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: 4.39). 08/2003; 33(4):448-60. DOI: 10.1097/00126334-200308010-00005
Source: PubMed

ABSTRACT 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.

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    ABSTRACT: Most studies describing phenotypic resistance to integrase strand transfer inhibitors have analyzed viruses carrying only patient-derived HIV-1 integrase genes (INT-recombinant viruses). However, to date, many of the patients on INSTI-based treatment regimes, such as raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG) are infected with multidrug-resistant HIV-1 strains. Here we analyzed the effect of drug resistance mutations in Gag (p2/NCp7/p1/p6), protease (PR), reverse transcriptase (RT), and integrase (IN) coding regions on susceptibility to INSTIs and viral replicative fitness using a novel HIV-1 phenotyping assay. Initial characterization based on site-directed mutant INSTI-resistant viruses confirmed the effect of a series of INSTI mutations on reduced susceptibility to EVG and RAL and viral replicative fitness (0.6% to 99% relative to the HIV-1NL4-3 control). Two sets of recombinant viruses containing a 3,428-bp gag-p2/NCp7/p1/p6/pol-PR/RT/IN (p2-INT) or a 1,088 bp integrase (INT) patient-derived fragment were constructed from plasma samples obtained from 27 virologic failure patients participating in a 48-week dose-ranging study of elvitegravir, GS-US-183-0105. A strong correlation was observed when susceptibility to EVG and RAL was assayed using p2-INT- vs. INT-recombinant viruses (Pearson coefficient correlation 0.869 and 0.918, P<0.0001 for EVG and RAL, respectively), demonstrating that mutations in the protease and RT have limited effect on susceptibility to these INSTIs. On the other hand, the replicative fitness of viruses harboring drug resistance mutations in PR, RT, and IN was generally impaired compared to viruses carrying only INSTI-resistance mutations. Thus, in the absence of drug pressure, drug resistance mutations in the PR and RT contribute to decrease the replicative fitness of the virus already impaired by mutations in the integrase. The use of recombinant viruses containing most or all HIV-1 regions targeted by antiretroviral drugs might be essential to understand the collective effect of epistatic interactions in multidrug-resistant viruses.
    PLoS ONE 06/2013; 8(6):e65631. · 3.53 Impact Factor
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    ABSTRACT: The pol nucleotide sequences coding for protease and reverse transcriptase were examined to study the frequency of drug resistance mutations in HIV-1 subtype A in Russia. The sample included 141 HIV-infected subjects who had never received antiretroviral drugs before. Primary resistance mutations occurred at a low (less than 1%) frequency, while unusually high frequencies were observed for the secondary mutations causing substitutions V77I in protease (67%) and A62V in reverse transcriptase (63%). The V77I and A62V mutations were associated in most cases. HIV-1 isolates carrying both mutations (MutV77I/A62V) had several synonymous substitutions in pol, which was indicative of their common origin. Examination of a larger sample of HIV-1 isolates (N = 319) by hybridization with biological microchips and by restriction enzyme analysis showed that the MutV77I/A62V variant dominated in Russia in terms of both frequency (56%) and geographic distribution, prevailing in regions with the highest incidence of HIV-1 infection (e.g., Irkutsk, Samara, and Moscow regions). In addition, analysis revealed the genotypes that contained none of the V77I and A62V mutations or only one of them. The evolutionary relationships of the four HIV-1 variants and the role of pol gene polymorphism in replicative activity and drug resistance of HIV-1 are discussed.
    Molecular Biology 11/2005; 39(6):934-941. · 0.74 Impact Factor


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Jan 16, 2015