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.

Systems biology of virus-host signaling network interactions

“…More interestingly, the model demonstrated that high synergistic inhibition of HCV replication can be achieved by combinatorial targeting of two downstream enzymes in the sterol pathway, revealing a potential strategy for HCV therapy. As demonstrated by the HCV study, combinatorial drug therapy is an approach increasingly used to overcome viral drug resistance by targeting multiple factors or pathways necessary for infection (38). For the treatment of many viruses, including HIV, HCV and Influenza, combinatorial drug administration has shown increased and broadened efficacy (38)(39)(40).…”

“…As demonstrated by the HCV study, combinatorial drug therapy is an approach increasingly used to overcome viral drug resistance by targeting multiple factors or pathways necessary for infection (38). For the treatment of many viruses, including HIV, HCV and Influenza, combinatorial drug administration has shown increased and broadened efficacy (38)(39)(40). However, not all drugs can be combined in an effective way without increased toxicity, and therefore investigations into the combined effects of two or more anti-viral drugs are especially significant.…”

Enhanced activity of carbosilane dendrimers against HIV when combined with reverse transcriptase inhibitor drugs: searching for more potent microbicides

“…18 Therefore, the combinatorial approach should be taken into consideration when designing future microbicide studies. Some novel studies have examined the efficacy of ARV combinations as microbicides.…”

“…18 Additionally, a reduction in the amounts of ARVs used in vivo may result in a reduction of adverse effects, limiting the local injuries, the toxicity, and the inflammation caused by local microbicide application before sexual intercourse.…”

Efficient Single Tobamoviral Vector-Based Bioproduction of Broadly Neutralizing Anti-HIV-1 Monoclonal Antibody VRC01 in Nicotiana benthamiana Plants and Utility of VRC01 in Combination Microbicides

“…These findings suggest that a single-component microbicide based on VRC01 or any other bnMAb may fail to provide sufficient protection and could even lead to the accumulation of resistant strains in circulating virus populations. In practice, a combinatorial strategy will have to be implemented for any microbicide candidates, as has been the case in the treatment of HIV-1-infected patients (22). Thus, analysis of VRC01's potential for synergy with other microbicide candidates would provide valuable information toward the bnMAb's potential as a component of combination microbicides.…”