Current drugs for HIV-1: from challenges to potential in HIV/AIDS

Abstract

The human immunodeficiency virus (HIV) persists in latently infected CD4⁺T cells and integrates with the host genome until cell death. Acquired immunodeficiency syndrome (AIDS) is associated with HIV-1. Possibly, treating HIV/AIDS is an essential but challenging clinical goal. This review provides a detailed account of the types and mechanisms of monotherapy and combination therapy against HIV-1 and describes nanoparticle and hydrogel delivery systems. In particular, the recently developed capsid inhibitor (Lenacapavir) and the Ainuovirine/tenofovir disoproxil fumarate/lamivudine combination (ACC008) are described. It is interestingly to note that the lack of the multipass transmembrane proteins serine incorporator 3 (SERINC3) and the multipass transmembrane proteins serine incorporator 5 (SERINC5) may be one of the reasons for the enhanced infectivity of HIV-1. This discovery of SERINC3 and SERINC5 provides new ideas for HIV-1 medication development. Therefore, we believe that in treating AIDS, antiviral medications should be rationally selected for pre-exposure and post-exposure prophylaxis to avoid the emergence of drug resistance. Attention should be paid to the research and development of new drugs to predict HIV mutations as accurately as possible and to develop immune antibodies to provide multiple guarantees for the cure of AIDS.

Keywords: HIV/AIDS treatment; SERINC3; SERINC5; anti-HIV-1 drugs; combination therapy; monotherapy; predict HIV mutations.

FIGURE 1

Molecular biological structure of HIV-1. HIV-1 is a single-stranded positive-stranded RNA virus with a genome containing structural genes (Gag, Pol, and Env) and regulatory genes (Vif, Vpr, Vpu, Nef, Tat, Rev, and Env). Among them, the regulatory gene Env transcribes and translates the gp160 protein. This protein is cleaved by the host protease into gp120 and gp41 to form the envelope glycoprotein spines. Reverse transcriptase, protease, integrase, and RNase H are scattered within the CA. These structures work together to make HIV-1 biologically active (Frankel and Young, 1998).

FIGURE 2

Host mechanism of HIV-1 infection and targets of anti-HIV-1 drugs. HIV infection of cells involves five processes: adsorption, invasion, decapitation, synthesis, and assembly. The viral glycoprotein spike gp120 binds to CD4 on the host cell surface. Under the mediation of CCR5 or CXCR4, the virus fuses with the host cell membrane. In this process, fostemsavir tromethamine (Wang et al., 2021) is active on gp120, enfuvirtide (Monteiro et al., 2021; Yeruva and Lee, 2022) and albuvirtide (Chong et al., 2012) act on gp41 6-HB, maraviroc, plerixafor, and salmeterol function on CCR5 or CXCR4 (Woollard and Kanmogne, 2015; Mirza et al., 2020; Wang et al., 2020), and ibalizumab (Bettiker et al., 2018) acts on CD4 receptor in host cells. All of these drugs’ act to prevent viral adsorption or invasion. When viral RNA is reverse-transcribed to form RNA-DNA and enters the host cell nucleus, integrase inhibitors such as cabotegravir sodium prevent its integration into host DNA. Even if viral genetic material is already successfully integrated, foscarnet sodium (Devianne-Garrigue et al., 1998) and resveratrol (Zhang et al., 2009) can prevent its transcription and translation to form viral proteins, respectively. Impressively, the capsid protein inhibitor lenacapavir and GSK878 are now available and efficiently blocks viral infection of host cells (Segal-Maurer et al., 2022). Created with BioRender.com.

FIGURE 3

Mechanism of action of reverse transcriptase inhibitors. Reverse transcriptase inhibitors are classified into NRTIs and NNRTIs. The virus enters the host cell, sheds its capsid, and exposes genetic material. Cellular kinases phosphorylate the NRTIs and bind competitively with dNTP to template RNA, which blocks the transcription of viral genes. In contrast, NNRTIs bind to hydrophobic pockets close to the RT active site and inhibit viral gene transcription (Maga et al., 2010). Created with BioRender.com.

FIGURE 4

Mechanism of action of integrase inhibitors. The integrase is in the host cell and attaches to the 3′ end of the virus DNA, initiating the integration of the viral cDNA into the host DNA, which in turn is transcribed to form the precursor protein. This process requires a functionally intact integrase and the integrity of the last 10–20 base pairs at both ends of the viral cDNA (Aquaro et al., 2020). There are two types of integrase inhibitors: INSTIs and INBIs. The former attaches to the catalytic core domain of the integrase and prevents the enzyme from binding to DNA. The latter binds to the heterologous pocket of IN and hinders the conformational changes required for the strand transfer reaction (Trivedi et al., 2020). Created with BioRender.com.