The implications of viral reservoirs on the elite control of HIV-1 infection

Abstract

The mechanisms by which a small percentage of HIV-1 infected individuals known as elite suppressors or controllers are able to control viral replication are not fully understood. Early cases of viremic control were attributed to infection with defective virus, but subsequent work has demonstrated that infection with a defective virus is not the exclusive cause of control. Replication-competent virus has been isolated from patients who control viral replication, and studies have demonstrated that evolution occurs in plasma virus but not in virus isolates from the latent reservoir. Additionally, transmission pair studies have demonstrated that patients infected with similar viruses can have dramatically different outcomes of infection. An increased understanding of the viral factors associated with control is important to understand the interplay between viral replication and host control, and has implications for the design of an effective therapeutic vaccine that can lead to a functional cure of HIV-1 infection.

Fig. 1

Models to explain the seeding of the latent reservoir: comparison between EC and CP. Top panel CP natural history: HIV-1 infection is typical characterized by robust viral replication during acute infection. As HIV-1 plasma RNA levels increase (blue line), there is a parallel increase in the number of latently infected cells (infectious units per million, IUPM; red line). A drop in both the HIV-1 plasma RNA levels and IUPM occurs with the initiation of the acquired immune response, likely due to CTL pressure. Without ART, viral replication continues, and escape mutations occur early (dotted red and blue lines). High levels of replication result in an equilibrium between seeding of the latent reservoir and reactivation of the latent reservoir (red and blue solid arrows), thus resulting in the reseeding of the latent reservoir with mutated virus. Upon the initiation of ART therapy, HIV-1 plasma RNA levels fall to undetectable levels, in concert with a decline in IUPM. ART halts ongoing replication, but reactivation of the latent reservoir results in the release of low levels of virus with escape mutations (red dashed arrow). Bottom panel EC natural history. During acute infection, HIV-1 plasma RNA level increases, but has been documented to be lower in EC compared to CP (blue line). The frequency of latently infected CD4⁺ T cells increases in parallel, but to levels that are lower compared to CP (red line). CTL pressure reduced viral replication to below the limit of detection, and there is limited seeding of the latent reservoir, resulting in a reduced IUPM in EC compared to CP. Escape occurs early in infection in EC, but there is limited seeding of the latent reservoir due to CTL pressure (blue dashed arrow). The majority of sequences in the latent reservoir do not contain escape mutations, as the seeding of the latent reservoir is limited by CTL pressure

Fig. 2

Discordance between plasma and proviral sequences: evidence for ongoing replication in EC. Representative phylogenetic data from an EC demonstrating the discordance between plasma and proviral sequences as identified by limiting dilution PCR to obtain clonal gag sequences. All sequences were estimated using a classical approach using the maximum likelihood analysis. Clonal sequences from resting CD4⁺ T cells, activated CD4⁺ T cells, and plasma sequences were amplified [64]. A clear discordance between the proviral compartments in resting CD4⁺ T cells (circles) and activated CD4⁺ T cells (squares) can be observed compared to the plasma viral sequences (triangles) over a period of 6 years. The proviral compartment cluster together, with the plasma virions showing evidence of ongoing replication

Fig. 3

Understanding the relationship between the latent reservoir and the plasma virus in EC. a The latent reservoir represents a major barrier to eradication, and resting CD4⁺ T cells remain in a resting quiescent state. Integrated provirus remains silenced by poorly understood mechanisms, but minimal evolution occurs within this compartment. Upon immune activation, virus is released from these latently infected cells, and nonsynonymous mutations likely result in virions that escape immune pressure. Continuous, ongoing replication occurs in EC, the location of the replication is unknown but may be represented by either activated CD4⁺ T cells, the gut-associated lymphoid tissue or other lymphoid organs, or the central nervous system. Plasma virions with escape mutations are not commonly represented in the latent reservoir, thus the source of these viruses are currently unknown. It has been shown that evolution occurs during low level ongoing replication, but is most commonly characterized by synonymous changes. The production of virus from this unknown compartment results in low level viremia that may re-infect the latent reservoir at very low levels or contribute to ongoing replication. b Representative data showing that there are clear differences in fitness between isolates cultured from resting CD4⁺ T cells containing wild type sequence and escape mutants cultured from activated CD4⁺ T cells [71]. Primary CD4⁺ T cells were infected, and viral production was measured by p24 ELISA. These data indicate that the latent virus (blue) is more fit compared to the escape mutant (red line), likely due to the attenuating effect of the escape mutations. Thus, it is likely that plasma virions that contain similar escape mutations do not accurately reflect the fitness of the infecting virus that is archived in the latent reservoir