Nonsuppressible HIV-1 viremia: a reflection of how the reservoir persists

Abstract

Antiretroviral therapy (ART) generally reduces plasma HIV to undetectable levels, although virus persists in latently infected CD4+ T cells. In some individuals, viremia remains detectable despite adherence to ART and the absence of drug resistance mutations. In this issue of the JCI, Halvas et al. describe HIV RNA sequences from plasma of 8 donors with persistent viremia. Residual viremia was dominated by identical HIV-1 RNA sequences that remained relatively constant over 4 years. Plasma virus matched replication-competent virus cultured from CD4+ T cells. Integration site analysis confirmed the presence of large clones of infected cells. These results indicate that nonsuppressible viremia can be due to expanded clones of infected CD4+ T cells carrying replication-competent virus. The individuals described here represent extreme examples of a phenomenon that is seen in all infected individuals and that is a major barrier to curing HIV infection, the in vivo proliferation of latently infected cells.

Figure 1. Nonsuppressible viremia can result from large clones of infected cells.

(A) Plasma virus levels before and following initiation of antiretroviral therapy (ART). ART, represented as 3 gray bars to show a combination therapy regimen, generally blocks new infection of susceptible cells and reduces viremia to below the limit of detection of clinical assays (dotted black line). However, low-level viremia persists (dashed red line), representing virus release from cells in the latent reservoir that have become activated. (B) CD4⁺ T cells comprise the latent reservoir, with colors representing different clonal lineages. The size and composition of the reservoir are generally such that the level of virus released from reservoir cells is below the limit of detection of clinical assays (dotted line). However, in some individuals, clones can expand to a very large size (yellow and blue cells) and release a sufficient amount of virus to produce detectable viremia. This viremia cannot be suppressed by ART, which continues to block new infection of susceptible cells but not virus release from previously infected cells.