Drug resistance mutations and viral load in human immunodeficiency virus type 2 and dual HIV-1/HIV-2 infected patients in Ghana

The reverse transcriptase (RT) and protease genes from 12 human immunodeficiency virus type 2 (HIV-2)-infected individuals who had been exposed to antiretroviral drugs for longer than 6 months were examined for the presence of mutations which could be involved in drug resistance. Four individuals carried virus genotypes with amino acid substitutions potentially associated with resistance to nucleoside analogues: two at codon 70 (K→R) and two at codon 184 (M→V). Moreover, the latter two patients harbored a codon Q151M mutation which is associated to multidrug resistance in HIV-1, and one of these subjects carried some of the typically linked mutations at codons 65 and 69. With regard to the protease inhibitors, substitutions associated with resistance to protease inhibitors at codon 46 were observed in all individuals. Moreover, minor resistance mutations, as well as new ones of unknown meaning, were often seen in the protease gene. In conclusion, amino acid changes in the HIV-2 RT and protease genes which could be associated with drug resistance seem to occur at positions identical to those for HIV-1.

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Genotypic Testing for Human Immunodeficiency Virus Type 1 Drug Resistance

Clinical Microbiology Reviews ◽

10.1128/cmr.15.2.247-277.2002 ◽

2002 ◽

Vol 15 (2) ◽

pp. 247-277 ◽

Cited By ~ 176

Author(s):

Robert W. Shafer

Keyword(s):

Human Immunodeficiency Virus ◽

Drug Resistance ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Resistance Mutations ◽

Drug Resistance Mutations ◽

Immunodeficiency Virus ◽

Rt Inhibitors ◽

Hiv 1

SUMMARY There are 16 approved human immunodeficiency virus type 1 (HIV-1) drugs belonging to three mechanistic classes: protease inhibitors, nucleoside and nucleotide reverse transcriptase (RT) inhibitors, and nonnucleoside RT inhibitors. HIV-1 resistance to these drugs is caused by mutations in the protease and RT enzymes, the molecular targets of these drugs. Drug resistance mutations arise most often in treated individuals, resulting from selective drug pressure in the presence of incompletely suppressed virus replication. HIV-1 isolates with drug resistance mutations, however, may also be transmitted to newly infected individuals. Three expert panels have recommended that HIV-1 protease and RT susceptibility testing should be used to help select HIV drug therapy. Although genotypic testing is more complex than typical antimicrobial susceptibility tests, there is a rich literature supporting the prognostic value of HIV-1 protease and RT mutations. This review describes the genetic mechanisms of HIV-1 drug resistance and summarizes published data linking individual RT and protease mutations to in vitro and in vivo resistance to the currently available HIV drugs.

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Interactions Between Drug Resistance Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase

Journal of General Virology ◽

10.1099/0022-1317-75-5-951 ◽

1994 ◽

Vol 75 (5) ◽

pp. 951-957 ◽

Cited By ~ 99

Author(s):

B. A. Larder

Keyword(s):

Human Immunodeficiency Virus ◽

Drug Resistance ◽

Reverse Transcriptase ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Resistance Mutations ◽

Drug Resistance Mutations ◽

Immunodeficiency Virus

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Expanded Spectrum of Antiretroviral-Selected Mutations in Human Immunodeficiency Virus Type 2

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa026 ◽

2020 ◽

Vol 221 (12) ◽

pp. 1962-1972 ◽

Cited By ~ 1

Author(s):

Philip L Tzou ◽

Diane Descamps ◽

Soo-Yon Rhee ◽

Dana N Raugi ◽

Charlotte Charpentier ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Drug Resistance ◽

