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Review
. 2019 Dec 18:10:2878.
doi: 10.3389/fmicb.2019.02878. eCollection 2019.

New Frontiers in Measuring and Characterizing the HIV Reservoir

Shane D Falcinelli  1   2 , Cristina Ceriani  1   3 , David M Margolis  1   2   3 , Nancie M Archin  1   3
Affiliations
Review

New Frontiers in Measuring and Characterizing the HIV Reservoir

Shane D Falcinelli et al. Front Microbiol. .

Abstract

A cure for HIV infection remains elusive due to the persistence of replication-competent HIV proviral DNA during suppressive antiretroviral therapy (ART). With the exception of rare elite or post-treatment controllers of viremia, withdrawal of ART invariably results in the rebound of viremia and progression of HIV disease. A thorough understanding of the reservoir is necessary to develop new strategies in order to reduce or eliminate the reservoir. However, there is significant heterogeneity in the sequence composition, genomic location, stability, and expression of the HIV reservoir both within and across individuals, and a majority of proviral sequences are replication-defective. These factors, and the low frequency of persistently infected cells in individuals on suppressive ART, make understanding the reservoir and its response to experimental reservoir reduction interventions challenging. Here, we review the characteristics of the HIV reservoir, state-of-the-art assays to measure and characterize the reservoir, and how these assays can be applied to accurately detect reductions in reservoir during efforts to develop a cure for HIV infection. In particular, we highlight recent advances in the development of direct measures of provirus, including intact proviral DNA assays and full-length HIV DNA sequencing with integration site analysis. We also focus on novel techniques to quantitate persistent and inducible HIV, including RNA sequencing and RNA/gag protein staining techniques, as well as modified viral outgrowth methods that seek to improve upon throughput, sensitivity and dynamic range.

Keywords: HIV; IPDA; QVOA; cure; defective provirus; replication-competent; reservoir; stability.

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Figures

FIGURE 1
FIGURE 1
Overview of cell types and anatomic sites reported to harbor the latent reservoir. (A) Cell types thought to harbor the HIV reservoir. Cell types with demonstrated recovery of replication-competent virus (defined as propagating virus in an outgrowth assay) in humans following years of suppressive ART are in bold. Cell types in regular font represent cells where HIV nucleic acid has been detected by PCR and/or sequencing either in humans or animal models but recovery of replication-competent virus in humans after years of suppressive ART has not been demonstrated. It is important to note that for many cell types, there has been very sparse sampling for replication-competent virus. NA, naïve; SCM, stem cell memory; CM, central memory; TM, transitional memory; EM, effector memory; TD, terminally differentiated; MM, migratory memory; RM, resident memory. (B) Anatomic sites with demonstrated recovery of replication-competent virus in humans following years of suppressive ART are highlighted in bold. Potential replication-competent anatomic reservoir sites are in regular font. These sites represent tissues/organs where HIV nucleic acid has been detected either in humans or animal models but recovery of replication-competent virus in humans after years of suppressive ART has not been demonstrated. It is important to note that for many tissue types, there has been very sparse sampling for replication-competent virus. Images were derived and modified from Servier Medical Arts under a Creative Commons Attribution 3.0 Unported License.
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