HIV latency

Abstract

HIV-1 can establish a state of latent infection at the level of individual T cells. Latently infected cells are rare in vivo and appear to arise when activated CD4(+) T cells, the major targets cells for HIV-1, become infected and survive long enough to revert back to a resting memory state, which is nonpermissive for viral gene expression. Because latent virus resides in memory T cells, it persists indefinitely even in patients on potent antiretroviral therapy. This latent reservoir is recognized as a major barrier to curing HIV-1 infection. The molecular mechanisms of latency are complex and include the absence in resting CD4(+) T cells of nuclear forms of key host transcription factors (e.g., NFκB and NFAT), the absence of Tat and associated host factors that promote efficient transcriptional elongation, epigenetic changes inhibiting HIV-1 gene expression, and transcriptional interference. The presence of a latent reservoir for HIV-1 helps explain the presence of very low levels of viremia in patients on antiretroviral therapy. These viruses are released from latently infected cells that have become activated and perhaps from other stable reservoirs but are blocked from additional rounds of replication by the drugs. Several approaches are under exploration for reactivating latent virus with the hope that this will allow elimination of the latent reservoir.

Figure 1.

Establishment of a latent reservoir for HIV-1. HIV-1 latency may be viewed as a consequence of the tropism of the virus for activated CD4⁺ T cells. (A) Generation of memory CD4⁺ T cells. A fraction of the CD4⁺ T cells that respond to a given antigen survive and revert back to a resting state as long-lived memory T cells. (B) Generation of latently infected cells. Latency is established when activated CD4⁺ T cells become infected and survive long enough to revert back to a resting memory state that is nonpermissive for viral gene expression. The resulting latent reservoir is intrinsically stable because memory cells have a long lifespan and can undergo a process of proliferative renewal through homeostatic proliferation.

Figure 2.

Compaction of chromatin around integrated HIV-1 proviruses may restrict access of key transcription factors to the 5′ long terminal repeat. However, this condensed chromatin state is reversed when cells are activated. Activation leads to transcription factor access and effective RNA Pol II elongation, giving rise to high-level virus production when HIV-1 Tat is produced.

Figure 3.

Two scenarios in which transcriptional interference may promote HIV-1 latency. In the first case, the HIV-1 provirus is integrated in the same polarity as an upstream gene within an intron of this gene. Read through by RNA Pol II initiating at the upstream promoter occludes the 5′LTR and displaces key transcription factors thereby promoting viral latency. Alternatively, the HIV-1 provirus and the cellular gene may be arranged in opposite polarity. In this situation, initiating polymerases collide, leading to decreased expression of one or both transcription units. The fact that latent HIV-1 proviruses are commonly found in actively transcribed genes suggests that transcriptional interference may be important in the maintenance of proviral latency.

Figure 4.

HIV-1 Tat effectively antagonizes HIV-1 latency by liberating P-TEFb from an inactive 7SK snRNP complex. In addition to the Tat-Cyclin T1-CDK9 complex that binds to TAR and promotes serine-2 phosphorylation of the carboxy-terminal domain of RNA Pol II, thereby eliminating promoter proximal pausing, two additional Tat complexes have recently been discovered. Tat complex 1 corresponds to the assembly of Tat-Cyclin T1-CDK9 with AFF1, AFF4, AFR, ENL, EAF1, and ELL2. This complex has been termed a “super-elongation complex.” ELL2 blocks backtracking by RNA Pol II. AFR, ENL, and AF9 correspond to transcription factors/coactivators; AF9 potentiates CDK9 kinase activity. Tat complex 2 corresponds to the 7SK snRNP complex lacking HEXIM. This RNP complex may correspond to an additional reservoir of Tat-CyclinT1-CDk9 within cells. However, its precise function remains to be delineated.

Figure 5.

Dynamics of viral decay in patients on HAART medications. After initiation of HAART, levels of plasma virus fall rapidly, reflecting the exponential decay of the activated CD4⁺ T cells that produce most of the plasma virus and the slower decay of a second population of infected cells that have a half-life of about 2 weeks. The second phase decay brings the level of plasma virus down to a new steady state that is below the limit of detection of clinical assays (50 copies/ml). The average level of residual viremia is around 1 copy/ml. Residual viremia appears to reflect release of virus from stable reservoirs and is not reduced further by treatment intensification. Biological and statistical fluctuations in the level of this residual viremia are occasionally captured in clinical measurements as “blips,” but these transient elevations do not reflect the evolution of resistant virus.