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Human immunodeficiency virus type 1 group m protease in cameroon: genetic diversity and protease inhibitor mutational features.

ABSTRACT: To establish a baseline for monitoring resistance to protease inhibitors (PIs) and examining the efficacy of their use among persons in Cameroon infected with human immunodeficiency virus type 1 (HIV-1), we analyzed genetic variability and PI resistance-associated substitutions in PCR-amplified protease (PR) sequences in strains isolated from 110 HIV-1-infected, drug-naïve Cameroonians. Of the 110 strains, 85 were classified into six HIV-1 PR subtypes, A (n = 1), B (n = 1), F (n = 4), G (n = 7), H (n = 1), and J (n = 7), and a circulating recombinant form, CRF02-AG (n = 64). PR genes from the remaining 25 (23%) specimens were unclassifiable, whereas 2% (7 of 301) unclassifiable PR sequences were reported for a global collection. Two major PI resistance-associated mutations, 20M and 24I, were detected in strains from only two specimens, whereas secondary mutations were found in strains from all samples except one strain of subtype B and two strains of CRF02-AG. The secondary mutations showed the typical PI resistance-associated pattern for non-subtype B viruses in both classifiable and unclassifiable PR genes, with 36I being the predominant (99%) mutation, followed by 63P (18%), 20R (15%), 77I (13%), and 10I or 10V (11%). Of these mutations, dual and triple PI resistance-associated substitutions were found in 38% of all the Cameroonian strains. Compared with classifiable PR sequences, unclassifiable sequences had significantly more dual and triple substitutions (64% versus 30%; P = 0.004). Phenotypic and clinical evaluations are needed to estimate whether PI resistance during antiretroviral drug treatment occurs more rapidly in individuals infected with HIV-1 strains harboring multiple PI resistance-associated substitutions. This information may be important for determination of appropriate drug therapies for HIV-1-infected persons in Cameroon, where more than one-third of HIV-1 strains were found to carry dual and triple minor PI resistance-associated mutations.

SUBMITTER: Fonjungo PN

PROVIDER: S-EPMC120267 | biostudies-literature | 2002 Mar

REPOSITORIES: biostudies-literature

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Human immunodeficiency virus type 1 group m protease in cameroon: genetic diversity and protease inhibitor mutational features.

Fonjungo Peter N PN Mpoudi Eitel N EN Torimiro Judith N JN Alemnji George A GA Eno Laura T LT Lyonga Esther J EJ Nkengasong John N JN Lal Renu B RB Rayfield Mark M Kalish Marcia L ML Folks Thomas M TM Pieniazek Danuta D

Journal of clinical microbiology 20020301 3

To establish a baseline for monitoring resistance to protease inhibitors (PIs) and examining the efficacy of their use among persons in Cameroon infected with human immunodeficiency virus type 1 (HIV-1), we analyzed genetic variability and PI resistance-associated substitutions in PCR-amplified protease (PR) sequences in strains isolated from 110 HIV-1-infected, drug-naïve Cameroonians. Of the 110 strains, 85 were classified into six HIV-1 PR subtypes, A (n = 1), B (n = 1), F (n = 4), G (n = 7), ...[more]

PMID: 11880402

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Project description:Human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) are two highly variable RNA viruses that cause chronic infections in humans. Although HCV likely preceded the AIDS epidemic by some decades, the global spread of both viruses is a relatively recent event. Nevertheless, HCV global diversity is higher than that of HIV-1. To identify differences in mutant diversity, we compared the HIV-1 protease and HCV NS3 protease quasispecies. Three protease gene quasispecies samples per virus, isolated from a total of six infected patients, were genetically and phenotypically analyzed at high resolution (HIV-1, 308 individual clones; HCV, 299 clones). Single-nucleotide variant frequency did not differ between quasispecies from the two viruses (HIV-1, 2.4 × 10(-3) ± 0.4 × 10(-3); HCV, 2.1 × 10(-3) ± 0.5 × 10(-3)) (P = 0.1680). The proportion of synonymous substitutions to potential synonymous sites was similar (3.667 ± 0.6667 and 2.183 ± 0.9048, respectively) (P = 0.2573), and Shannon's entropy values did not differ between HIV-1 and HCV (0.84 ± 0.02 and 0.83 ± 0.12, respectively) (P = 0.9408). Of note, 65% (HIV-1) and 67% (HCV) of the analyzed enzymes displayed detectable protease activity, suggesting that both proteases have a similar mutational robustness. In both viruses, there was a rugged protease enzymatic activity landscape characterized by a sharp peak, representing the master sequence, surrounded by a collection of diverse variants present at lower frequencies. These results indicate that nucleotide quasispecies diversification during chronic infection is not responsible for the higher worldwide genetic diversity observed in HCV.HCV global diversity is higher than that of HIV-1. We asked whether HCV genetic diversification during infection is responsible for the higher worldwide genetic diversity observed in HCV. To this end, we analyzed and compared the genotype and enzymatic activities of HIV-1 and HCV protease quasispecies existing in infected individuals. Our results indicate that HIV-1 and HCV protease quasispecies have very similar genetic diversity and comparable rugged enzymatic activity landscapes. Therapy for HCV has expanded, with new therapeutic agents such as the direct-acting antivirals (DAAs). DAAs, which target HCV NS3 protease and other virus proteins, have improved cure rates. However, major questions remain to be elucidated regarding the virologic correlates of HCV eradication. The findings shown here may help our understanding of the different therapeutic responses observed during chronic HCV infection.

Project description:The initiation of drug therapy or the addition of a new drug to preexisting therapy can have a significant impact on human immunodeficiency virus type 1 (HIV-1) populations within a person. Drug therapy directed at reverse transcriptase and protease can result in dramatic decreases in virus load, causing a contraction in the virus population that represents a potential genetic bottleneck as a subset of virus with genomes carrying resistance mutations repopulate the host. While this bottleneck exerts an effect directly on the region that is being targeted by the drugs, it also affects other regions of the viral genome. We have applied heteroduplex tracking assays (HTA) specific to variable regions 1 and 2 (V1/V2) and variable region 3 (V3) of the HIV-1 env gene to analyze the effect of a genetic bottleneck created by the selection of resistance to ritonavir, a protease inhibitor. Subjects were classified into groups on the basis of the extent of the initial drop in virus load and the duration of virus load reduction. Subjects with a strong initial drop in virus load exhibited a loss of heterogeneity in the env region at virus load rebound; in contrast, subjects with a weak initial drop in virus load exhibited little to no loss of heterogeneity at virus load rebound in either region of env examined. The duration of virus load reduction also affected env populations. Subjects that had prolonged reductions exhibited slower population diversification and the appearance of new V1/V2 species after rebound. The longer reduction of virus load in these subjects may have allowed for improved immune system function, which in turn could have selected for new escape mutants. Subjects with rapid rebound quickly reequilibrated the entry env variants back into the resistant population. When the pro gene developed further resistance mutations subsequent to virus load rebound, no changes were observed in V1/V2 or V3 populations, suggesting that the high virus loads allowed the env populations to reequilibrate rapidly. The rapid equilibration of env variants during pro gene sequence transitions at high virus load suggests that recombination is active in defining the HIV-1 sequence population. Conversely, part of the success of suppressive antiviral therapy may be to limit the potential for evolution through recombination, which requires dually infected cells.

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Human immunodeficiency virus type 1 group m protease in cameroon: genetic diversity and protease inhibitor mutational features.

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Human immunodeficiency virus type 1 group m protease in cameroon: genetic diversity and protease inhibitor mutational features.

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