The entry of entry inhibitors: A fusion of science and medicine

Abstract

For HIV-1 to enter a cell, its envelope protein (Env) must sequentially engage CD4 and a chemokine coreceptor, triggering conformational changes in Env that ultimately lead to fusion between the viral and host cell membranes. Each step of the virus entry pathway is a potential target for novel antiviral agents termed entry inhibitors. A growing number of entry inhibitors are under clinical development, with one having already been licensed by the Food and Drug Administration. With the emergence of virus strains that are largely resistant to existing reverse transcriptase and protease inhibitors, the development of entry inhibitors comes at an opportune time. Nonetheless, because all entry inhibitors target in some manner the highly variable Env protein of HIV-1, there are likely to be challenges in their efficient application that are unique to this class of drugs. Env density, receptor expression levels, and differences in affinity and receptor presentation are all factors that could influence the clinical response to this promising class of new antiviral agents.

Viral membrane fusion: is glycoprotein G of rhabdoviruses a representative of a new class of viral fusion proteins?

“…Indeed, although most of the antiviral drugs have been developed against viral enzymes involved in virus replication, recent studies have demonstrated that the entry events can also serve as a new target to block viral infection (59,60). As an example, the progress in understanding the mechanisms of HIV-1 cell entry into target cells permitted the design of a new class of anti-HIV-1 drugs: compounds that act as fusion or entry inhibitors that are currently being evaluated in clinical trials (60). Thus, new insights concerning the fusion mechanisms might be successfully applied to the development of entry inhibitors directed at other viruses.…”

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 + T Cells

“…Upon binding to coreceptor, which is either CCR5 or CXCR4 for primary HIV isolates, Env undergoes further conformational changes resulting in insertion of the gp41 fusion peptide into the host cell membrane and gp41-mediated membrane fusion (8,15,26). Targeting stages of the HIV entry process with antiretroviral drugs is a productive method of inhibiting HIV replication, as demonstrated by the potent antiviral effects of small-molecule CCR5 antagonists and fusion inhibitors (23,35,49). As with other antiretroviral drugs, HIV can develop resistance to entry inhibitors, and a detailed understanding of viral and host determinants of resistance will be critical to the optimal clinical use of these agents.…”

Llama Antibody Fragments with Cross-Subtype Human Immunodeficiency Virus Type 1 (HIV-1)-Neutralizing Properties and High Affinity for HIV-1 gp120

“…Thus, there is a need for effective preventive methods to control the HIV-1 pandemic, such as an HIV-1 vaccine or a topically applied HIV-1 microbicide. Agents that inhibit HIV-1 entry have potential use as microbicides, antiretroviral drugs, or prophylactics (42,51). Furthermore, they may be useful tools in HIV-1 vaccine design in that they can help characterization of HIV-1 envelope proteins.…”