Combinatorial approaches to the prevention and treatment of HIV-1 infection

Abstract

The discovery of the human immunodeficiency virus type 1 (HIV-1) in 1982 soon led to the identification and development of antiviral compounds to be used in treatment strategies for infected patients. Early in the epidemic, drug monotherapies frequently led to treatment failures because the virus quickly developed resistance to the single drug. Following the advent of highly active antiretroviral therapy (HAART) in 1995, dramatic improvements in HIV-1-infected patient health and survival were realized as more refined combination therapies resulted in reductions in viral loads and increases in CD4+ T-cell counts. In the absence of an effective vaccine, prevention of HIV-1 infection has also gained traction as an approach to curbing the pandemic. The development of compounds as safe and effective microbicides has intensified and has focused on blocking the transmission of HIV-1 during all forms of sexual intercourse. Initial preclinical investigations and clinical trials of microbicides focused on single compounds effective against HIV-1. However, the remarkable successes achieved using combination therapy to treat systemic HIV-1 infection have subsequently stimulated the study and development of combination microbicides that will simultaneously inhibit multiple aspects of the HIV-1 transmission process by targeting incoming viral particles, virus-infected cells, and cells susceptible to HIV-1 infection. This review focuses on existing and developing combination therapies, covering preclinical development, in vitro and in vivo efficacy studies, and subsequent clinical trials. The shift in focus within the microbicide development field from single compounds to combination approaches is also explored.

Fig. 1.

Inhibition of HIV-1 replication can be accomplished at different steps in the viral life cycle. Within the HIV-1 replication cycle, multiple events can be targeted by systemic inhibitors as well as topically applied microbicides. The first compounds developed with anti-HIV-1 activity were reverse transcriptase inhibitors (RTIs). RTIs are currently being used therapeutically to treat HIV-1-infected individuals and are also being investigated as candidate microbicides. Protease inhibitors, which inhibit the activity of HIV-1 protease, are currently part of the recommended standard of care for HIV-1-infected patients. Additional mechanisms of inhibition can involve inactivating the virus or inhibiting viral binding and entry through direct interactions with viral proteins (gp120 and gp41) or with cell surface molecules that interact with the virus (CD4, CXCR4, or CCR5). Maraviroc (MVC) is a recently approved inhibitor that acts by inhibiting viral binding to CCR5. Although approved for use in HIV-1-infected patients, it is used mainly as a salvage therapy once the patient has developed resistance to established treatment regimens. Raltegravir is the first HIV-1 integrase inhibitor approved for clinical use.

Fig. 2.

Combinations of inhibitors with different mechanisms of action may provide more complete protection from HIV-1 sexual transmission. Because of the multiple modes of transmission and susceptible cell types in the cervicovaginal compartment, it is likely that multiple compounds used in combination will be required to provide full protection from infection. Potential combination strategies for preventing HIV-1 sexual transmission may involve the following: enhancement of innate defenses (e.g., maintaining the low pH within the vaginal environment, and the enhancement/enrichment of cervicovaginal secretions that provide barrier and antimicrobial activities) within the cervicovaginal environments (1), inactivation of cell-free and cell-associated viruses (2), prevention of infection by inhibiting viral binding and entry either through the blocking of viral envelope proteins or the blocking of host cellular receptors (e.g., CD4, CCR5, and CXCR4) (3), inhibition of mechanisms that facilitate viral dissemination (e.g., DC-SIGN on dendritic cells which acts to disperse HIV-1 virions throughout the body undetected) (4), and inhibition of critical replicative events (e.g., reverse transcription and integration) in the HIV-1-infected cell (5). To date, the majority of microbicides in development for use as either single agents or as a partner in a combination act to inhibit binding and entry or act to inhibit reverse transcription. However, the current development of microbicidal agents that exploit other mechanisms of inhibition will add to the repertoire of possible combination partners, potentially increasing the likelihood that a combination with efficacy against HIV-1 transmission and infection during sexual intercourse will be developed.