Current perspectives on HIV-1 antiretroviral drug resistance

Abstract

Current advancements in antiretroviral therapy (ART) have turned HIV-1 infection into a chronic and manageable disease. However, treatment is only effective until HIV-1 develops resistance against the administered drugs. The most recent antiretroviral drugs have become superior at delaying the evolution of acquired drug resistance. In this review, the viral fitness and its correlation to HIV-1 mutation rates and drug resistance are discussed while emphasizing the concept of lethal mutagenesis as an alternative therapy. The development of resistance to the different classes of approved drugs and the importance of monitoring antiretroviral drug resistance are also summarized briefly.

Figure 1

Schematic representation of HIV-1 lethal mutagenesis.

Figure 2

Chemical structures of KP-1212 in amino and imino isomer.

Figure 3

Overall view of the HIV-1 RT/DNA/dNTP ternary complex showing the corresponding binding sites of non-nucleoside reverse transcriptase inhibitor (NNRTI) (circled in magenta, efavirenz (EFV) is shown as magenta sticks) and NRTI (circled in red, dNTP is shown as sticks). The p66 and p51 subunits are represented in cyan and blue, respectively. PDB 1RTD [94].

Figure 4

Detailed view of the NRTI binding pocket. The drug resistant mutation sites are shown in cyan sticks. dNTP is highlighted in sticks. PDB 1RTD [94].

Figure 5

Detailed view of the NNRTI binding pocket. EFV is shown as magenta sticks and the EFV-resistant mutation sites are shown in white sticks. PDB 1FK9 [152].

Figure 6

Detailed view of the protease inhibitor binding pocket. Nelfinavir (NFV) is shown as magenta sticks and the NFV-resistant mutation sites are shown in green sticks. PDB 1OHR [218].