Amino Acid ◽

Meta Analysis ◽

Multiple Comparisons ◽

Resistance Mutations ◽

Drug Resistance Mutations ◽

Immunodeficiency Virus ◽

Hiv 1

Abstract Background HIV-1 and HIV-2 differ in their antiretroviral (ARV) susceptibilities and drug resistance mutations (DRMs). Methods We analyzed published HIV-2 pol sequences to identify HIV-2 treatment-selected mutations (TSMs). Mutation prevalences were determined by HIV-2 group and ARV status. Nonpolymorphic mutations were those in <1% of ARV-naive persons. TSMs were those associated with ARV therapy after multiple comparisons adjustment. Results We analyzed protease (PR) sequences from 483 PR inhibitor (PI)-naive and 232 PI-treated persons; RT sequences from 333 nucleoside RT inhibitor (NRTI)-naive and 252 NRTI-treated persons; and integrase (IN) sequences from 236 IN inhibitor (INSTI)-naive and 60 INSTI-treated persons. In PR, 12 nonpolymorphic TSMs occurred in ≥11 persons: V33I, K45R, V47A, I50V, I54M, T56V, V62A, A73G, I82F, I84V, F85L, L90M. In RT, 9 nonpolymorphic TSMs occurred in ≥10 persons: K40R, A62V, K70R, Y115F, Q151M, M184VI, S215Y. In IN, 11 nonpolymorphic TSMs occurred in ≥4 persons: Q91R, E92AQ, T97A, G140S, Y143G, Q148R, A153G, N155H, H156R, R231 5-amino acid insertions. Nine of 32 nonpolymorphic TSMs were previously unreported. Conclusions This meta-analysis confirmed the ARV association of previously reported HIV-2 DRMs and identified novel TSMs. Genotypic and phenotypic studies of HIV-2 TSMs will improve approaches to predicting HIV-2 ARV susceptibility and treating HIV-2–infected persons.

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Natural Polymorphisms in the Human Immunodeficiency Virus Type 2 Protease Can Accelerate Time to Development of Resistance to Protease Inhibitors

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00870-06 ◽

2006 ◽

Vol 51 (2) ◽

pp. 604-610 ◽

Cited By ~ 43

Author(s):

Michel Ntemgwa ◽

Bluma G. Brenner ◽

Maureen Oliveira ◽

Daniela Moisi ◽

Mark A. Wainberg

Keyword(s):

Human Immunodeficiency Virus ◽

Drug Resistance ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Serial Passage ◽

Drug Susceptibility ◽

Genotypic Analysis ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Human immunodeficiency virus type 2 (HIV-2) contains numerous natural polymorphisms in its protease (PR) gene that are implicated in drug resistance in the case of HIV-1. This study evaluated emergent PR resistance in HIV-2. Three HIV-2 isolates were selected for resistance to amprenavir (APV), nelfinavir (NFV), indinavir (IDV), and tipranavir (TPV) in cell culture. Genotypic analysis determined the time to the appearance of protease inhibitor (PI)-associated mutations compared to HIV-1. Phenotypic drug susceptibility assays were used to determine the levels of drug resistance. Within 10 to 15 weeks of serial passage, three major mutations—I54M, I82F, and L90M—arose in HIV-2 viral cultures exposed to APV, NFV, and IDV, whereas I82L was selected with TPV. After 25 weeks, other cultures had developed I50V and I84V mutations. In contrast, no major PI mutations were selected in HIV-1 over this period except for D30N in the context of NFV selective pressure. The baseline phenotypes of wild-type HIV-2 isolates were in the range observed for HIV-1, except for APV and NFV for which a lower degree of sensitivity was seen. The acquisition of the I54M, I84V, L90M, and L99F mutations resulted in multi-PI-resistant viruses, conferring 10-fold to more than 100-fold resistance. Of note, we observed a 62A/99F mutational motif that conferred high-level resistance to PIs, as well as novel secondary mutations, including 6F, 12A, and 21K. Thus, natural polymorphisms in HIV-2 may facilitate the selection of PI resistance. The increasing incidence of such polymorphisms in drug-naive HIV-1- and HIV-2-infected persons is of concern.

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