Clonal Expansion of Infected CD4+ T Cells in People Living with HIV

Abstract

HIV infection is not curable with current antiretroviral therapy (ART) because a small fraction of CD4+ T cells infected prior to ART initiation persists. Understanding the nature of this latent reservoir and how it is created is essential to development of potentially curative strategies. The discovery that a large fraction of the persistently infected cells in individuals on suppressive ART are members of large clones greatly changed our view of the reservoir and how it arises. Rather than being the products of infection of resting cells, as was once thought, HIV persistence is largely or entirely a consequence of infection of cells that are either expanding or are destined to expand, primarily due to antigen-driven activation. Although most of the clones carry defective proviruses, some carry intact infectious proviruses; these clones comprise the majority of the reservoir. A large majority of both the defective and the intact infectious proviruses in clones of infected cells are transcriptionally silent; however, a small fraction expresses a few copies of unspliced HIV RNA. A much smaller fraction is responsible for production of low levels of infectious virus, which can rekindle infection when ART is stopped. Further understanding of the reservoir will be needed to clarify the mechanism(s) by which provirus expression is controlled in the clones of cells that constitute the reservoir.

HIV infected CD4+ T cell clones are more stable than uninfected clones during long-term antiretroviral therapy

“…It is important to state that sampling limitations mean that there is no good way to determine if the large numbers of integration sites that were obtained only once were derived from clones that are too small for us to detect, or if they were from infected cells that were present only once in vivo. Thus, it is inappropriate to claim that there are infected cells that are “singles” [ 28 ] nor is it possible to claim that essentially all the HIV infected cells in a person living with HIV are in clones [ 29 ], either using the data that are now available, or data that can reasonably be expected to be obtained [ 30 ].…”

“…Data available for the three clones that carry infectious proviruses show that, although all three of the clones must all have persisted for at least 9 years, “old” clones that carry intact infectious proviruses can still change in size. Importantly, our results show that clones of CD4+ T cell that carry infectious proviruses can still increase in size, perhaps in response to antigenic or homeostatic stimulation [ 11 , 12 , 30 ], many years after the cell that gave rise to the clone was first infected. This suggests, even if the clones of infected cells that make up the reservoir are reduced in size by some therapeutic intervention, that at least some of the clones that carry infectious proviruses, and comprise part of the reservoir, could increase in size after an intervention, even if viral replication is completely blocked.…”

Strategies for HIV-1 vaccines that induce broadly neutralizing antibodies

“…A protective HIV-1 vaccine will likely be the most complex vaccine ever designed, employing novel vaccine platform technologies such as modified mRNAs in LNPs or novel vectors. Early after infection, HIV-1 provirus can integrate into the host genome as latent virus without producing viral proteins 179,180 , becoming, in effect, invisible to the immune system. For this reason, an effective HIV-1 bnAb vaccine that aims to prevent transmission with sterilizing immunity will need to be essentially 100% effective for both blood and mucosal exposure, an extraordinary bar that no vaccine has yet achieved 16,181 .…”

Insights Into Persistent HIV-1 Infection and Functional Cure: Novel Capabilities and Strategies

“…Although HIV-1 rebounds from replication-competent reservoir cells harboring intact proviral DNA upon cART cessation, the majority of proviruses are defective with large internal deletions or lethal mutations and clonally expand in vivo ( Coffin and Hughes, 2021 ). Defective proviruses account for more than 95% of the total proviruses in the peripheral blood isolated from cART-treated PLWH ( Siliciano et al, 2003 ; Eriksson et al, 2013 ; Crooks et al, 2015 ).…”