HIV-1 antiretroviral drug therapy

Abstract

The most significant advance in the medical management of HIV-1 infection has been the treatment of patients with antiviral drugs, which can suppress HIV-1 replication to undetectable levels. The discovery of HIV-1 as the causative agent of AIDS together with an ever-increasing understanding of the virus replication cycle have been instrumental in this effort by providing researchers with the knowledge and tools required to prosecute drug discovery efforts focused on targeted inhibition with specific pharmacological agents. To date, an arsenal of 24 Food and Drug Administration (FDA)-approved drugs are available for treatment of HIV-1 infections. These drugs are distributed into six distinct classes based on their molecular mechanism and resistance profiles: (1) nucleoside-analog reverse transcriptase inhibitors (NNRTIs), (2) non-nucleoside reverse transcriptase inhibitors (NNRTIs), (3) integrase inhibitors, (4) protease inhibitors (PIs), (5) fusion inhibitors, and (6) coreceptor antagonists. In this article, we will review the basic principles of antiretroviral drug therapy, the mode of drug action, and the factors leading to treatment failure (i.e., drug resistance).

Figure 1.

Timeline for FDA approval for current antiviral and antiretroviral drugs.

Figure 2.

Identifying distinct steps in HIV-1 life cycle as potential or current target for antiretroviral drugs. (A) Schematic of the HIV-1 life cycle in a susceptible CD4⁺ cell. (B) Time frame for antiretroviral drug action during a single-cycle HIV-1 replication assay. In this experiment, HIV-1 inhibitors are added following a synchronized inhibition. The addition of drug following the HIV-1 replication step targeted by the drug will result in a lack of inhibition. The time window of drug inhibition provides an estimate for the time required for these replication steps. For example, T30 or enfuvirtide (T20) only inhibits within 1–2 h of infection, whereas lamivudine (3TC) inhibits within a 2- to 10-h time frame, which coincides with reverse transcription. (C) Preclinical, abandoned (normal text), or FDA-approved (bold italic text) inhibitors are listed in relation to specificity of action and drug target.

Figure 3.

Nucleos(t)ide reverse transcriptase inhibitors and X-ray crystal structure of HIV-1 RT in complex with DNA primer/template chain terminated with ddAMP and with an incoming dTTP. The cartoon of the crystal structure data was adapted from coordinates deposited by Huang et al. (1998) (1RTD).

Figure 4.

Non–nucleoside RT inhibitors and the X-ray crystal structure of HIV-1 RT complexed with etravirine (Lansdon et al. 2010) (3MEE).

Figure 5.

Integrase strand transfer inhibitors and the crystal structure of prototype human foamy virus integrase (as a model of HIV-1 IN) complexed to dsDNA and Raltegravir (Hare et al. 2010) (3OYH). N-term, amino-terminal; C-term, carboxy-terminal.

Figure 6.

Protease inhibitors and the crystal structure of HIV-1 protease complexed with atazanavir (CA Schiffer, unpubl.) (3EKY).

Figure 7.

Structure predictions of various viral-host components involved in the HIV-1 entry process and the inhibitors. Section 1 describes the components involved for initial CD4 attachment, specifically the D1 domain of CD4 and the C4 domain of gp120. The gp120 structure is shown as an overlay of two structures (2NY2 and 3HI1) (Zhou et al. 2007; Chen et al. 2009). Inhibitors of this CD4 process are listed. Interactions between gp120 and CXCR4 are described in section 2. A rough model of maraviroc (MVC) binding to CCR5 in Figure 7 is based on data from a recently published structure of CXCR4 complexed to a small molecule, IT1t (Wu et al. 2010). The final step in the entry process involves the formation of the gp41 six alpha-helix bundle, which can be blocked by T20 (enfuvirtide). The structure for HIV-1 gp41 six alpha-helix bundle is based on that of SIV gp41 (Malashkevich et al. 1998) (2SIV).