HIV-infected CD4+ T Cell Proliferation as a Crucial Mechanism of Viral Persistence

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The stability of the latent HIV-1 reservoir presents a challenge to virus eradication.
The stability of the latent HIV-1 reservoir presents a challenge to virus eradication.

The inherent stability of a small population of T cells that are latently infected with HIV despite antiretroviral therapy (ART) remains a stubborn obstacle to curing HIV. The exact mechanisms underlying the stability of the HIV reservoir remain unclear.

One potential mechanism of viral persistence is through proliferation of T cells carrying replication-competent provirus. Proliferation of HIV-infected cells is to some extend unexpected: activation of T cells by antigens or cytokines can drive cellular proliferation but likely also reverse HIV latency, resulting in productive viral infection and cell death.

Recent studies1-3 provided direct evidence of proliferation of HIV-infected cells in vivo using integration site analysis but without establishing replication competence. Other studies4-6 reported identical replication-competent viral isolates from the same individual without definitive evidence for clonal expansion.

Because of technical limitations of each assay, these previous studies were unable to demonstrate if expanded cellular clones can effectively carry replication-competent virus.

In a recent study published in the Journal of Experimental Medicine, Robert F. Siliciano, MD, PhD, professor in the department of medicine at Johns Hopkins Medicine in Baltimore, Maryland, and colleagues describe a new technique that combines limiting dilution viral outgrowth and viral sequencing to simultaneously quantitatively and qualitatively characterize replication-competent viruses in the latent reservoir.7 

The investigators subjected resting CD4+ T cells from individuals on suppressive ART to multiple rounds of stimulation ex vivo with phytohemagglutinin and irradiated allogenic peripheral blood mononuclear cells. They demonstrated that cells carrying replication-competent HIV can proliferate without producing infectious virus and then release virus upon subsequent stimulation. Subsequent sequencing of independent clonal isolates of replication-competent virus (i.e. viral RNA in supernatant of p24+ wells) demonstrated that 57% had env sequences identical to other isolates from the same patient. Two independent phylogenetic and statistical approaches suggested that these identical sequences arose through proliferation of latently infected cells, rather than infection of multiple cells by similar viral variants.

This study has important implications: first, it suggests that standard quantitative viral outgrowth assay and other assays that rely on single-round stimulation to induce HIV significantly underestimate the real magnitude of the replication-competent HIV reservoir. Second, the possibility that the HIV reservoir is maintained by proliferation of HIV-infected cells during ART represents an additional challenge to HIV cure efforts. Future studies will need to determine what factors are driving the proliferation of HIV-infected cells in vivo, and if this phenomenon can be overcome by enhancing cell loss to promote a cure.


References

  1. Maldarelli F, Wu X, Su L, et al. Specific HIV integration sites are linked to clonal expansion and persistence of infected cells. Science. 2014;345(6193):179-183. doi: 10.1126/science.1254194
  2. Wagner TA, McLaughlin S, Garg K, et al. Proliferation of cells with HIV integrated into cancer genes contributes to persistent infection. Science. 2014;345(6196):570-573. doi: 10.1126/science.1256304
  3. Cohn LB, Silva IT, Oliveira TY, et al. HIV-1 integration landscape during latent and active infection. Cell. 2015;160(3):420-432. doi: 10.1016/j.cell.2015.01.020
  4. Lorenzi JC, Cohen YZ, Cohn LB, et al. Paired quantitative and qualitative assessment of the replication-competent HIV-1 reservoir and comparison with integrated proviral DNA. Proc Natl Acad Sci U S A. 2016;113(49):E7908-E7916. doi: 10.1073/pnas.1617789113
  5. Bruner KM, Murray AJ, Pollack RA, et al. Defective proviruses rapidly accumulate during acute HIV-1 infection. Nat Med. 2016;22(9):1043-1049. doi: 10.1038/nm.4156
  6. von Stockenstrom S, Odevall L, Lee E, et al. Longitudinal genetic characterization reveals that cell proliferation maintains a persistent HIV type 1 DNA pool during effective HIV therapy. J Infect Dis. 2015;212(4):596-607. doi: 10.1093/infdis/jiv092
  7. Hosmane NN, Kwon KJ, Bruner KM, et al. Proliferation of latently infected CD4+ T cells carrying replication-competent HIV-1: potential role in latent reservoir dynamics. J Exp Med. 2017;214(4):959-972. doi: 10.1084/jem.20170193
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