Perspectives on Human Immunodeficiency Virus (HIV) Cure: HIV Persistence in Tissue

Abstract

The uneven anatomic distribution of cell subsets that harbor human immunodeficiency virus (HIV) during antiretroviral therapy (ART) complicates investigation of the barriers to HIV cure. Here we propose that while previous studies done largely in blood cells have led to important investigations into HIV latency, other important mechanisms of HIV persistence during ART may not be readily apparent in the bloodstream. We specifically consider as an example the question of ongoing HIV replication during ART. We discuss how growing understanding of key anatomic sanctuaries for the virus can inform future experiments aimed at further clarifying this issue.

Keywords: HIV; T follicular helper cells; antiretroviral therapy.; lymph nodes; phylogenetics.

Figure 1.

Proposed model of anatomic and virus genetic relationships among distinct subsets of human immunodeficiency virus (HIV)–infected CD4 T cells during antiretroviral therapy (ART) that could account for the lack of observed evolution of HIV sequences over time in ART-treated individuals despite ongoing replenishment of the infected cell pool by new infections. For comparison, a similar model is proposed for HIV controllers based on our previous findings [58]. In HIV controllers (left), CD4 T cells harboring transcriptionally active viruses are enriched within the T-follicular helper (T_FH) subset (illustrated here as within a follicle). Sequences of these viruses are divergent from ancestral sequences and closely related to plasma virion RNA sequences, which were previously shown to evolve over time in HIV controllers [60, 61] and thus likely reflect an actively replicating virus pool. We propose that ongoing cell-to-cell HIV transmissions among T_FH cells in HIV controllers are associated with dissemination of related viruses to extrafollicular lymph node (LN) sites, which contain most of the CD4 T cells in lymphoid tissue, and also with hematogenous dissemination of some cells containing closely related viruses. Single-copy sequencing of LN CD4 T cell-associated viruses in HIV controllers reveals genetic markers consistent with recent infection, including high divergence from ancestral and a strong temporal structure (as described in [65]). In the bloodstream in HIV controllers, where cell-to-cell HIV transmissions are likely to be uncommon or absent, most CD4 T-cell–associated HIV DNA sequences are archival. Such sequences are often associated with expanded cellular clones whose proliferation further dilutes the phylogenetic signal from rare, recently infected cells. In ART-treated individuals (right), antiretroviral drugs limit any cell-to-cell HIV transmission that might occur within follicles. At the same time, the numbers of cells harboring archival HIV DNA sequences in LN and blood are likely to be higher in ART-treated individuals than in HIV controllers. As a result, sequencing limited numbers of cell-associated HIV DNA sequences in total LN or blood cells almost exclusively reflects long-lived cells harboring archival viruses. These sequences would not be expected to evolve over time. In addition, new cellular infections within LN in ART-treated individuals may in part result from intermittent reactivations of archival viruses. As a result, HIV DNA sequences from recently infected cells might show neither a temporal structure nor evolution in serial samples.