Uncovering the secrets of HIV latency

From the Cohn lab, Vaccine and Infectious Disease Division

Antiretroviral therapy (ART) effectively suppresses HIV viral load and controls disease, but does not fully eradicate latent HIV. Transcriptionally silent proviruses integrate in CD4+ T cells and reactivate when ART is interrupted, and this latent viral reservoir is estimated to have a half-life of up to 18 years, representing the primary barrier to an HIV cure. The factors that determine whether an integrated provirus will become latent, or if it will reactivate, are largely unknown.

Dr. Lillian Cohn, a new faculty member in the Vaccine and Infectious Disease Division, along with the Nussenzweig lab at Rockefeller University, explored this topic in a publication in the Journal of Experimental Medicine. It is known that latent, integrated proviruses are enriched in clonally expanded CD4+ T cells, or cells that share a T cell receptor (TCR) and arise due to proliferation in response to antigenic stimulation. However, the factors that allow CD4+ T cells with intact, integrated provirus to proliferate and be maintained are unknown, as proliferation paradoxically causes HIV activation and host cell death. The authors sequenced proviruses from 6 chronically infected people on ART and confirmed that proviral integration was concentrated in clonally expanded CD4+ T cell populations. They next mapped the integration sites within the CD4+ T cell genome. Consistent with previous studies, they found that integrations were enriched on chromosome 19. Specifically, intact proviral integrations were largely concentrated in the zinc-finger (ZNF) genes containing Kruppel-associated box (KRAB) domains, where proviruses have also been shown to be enriched in individuals who spontaneously control HIV-1 without ART.

Frequency of integrations into ZNF genes.
Frequency of integrations into ZNF genes. Image from publication.

Interestingly, when comparing all published integration site data, this enrichment in ZNF genes was only significant within expanded CD4+ T cell clones, not in all integration sites, suggesting that integration within distinct genomic sites favors clonal expansion of CD4+ T cells. In support of this, the authors assessed previously published data comparing the transcriptomes of resting and activated CD4+ T cells and found that ZNF genes harboring intact integrations are repressed during activation. This evidence suggests a survival advantage for cells with ZNF proviral integrations and provides one explanation for the apparent paradox of cells that proliferate without activating HIV-1 transcription, preventing host cell death.

A cure for HIV lies in the secrets of latency. The current work uncovers a piece of the mechanism behind latency by showing that proviruses preferentially integrate into ZNF genes that are repressed during cellular proliferation. However, whether this silencing is facilitated by repressors of HIV-1 transcription, the genomic content of HIV-1 integration, or both is still unclear. Additionally, the contribution of clonal CD4+ T cell populations containing proviral integrations to HIV-1 rebound is also unknown. Although much of this work was performed at Rockefeller University, some of the remaining questions will be addressed in Dr. Cohn’s new lab. At Fred Hutch, Dr. Cohn and her lab are continuing to study latent HIV reservoirs and the mechanisms that allow for latent cell persistence and reactivation. “The data from this study has illuminated one pathway for long-term infected cell survival, but we think it’s only a small piece of the puzzle. My group is focused on uncovering how the basic biology of human CD4+ T cells allows for HIV persistence in the presence of ART, and the work described here provides a foundation for our ongoing studies to progress,” Dr. Cohn said.

This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, the Bill and Melinda Gates Foundation, the Einstein-Rockefeller-City University of New York Center for AIDS Research, BEAT-HIV, the Robertson Foundation, Robert S. Wennett Post-Doctoral Fellowship, and by the Shapiro-Silverberg Fund for the Advancement of Translational Research.

Huang AS, Ramos V, Oliveira TY, Gaebler C, Jankovic M, Nussenzweig MC, Cohn LB. Integration features of intact latent HIV-1 in CD4+ T cell clones contribute to viral persistence. Journal of Experimental Medicine. 2021 Dec 6;218(12):e20211427. doi: 10.1084/jem.20211427. Epub 2021 Oct 12.