Long-Term Reduction in Peripheral Blood HIV Type 1 Reservoirs Following Reduced-Intensity Conditioning Allogeneic Stem Cell Transplantation

Henrich, Timothy J.; Hu, Zixin; Li, Jonathan Z.; Sciaranghella, Gaia; Busch, Michael P.; Keating, Sheila M.; Gallien, Sébastien; Lin, Nina; Giguel, Françoise; Lavoie, Laura; Ho, Vincent T.; Armand, Philippe; Soiffer, Robert J.; Sagar, Manish; LaCasce, Ann S.; Kuritzkes, Daniel R.

doi:10.1093/infdis/jit086

Cited by 242 publications

(214 citation statements)

References 39 publications

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“…Although the child was infected in utero, it is likely that, at the time of treatment, the child's latent reservoir was small, because the largest contributor to the reservoir are memory cells (14), and the memory response only develops after birth. The two HIV-1-infected "Boston patients" (61) also experienced delayed rebound, by 12 wk and 8 mo, following cessation of ART after allogenic hematopoietic stem cell transplants for the treatment of lymphoma; their latent reservoirs were also likely very small, because HIV-1 DNA and RNA were not detectable in peripheral blood mononuclear cells, CD4 + T cells, and plasma up to 21 and 42 mo after transplantation in the two patients (62). Although our predictions are consistent with these observations, Table S1.…”

Section: Discussionmentioning

confidence: 99%

Post-treatment control of HIV infection

Conway

Perelson

2015

Proc. Natl. Acad. Sci. U.S.A.

188

280

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Antiretroviral therapy (ART) for HIV is not a cure. However, recent studies suggest that ART, initiated early during primary infection, may induce post-treatment control (PTC) of HIV infection with HIV RNA maintained at <50 copies per mL. We investigate the hypothesis that ART initiated early during primary infection permits PTC by limiting the size of the latent reservoir, which, if small enough at treatment termination, may allow the adaptive immune response to prevent viral rebound (VR) and control infection. We use a mathematical model of within host HIV dynamics to capture interactions among target cells, productively infected cells, latently infected cells, virus, and cytotoxic T lymphocytes (CTLs). Analysis of our model reveals a range in CTL response strengths where a patient may show either VR or PTC, depending on the size of the latent reservoir at treatment termination. Below this range, patients will always rebound, whereas above this range, patients are predicted to behave like elite controllers. Using data on latent reservoir sizes in patients treated during primary infection, we also predict population-level VR times for noncontrollers consistent with observations.

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Section: Discussionmentioning

confidence: 99%

Post-treatment control of HIV infection

Conway

Perelson

2015

Proc. Natl. Acad. Sci. U.S.A.

188

280

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“…One paradoxical observation is that, despite prolonged viral suppression with no evidence of active viral replication, the majority of HIV-infected patients exhibit persistent presence of HIV-1 proviruses (2-4), persistent seropositivity to HIV-1 (5), and evidence of immune activation (6)(7)(8)(9)(10). The only setting in which this has not been the case has been following bone marrow transplantation in which seronegativity has been reported in association with a loss of peripheral blood proviral DNA (11,12). Over 90% of proviruses in the peripheral blood are thought to be "defective" by having lethal genetic alterations that include G-to-A hypermutations (13,14) and small insertions/deletions (indels) that disrupt ORFs (13), or large internal deletions (13,15,16).…”

mentioning

confidence: 99%

Defective HIV-1 proviruses produce novel protein-coding RNA species in HIV-infected patients on combination antiretroviral therapy

Imamichi

Dewar

Adelsberger

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

295

313

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Despite years of plasma HIV-RNA levels <40 copies per milliliter during combination antiretroviral therapy (cART), the majority of HIV-infected patients exhibit persistent seropositivity to HIV-1 and evidence of immune activation. These patients also show persistence of proviruses of HIV-1 in circulating peripheral blood mononuclear cells. Many of these proviruses have been characterized as defective and thus thought to contribute little to HIV-1 pathogenesis. By combining 5′LTR-to-3′LTR single-genome amplification and direct amplicon sequencing, we have identified the presence of “defective” proviruses capable of transcribing novel unspliced HIV-RNA (usHIV-RNA) species in patients at all stages of HIV-1 infection. Although these novel usHIV-RNA transcripts had exon structures that were different from those of the known spliced HIV-RNA variants, they maintained translationally competent ORFs, involving elements of gag, pol, env, rev, and nef to encode a series of novel HIV-1 chimeric proteins. These novel usHIV-RNAs were detected in five of five patients, including four of four patients with prolonged viral suppression of HIV-RNA levels <40 copies per milliliter for more than 6 y. Our findings suggest that the persistent defective proviruses of HIV-1 are not “silent,” but rather may contribute to HIV-1 pathogenesis by stimulating host-defense pathways that target foreign nucleic acids and proteins.

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“…134 Initially during the posttransplantation period while they were on ART, viral nucleic acids could be detected in their blood CD4 T cells or plasma for some time (*2-3 months), 134 but later these could not be detected for up to 4.3 years for one patient and 2.6 years for another in sensitive quantitative PCR assays. 135 Subsequently, these patients underwent analytical ART interruption when their blood and rectal mucosa both tested negative for HIV DNA and RNA.…”

Section: Late Rebound Of Viral Loads In the ''Boston Patients''mentioning

confidence: 99%