidemic in Brazil is necessary. Blood samples were collected from individuals in 13 municipalities in the Brazilian southern region. HIV-1 env and pol genes were submitted to phylogenetic analyses for assignment of subtype, and viral population phylodynamics were reconstructed by applying Skygrid and logistic coalescent models in a Bayesian analysis. A high prevalence of subtype C was observed in all sampled locations; however, an increased frequency of recombinant strains was found in RS, with evidence for new circulating forms (CRFs). In the SC state, subtype B and C epidemics were associated with distinct exposure groups. Although logistic models estimated similar growth rates for HIV-1 subtype C (HIV-1C) and HIV-1B, a Skygrid plot reveals that the former epidemic has been expanding for a longer time. Our results highlight a consistent expansion of HIV-1C in south Brazil, and we also discuss how heterosexual and men who have sex with men (MSM) transmission chains might have impacted the current prevalence of HIV-1 subtypes in this region. IMPORTANCEThe AIDS epidemic in south Brazil is expanding rapidly, but the circumstances driving this condition are not well known. A high prevalence of HIV-1 subtype C was reported in the capital cities of this region, in contrast to the subtype B dominance in the rest of the country. This study sought to comparatively investigate the HIV-1 subtype B and C epidemics by sampling individuals from several cities in the two states with the highest AIDS incidences in Brazil. Our analyses showed distinct epidemic growth curves for the two epidemics, and we also found evidence suggesting that separate transmission chains may be impacting the viral phylodynamics and the emergence of new recombinant forms. High-level molecular diversity is one of the main features of HIV-1. Due to the very high replication rate and the lack of a proofreading activity of the viral reverse transcriptase (RT) enzyme, HIV-1 group M, the pandemic strain, has evolved into a diverse number of variants (1). Among 9 HIV-1 group M subtypes, HIV-1 subtype C (HIV-1C) is responsible for Ͼ50% of infections worldwide, occurring mostly in southern and east African countries and India. HIV-1B, in turn, is widely dispersed throughout the world, being the dominant strain in Europe and in the Americas, but with a worldwide prevalence of only 10% (1, 2). The high level of variability of HIV-1 is also a consequence of the genetic recombination process, which can occur in unique recombinant forms (URFs), when fewer than three individuals are infected, or in circulating forms (C...

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 90%

Comprehensive Characterization of HIV-1 Molecular Epidemiology and Demographic History in the Brazilian Region Most Heavily Affected by AIDS

Gräf

Fritsch

Medeiros

et al. 2016

J Virol

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“…Several studies have reported an increase in HIV-1C prevalence in that region. [8][9][10][11][12][13][14][15][16] In the city of Rio Grande, one of the foci of this study, such an increase is clearly evident: from 22% in 2002 to 56% in 2010. 16,17 The introduction of highly active antiretroviral therapy (HAART) in HIV-infected patients is associated with a marked reduction in morbidity and mortality.…”

Section: Introductionmentioning

confidence: 79%

Identification of Novel Resistance-Related Polymorphisms in HIV-1 Subtype C RT Connection and RNase H Domains from Patients Under Virological Failure in Brazil

Barral

Sousa

Santos

et al. 2017

AIDS Research and Human Retroviruses

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Mutations in the connection and RNase H C-terminal reverse transcriptase (RT) domains of HIV-1 have been shown to impact drug resistance to RT inhibitors. However, their impact in the context of non-B subtypes has been poorly assessed. This study aimed to characterize resistance-related mutations in the C-terminal portions of RT in treatment-failing patients from southern Brazil, a region with endemic HIV-1 subtype C (HIV-1C). Viral RNA was isolated and reverse transcribed from 280 infected subjects, and genomic regions were analyzed by polymerase chain reaction, DNA sequencing, and phylogenetic analysis. Two novel mutations, M357R and E529D, were evidenced in Brazilian HIV-1C strains from treatment-failing patients. In global viral isolates of subjects on treatment, M357R was selected in HIV-1C and CRF01_AE and E529D was selected in HIV-1 subtype B (HIV-1B). While most C-terminal RT mutations described for HIV-1B also occur in HIV-1C, this work pinpointed novel mutations that display subtype-specific predominance or occurrence.

