Inhibition of Envelope-Mediated CD4⁺-T-Cell Depletion by Human Immunodeficiency Virus Attachment Inhibitors

Abstract

Human immunodeficiency virus type 1 (HIV-1) envelope (Env) binding induces proapoptotic signals in CD4؉ T cells without a requirement of infection. Defective virus particles, which represent the majority of HIV-1, usually contain a functional Env and therefore represent a potentially significant cause of such CD4؉ -T-cell loss. We reasoned that an HIV-1 inhibitor that prohibits Env-host cell interactions could block the destructive effects of defective particles. HIV-1 attachment inhibitors (AIs), which potently inhibit Env-CD4 binding and subsequent downstream effects of Env, display low-nanomolar antiapoptotic potency and prevent CD4؉ -T-cell depletion from mixed lymphocyte cultures, also with low-nanomolar potency. Specific Env amino acid changes that confer resistance to AI antientry activity eliminate AI antiapoptotic effects. We observed that CD4؉ -T-cell destruction is specific for CXCR4-utilizing HIV-1 strains and that the fusion blocker enfuvirtide inhibits Env-mediated CD4؉ -T-cell killing but is substantially less potent than AIs. These observations, in conjunction with observed antiapoptotic activities of soluble CD4 and the CXCR4 blocker AMD3100, suggest that this AI activity functions through a mechanism common to AI antientry activity, e.g., prevention of Env conformation changes necessary for specific interactions with cellular factors that facilitate viral entry. Our study suggests that AIs, in addition to having potent antientry activity, could contribute to immune system homeostasis in individuals infected with HIV-1 that can engage CXCR4, thereby mitigating the increased risk of adverse clinical events observed in such individuals on current antiretroviral regimens.

In VitroAntiviral Characteristics of HIV-1 Attachment Inhibitor BMS-626529, the Active Component of the Prodrug BMS-663068

“…Furthermore, as well as direct inhibition of virus attachment to CD4, the attachment inhibitor mechanism of action may have additional benefits not necessarily observed with agents that target other steps in HIV infection. In vitro studies have suggested that attachment inhibitors may inhibit apoptosis of CD4 ϩ T cells (1,25). This may be of benefit through inhibition of the bystander effect (2,24), similar to that suggested for HIV-1 entry inhibitors which act by alternative mechanisms (5,7).…”

ADS-J1 Inhibits HIV-1 Entry by Interacting with gp120 and Does Not Block Fusion-Active gp41 Core Formation

“…However, they failed to include a relevant control, that is, the activity of sCD4 alone. sCD4 binds to gp120-expressing cells, independently blocking gp120 binding to cell surface CD4 but also all subsequent downstream effects of Env leading to virus entry (1,25,29). Therefore, the alleged increased potency of ADS-J1 in the presence of sCD4, interpreted as an increased exposure of the drug-binding site in gp41, may be the consequence of the additive effect of two active compounds: ADS-J1 and sCD4.…”

In Vivo Patterns of Resistance to the HIV Attachment Inhibitor BMS-488043

“…However, BMS-378806 failed to achieve targeted plasma exposures in humans. Therefore, a related compound, BMS-488043, with improved in vitro antiviral activity and pharmacokinetic properties was advanced into clinical development (1,23,30,33). Taken with a high-fat meal, BMS-488043 achieved a 10-fold higher concentration in the plasma of human subjects than was observed for BMS-378806.…”

“…Attachment inhibitors (AIs) target the initial entry step, gp120 binding to the CD4 receptor (1,11,14,16,22). Since they act upstream of coreceptor binding, AIs are active against CCR5-and/or CXCR4-utilizing virus, as well as strains resistant to nucleoside and nonnucleoside reverse transcriptase, protease, and integrase inhibitors (22).…”