An Overview of Human Immunodeficiency Virus-1 Antiretroviral Drugs: General Principles and Current Status

Abstract

Treatment with highly active antiretroviral therapy (HAART) can prolong a patient's life-span by disrupting pivotal steps in the replication cycle of the human immunodeficiency virus-1 (HIV-1). However, drug resistance is emerging as a major problem worldwide due to the prolonged period of treatment undergone by HIV-1 patients. Since the approval of zidovudine in 1987, over thirty antiretroviral drugs have been categorized into the following six distinct classes based on their biological function and resistance profiles: (1) nucleoside analog reverse-transcriptase inhibitors; (2) non-nucleoside reverse transcriptase inhibitors; (3) integrase strand transferase inhibitors; (4) protease inhibitors; (5) fusion inhibitors; and (6) co-receptor antagonists. Additionally, several antiretroviral drugs have been developed recently, such as a long active drug, humanized antibody and pro-drug metabolized into an active form in the patient's body. Although plenty of antiretroviral drugs are beneficially used to treat patients with HIV-1, the ongoing efforts to develop antiretroviral drugs have overcome the drug resistances, adverse effects, and limited adherence of drugs observed in previous drugs to some extent. Furthermore, studies focused on agents targeting latent HIV-1 reservoirs should be strengthened, as that may lead to eradication of HIV-1.

Keywords: Anti-HIV-1 drugs; HIV-1 Tat; Human immunodeficiency virus.

Figure 1. Stages of the HIV-1 life cycle and current target for antiretroviral drugs.

HIV-1, human immunodeficiency virus-1; NRTIs, nucleoside analogue reverse transcriptase inhibitors; NNRTIs, non-nucleoside reverse transcriptase inhibitors; InSTIs, integrase strand transferase inhibitors.

Figure 2. Timeline for FDA-approved antiretroviral drugs.

FDA, food and drug administration; ZDV, zidovudine; ddI, didanosine; ddC, zalcitabine; d4T, stavudine; 3TC, lamivudine; SQV, saquinavir; NVP, nevirapine; RTV, ritonavir; IDV, indinavir; DEL, delavirdine; NFV, nelfinavir; EFV, efavirenz; ABC, abacavir; APV, asunaprevir; TDF, tenofovir disoproxil fumarate; T-20, enfuvirtide; FTC, emtricitabine; ATV, atazanavir; FPV, fosamprenavir; TPV, tipranavir; DRV, darunavir; MVC, maraviroc; RAL, raltgravir; ETR, etravirine; RPV, rilpivirine; DTG, dolutegravir; EVG, elvitegravir; TAF, tenofovir alafenamide; DOR, doravirine; IBA, ibalizumab; BIC, bictegravir; ; FTR, fostemsavir; NRTIs, nucleoside reverse-transcriptase inhibitors; NNRTIs, non-nucleoside reverse-transcriptase inhibitors; InSTIs, integrase strand transfer inhibitors; PIs, protease inhibitors.

Figure 3. X-ray crystal structure of HIV-1 RT in complex with viral DNA template/primer and Nucleos(t)ide reverse-transcriptase inhibitors. A nucleoside inhibitor didanosine (ddI) is converted to ddAMP missing OH, following termination of DNA synthesis by the incoming dTTP. The cartoon of the crystal structure has been adapted from data deposited by Huang et al. (1998) [87].

RT, reverse-transcriptase; HIV-1, human immunodeficiency virus-1; DNA, deoxyribonucleic acid; ddAMP, 2′3′-Dideoxyadenosine-5′monophosphate; dTTP, deoxythymidine triphosphate; OH, hydroxyl group.

Figure 4. Crystal structure of HIV-1 RT complexed with etravirine and Non-nucleoside reverse-transcriptase inhibitors. The cartoon of the crystal structure has been adapted from data deposited by Lansdon et al. (2010) [88].

HIV-1, human immunodeficiency virus-1; RT, reverse-transcriptase.

Figure 5. The crystal structure of HIV-1 protease blocked by atazanavir and protease inhibitors. The cartoon of the crystal structure has been adapted from data by King et al. (2012) [89].

HIV-1, human immunodeficiency virus-1.

Figure 6. Peptide sequences of T-20 and the mode of action of T-20.

The formation of the gp41 six alpha-helix bundle is blocked by T-20 (enfuvirtide) in the final step of the HIV-1 entry process. The cartoon has been adapted from data by Berkhout et al. (2012) [90]. HIV-1, human immunodeficiency virus-1.

Figure 7. Chemical structure of the CCR5 Antagonist (Maraviroc) [91].

Figure 8. The crystal structure of virus integrase complexed with raltegravir [41] and integrase strand transfer inhibitors.

Figure 9. Schematic diagram of discovery of the HIV-1 transcriptional inhibitor (A) and nucleoside analogues of novel HIV-1 transcription-repressing compounds (B) [86].

HIV-1, human immunodeficiency virus-1; DOX, doxycycline; Tat, viral transactivator; OFF, signal-off; ON, signal-on.