The Impact of Cellular Proliferation on the HIV-1 Reservoir

Abstract

Human immunodeficiency virus (HIV) is a chronic infection that destroys the immune system in infected individuals. Although antiretroviral therapy is effective at preventing infection of new cells, it is not curative. The inability to clear infection is due to the presence of a rare, but long-lasting latent cellular reservoir. These cells harboring silent integrated proviral genomes have the potential to become activated at any moment, making therapy necessary for life. Latently-infected cells can also proliferate and expand the viral reservoir through several methods including homeostatic proliferation and differentiation. The chromosomal location of HIV proviruses within cells influences the survival and proliferative potential of host cells. Proliferating, latently-infected cells can harbor proviruses that are both replication-competent and defective. Replication-competent proviral genomes contribute to viral rebound in an infected individual. The majority of available techniques can only assess the integration site or the proviral genome, but not both, preventing reliable evaluation of HIV reservoirs.

Keywords: HIV-1; HSPC; T cell; differentiation; integration; latency; proliferation; provirus.

Figure 1

Cellular potential and clonal expansion. (a) A hematopoietic stem cell becomes infected with human immunodeficiency virus (HIV) and can follow many fates including maintenance of the population, differentiation, and reactivation (top). Some of the daughter cells can clonally expand (bottom); (b) CD4+ T cell fates. A CD4+ T cell becomes infected and can maintain itself, clonally expand, and reactivate to produce more viruses.

Figure 2

Differentiation and proliferative potential of the latent reservoir. Hematopoietic stem cells (HSC) are multipotent and differentiate into both common myeloid and lymphoid progenitors. Through several more steps of differentiation, naïve CD4+ T cells emerge from the lymphoid lineage as the least differentiated of the terminally differentiated T cell subsets. T cells undergo successive rounds of activation and differentiation through memory stem cells (T_SCM), central memory (T_CM), transitional memory (T_TM), to effector memory (T_EM).

Figure 3

Proliferation of intact and defective proviruses build and maintain the viral reservoir. Cells with intact proviruses (green bar) can sometimes proliferate and expand but do not survive as abundantly as cells harboring defective provirus (red bar) and eventually decrease over time. Proliferation is more abundant for cells with defective proviruses.

Figure 4

Transcriptional orientation and chromatin states of proviruses. HIV proviruses (red bars) can be found throughout the genome, in both inactive regions of the host genome like heterochromatin (a) or actively expressed regions such as euchromatic regions (b). They can also be detected in intergenic regions (c) but are primarily found as integrations within introns of actively expressed genes (d,e) and can integrate in either the sense- or antisense-orientation regardless of their genomic location (d,e). Arrows indicate TSS and direction of transcription.

Figure 5

Integration site loop amplification (ISLA). Modified from [76]. Black segments represent long-terminal repeat (LTR) regions; purple, HIV open reading frames (ORFs); green, human chromosomal DNA.