Recent trends in HIV-1 drug resistance

Abstract

Once considered an inevitable consequence of HIV treatment, drug resistance is declining. This decline supports the hypothesis that antiretroviral therapy can arrest replication and prevent the evolution of resistance. Further support comes from excellent clinical outcomes, the failure of treatment intensification to reduce residual viremia, the lack of viral evolution in patients on optimal therapy, pharmacodynamics studies explaining the extraordinarily high antiviral activity of modern regimens, and recent reports of potential cures. Evidence supporting ongoing replication includes higher rates of certain complications in treated patients and an increase in circular forms of the viral genome after intensification with integrase inhibitors. Recent studies also provide an explanation for the observation that some patients fail protease-inhibitor based regimens without evidence for resistance.

Figure 1

Antiretroviral therapy for HIV-1 infection. The steps in the life cycle blocked by different classes of antiretroviral drugs are indicated. Current ART regimens consist of two NRTIs and either an NNRTI, a PI, or an InSTI. Inhibitors of HIV-1 entry, chemokine receptor antagonists and fusion inhibitors, can be used. Note that all current antiretroviral drugs act to prevent new cells from becoming infected. They do not block the production of virus particles by a cell that already carries an integrated provirus. The PIs prevent virus particles from maturing to an infectious form. Immature virus particles show defects at multiple downstream steps in the virus life cycle (dotted lines), including entry, reverse transcription, and integration. See text for references.

Figure 2

Explanations for PI failure without resistance mutations in the protease gene. (A) Pharmacodyamic properties of PIs restrict the evolution of resistance. During periods of non-adherence, resistant viruses emerge. As drug concentrations fall, there is a mutant selection window (MSW) in which the mutant virus has both a positive growth rate (R₀ > 1) and a selective advantage over wild type virus. The length of the MSW depends on drug half-life, the properties of the dose-response curves for wild type (green) and resistant (red) viruses, and the fitness cost of the resistance mutation. For PIs, the time spent in the MSW is extremely short and with non-adherence, wild type virus rapidly emerges. Note that this form of treatment failure does not represent drug resistance, and suppression of viremia can be achieved by restoring adherence. (B) Mutations inside of (red) and outside of (*) the protease coding region can contribute to resistance. As shown in Figure 1, part of the inhibitory effect of PIs is due to effects on HIV-1 entry. Interactions between the uncleaved Gag precursor protein and the cytoplasmic domain of the Env protein inhibit entry, and thus PI-mediate inhibition of Gag cleavage results in inhibition of infectivity. Resistance to PIs may arise through mutations affecting the Gag-Env interaction. Mutations in the protease cleavage sites in Gag can also contribute to resistance. Current clinical assays for PI resistance examine only the protease gene and could miss other mutations contributing to resistance.