This paper will review recent discoveries in the field of viral
pathogenesis and the development of a new antiretroviral class known as
AntiViral-HyperActivation Limiting Therapeutics (AV-HALTs) that has been
specifically designed in response to these findings. AV-HALTs are characterized
by the combination of two distinct activities – the direct inhibition of viral
replication (antiviral activity) and the reduction of excessive chronic immune
system hyperactivation (hyperactivation limiting effect). These two effects can be
achieved by combining two drugs (a first-generation AV-HALT) or by a single
molecule (second-generation AV-HALTs).
The medical need for AV-HALTs is best illustrated in the treatment of the Human
ImmunoDeficiency Virus Type 1 (HIV-1). Paradoxically, it is the chronic,
excessive hyperactivation of the immune system, resulting in cellular
hyperproliferation and systemic inflammation – throughout the course of HIV
disease – that is now recognized as the major driver of not only the continual loss
of CD4+ T cells and progression to the Acquired Immunodeficiency Syndrome
(AIDS), but also of the emergence of both AIDS-defining and non-AIDS-defining
events that negatively impact upon both morbidity and mortality despite otherwise
successful (ie, fully virus suppressive) HIV therapy. This review will focus upon
the establishment of the human proof of concept for AV-HALTs using a two-drug,
first-generation AV-HALT (VS411) and the development of single-molecule,
second-generation AV-HALTs for the treatment of HIV-1 disease and other
chronic viral infections.
Keywords: Immunotherapy, disease-modifying treatment, AV-HALT, inflammation, HIV.