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“…There are seven NRTIs approved for current clinical use, including the nucleoside emtricitabine (FTC) and the nucleotide tenofovir (TFV). Unfortunately, the frequent use of these drugs has resulted in the emergence of resistant virus strains (7,8,10,18). New compounds with potent activity on a wide range of isolates, including NRTI-resistant strains, are critically needed.…”

mentioning

confidence: 99%

Response of Simian Immunodeficiency Virus to the Novel Nucleoside Reverse Transcriptase Inhibitor 4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine In Vitro and In Vivo

Murphey‐Corb

Rajakumar

Michael

et al. 2012

Antimicrob Agents Chemother

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e Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) are essential components in first-line therapy for human immunodeficiency virus (HIV) infection. However, long-term treatment with existing NRTIs can be associated with significant toxic side effects and the emergence of drug-resistant strains. The identification of new NRTIs for the continued management of HIVinfected people therefore is paramount. In this report, we describe the response of a primary isolate of simian immunodeficiency virus (SIV) to 4=-ethynyl-2-fluoro-2=-deoxyadenosine (EFdA) both in vitro and in vivo. EFdA was 3 orders of magnitude better than tenofovir (TFV), zidovudine (AZT), and emtricitabine (FTC) in blocking replication of SIV in monkey peripheral blood mononuclear cells (PBMCs) in vitro, and in a preliminary study using two SIV-infected macaques with advanced AIDS, it was highly effective at treating SIV infection and AIDS symptoms in vivo. Both animals had 3-to 4-log decreases in plasma virus burden within 1 week of EFdA therapy (0.4 mg/kg of body weight, delivered subcutaneously twice a day) that eventually became undetectable. Clinical signs of disease (diarrhea, weight loss, and poor activity) also resolved within the first month of treatment. No detectable clinical or pathological signs of drug toxicity were observed within 6 months of continuous therapy. Virus suppression was sustained until drug treatment was discontinued, at which time virus levels rebounded. Although the rebound virus contained the M184V/I mutation in the viral reverse transcriptase, EFdA was fully effective in maintaining suppression of mutant virus throughout the drug treatment period. These results suggest that expanded studies with EFdA are warranted. N ucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) have proven highly effective in both the treatment of chronic human immunodeficiency virus (HIV) infection (11) and, more recently, as a promising microbicidal prevention strategy for sexually transmitted virus (12). There are seven NRTIs approved for current clinical use, including the nucleoside emtricitabine (FTC) and the nucleotide tenofovir (TFV). Unfortunately, the frequent use of these drugs has resulted in the emergence of resistant virus strains (7,8,10,18). New compounds with potent activity on a wide range of isolates, including NRTI-resistant strains, are critically needed.We and others have previously described a group of 4=-substituted NRTIs that are more potent and have higher selectivity indices in vitro than existing NRTIs (9,13,14,15,16,17). One of the most potent of these compounds, 4=-ethynyl-2-fluoro-2=de-oxyadenosine (EFdA), inhibits HIV-1 replication in primary peripheral blood mononuclear cells (PBMC) with a 50% effective concentration (EC 50 ) of 50 pM, a potency 4 orders of magnitude greater than that of TFV and 400-fold greater than that of AZT (15). It is also nontoxic in vitro at concentrations as high as 10 M, which results in an in vitro selectivity index greater than 200,000. Furthermore, EFdA retains...

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HIV-1 genetic diversity and drug resistance among treatment naïve patients from Southern Brazil: An association of HIV-1 subtypes with exposure categories

Cited by 37 publications

References 37 publications

Comprehensive Characterization of HIV-1 Molecular Epidemiology and Demographic History in the Brazilian Region Most Heavily Affected by AIDS

Comprehensive Characterization of HIV-1 Molecular Epidemiology and Demographic History in the Brazilian Region Most Heavily Affected by AIDS

Identification of Novel Resistance-Related Polymorphisms in HIV-1 Subtype C RT Connection and RNase H Domains from Patients Under Virological Failure in Brazil

Response of Simian Immunodeficiency Virus to the Novel Nucleoside Reverse Transcriptase Inhibitor 4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine In Vitro and In Vivo

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