How Does HIV Persist Under Antiretroviral Therapy: A Review of the Evidence.

Abstract

HIV-1 is a retrovirus capable of establishing viral reservoirs that remain stable for extended periods under suppressive antiretroviral therapy (ART). Immune dysfunction and latency are well known to contribute to this longevity, but the respective roles of viral replication and latently infected (LI) cell proliferation under suppressive antiretroviral therapy (ART) have long been controversial. This historical review critically appraises the body of evidence regarding possible viral replication and proliferation of infected cells under ART. An ever-growing body of genetic and phylogenetic studies has demonstrated that HIV-infected cells are able to proliferate and contribute to the longevity of the reservoir in ART-treated patients. The role of ongoing replication remains controversial: it has been well established that HIV does not undergo evolution during ART or develop drug resistance, but some genetic, phylogenetic, and in vivo imaging studies have suggested that there may be ongoing replication despite this. The respective roles of viral replication and cellular proliferation in maintaining the LI reservoir remains an area of controversy. Elucidating these processes may allow us design interventions to reduce the size of the LI reservoir, increasing the length of treatment interruptions during which the virus will remain adequately suppressed, bringing us closer to a functional cure. Novel experimental techniques such as immuno-PET and digital droplet PCR (ddPCR) are increasingly being employed, and these, along with rapid particle sorting techniques currently in develop-ment, will be necessary to fully answer this question.