Role of Baseline pol Genotype in HIV-1 Fitness Evolution

Department of Virology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
JAIDS Journal of Acquired Immune Deficiency Syndromes (Impact Factor: 4.56). 08/2003; 33(4):448-60. DOI: 10.1097/00126334-200308010-00005
Source: PubMed


Viral fitness can be modified upon development of antiretroviral drug resistance, usually by selection of compensatory mutations. In this study, we have used HIV-1 isolates from individuals receiving a protease inhibitor (PI)-based regimen to analyze the impact of basal genetic background on viral fitness evolution. Paired plasma samples and HIV-1 isolates were obtained from 10 PI-naive HIV-infected individuals enrolled in 2 different studies of combination antiretroviral therapy. Genomic regions from pol and env were sequenced. Viral fitness was measured using growth competition experiments followed by heteroduplex tracking analysis. Baseline genotypic analyses of pol showed that 9 of 10 viruses had a different degree of secondary mutations in the protease gene at codons associated with PI resistance (i.e., 10I, 36I, 63P, 71T, and 77I). After 48 weeks of PI-based therapy, a strong correlation was observed between protease genetic divergence and viral fitness difference (r = 0.78, P = 0.03), but not with reverse transcription or Env divergence, suggesting that genotypic changes in the protease gene were driving HIV-1 evolution in these patients. As expected, an inverse correlation was observed between the number of protease and reverse transcription primary mutations and viral fitness (r = -0.65, P < 0.0001). However, our results suggest that the preexistence of secondary mutations in protease genetic background may have implications in HIV-1 fitness evolution and virologic response to antiretroviral therapy.


Available from: Hector Rafael Rangel, Jan 16, 2015
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    • "Subsequent emergence of secondary mutations is thought to compensate or dampen this fitness loss [10]. An alternative hypothesis suggests that these 'secondary' mutations actually emerge first under drug selection to compensate and provide a framework for the emergence of primary drug-resistance mutations [11]. Regardless, the pathway to PI resistance under PI treatment is extremely complex and likely affected by both the baseline protease sequence of the HIV-1 population and additional selective pressures, for example, overlapping cytotoxic T cell epitopes and maintaining recognition of eight cleavage sites. "
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    ABSTRACT: Approximately 20 years has passed since the first human trial with HIV-1 protease inhibitors (PIs). PIs set the stage for combination therapy in the mid '90s but are now rarely used in first line combination therapy and reserved for salvage therapy. Initially, resistance to PIs was deemed unlikely due to the small enzymatic target with limited genetic diversity, the extended drug binding site in PR, and the need to cleave multiple sites in the HIV-1 precursor proteins. However, a highly PI resistant virus can emerge during treatment and is found to harbor a collection of primary drug resistant mutations near the drug/substrate binding site as well as secondary mutations that compensate for fitness loss. For years, the research field has debated the impact of these secondary mutations on the emergence rates of high level PI resistance. A recent study by Theys et al poses a more pertinent question related to disease progression in patients newly infected with virus harboring secondary PI-associated polymorphisms. They show that increased rates of disease progression, inferred by increased viral loads and decreased CD4 cell counts, correlate with a fitness score of the infecting virus. The modeled fitness scores increased with an accumulation of these secondary PI mutations, and not due to any one specific polymorphism. Please see related article:
    BMC Medicine 10/2012; 10(1):114. DOI:10.1186/1741-7015-10-114 · 7.25 Impact Factor
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    • "Furthermore, in the context of transmission, 'fitness' per se may not necessarily equate to infectivity. The impact of measures of fitness on the transmission of resistant HIV, remains an area of research activity (Brenner et al., 2002; Goudsmit et al., 1997; Martinez-Picadao et al., 1999; Simon et al., 2003; Weber et al., 2003). Since transmission of resistance is now well documented, the use of baseline resistance testing of newly diagnosed HIV infections is likely to become more routine (Little et al., 2002), especially where some resistance mutations appear to persist or become 'fixed' within a local HIV-infected population (Taylor et al., 2003), making the transmission of HIV resistance more likely. "
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    ABSTRACT: The use of highly-active anti-retroviral therapy (HAART) for treating HIV infections is increasing. Recent studies have demonstrated that HAART is improving both the length and quality of life in HIV-infected patients. Resistant strains of HIV arise when drug adherence is poor. This can lead to the transmission of drug-resistant strains of HIV to susceptible individuals. This can lead to suboptimal first-line therapy, if the resistance profile of the transmitted virus is unknown. To review the mechanisms of how drug resistance arises; the methods used to characterise drug resistance; the problems arising with compliance leading to the development of drug-resistant HIV strains; the evidence for the incidence, prevalence and trends in the transmission of resistant HIV strains in different risk groups; and the evidence of suboptimal response to first-line therapy where transmission of a resistant HIV strain has occurred. On the basis of this, a case is presented for the routine resistance testing of all newly diagnosed HIV-infected individuals. Literature review. There is evidence, though limited at present, that transmission of drug-resistant HIV strains can lead to suboptimal response to first-line therapy in newly diagnosed HIV-infected individuals. As the use of HAART can only increase in the future, and compliance will always be a problem in such HAART-treated patients, baseline resistance testing should become a routine part of their management.
    Journal of Clinical Virology 06/2004; 30(1):1-10. DOI:10.1016/j.jcv.2003.12.002 · 3.02 Impact Factor
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