HIV-1 DNA predicts disease progression and post-treatment virological control

Williams, James P.; Hurst, Jacob; Stöhr, Wolfgang; Robinson, Nicola; Brown, Helen; Fisher, Martin; Kinloch, S; Cooper, David A.; Schechter, Mauro; Tambussi, Giuseppe; Fidler, Sarah; Carrington, Mary; Babiker, Abdel; Weber, Jonathan; Koelsch, Kersten K.; Kelleher, Anthony D.; Phillips, Rodney E.; Frater, John

doi:10.7554/elife.03821

Cited by 266 publications

(272 citation statements)

References 38 publications

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“…S1B in the supplemental material) and other clinical studies (32,33). The magnitude and breadth of HIV-1-specific CD8 T cells determined by ELISpot assays and the proportions of HIV-1-specific CD8 T cells secreting any combination of the analyzed cytokines at the baseline and throughout the study were statistically unrelated to the baseline levels of CD4 T cell-associated HIV-1 DNA or to the relative changes in HIV-1 DNA levels during panobinostat treatment ( Fig.…”

Section: Resultsmentioning

confidence: 89%

Innate Immune Activity Correlates with CD4 T Cell-Associated HIV-1 DNA Decline during Latency-Reversing Treatment with Panobinostat

Olesen

Viganó

Rasmussen

et al. 2015

J Virol

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The pharmaceutical reactivation of dormant HIV-1 proviruses by histone deacetylase inhibitors (HDACi) represents a possible strategy to reduce the reservoir of HIV-1-infected cells in individuals treated with suppressive combination antiretroviral therapy (cART). However, the effects of such latency-reversing agents on the viral reservoir size are likely to be influenced by host immune responses. Here, we analyzed the immune factors associated with changes in proviral HIV-1 DNA levels during treatment with the potent HDACi panobinostat in a human clinical trial involving 15 cART-treated HIV-1-infected patients. We observed that the magnitude, breadth, and cytokine secretion profile of HIV-1-specific CD8 T cell responses were unrelated to changes in HIV-1 DNA levels in CD4 T cells during panobinostat treatment. In contrast, the proportions of CD3 ؊ CD56 ؉ total NK cells and CD16 ؉ CD56 dim NK cells were inversely correlated with HIV-1 DNA levels throughout the study, and changes in HIV-1 DNA levels during panobinostat treatment were negatively associated with the corresponding changes in CD69 ؉ NK cells. Decreasing levels of HIV-1 DNA during latency-reversing treatment were also related to the proportions of plasmacytoid dendritic cells, to distinct expression patterns of interferon-stimulated genes, and to the expression of the IL28B CC genotype. Together, these data suggest that innate immune activity can critically modulate the effects of latency-reversing agents on the viral reservoir and may represent a target for future immunotherapeutic interventions in HIV-1 eradication studies. IMPORTANCECurrently available antiretroviral drugs are highly effective in suppressing HIV-1 replication, but the virus persists, despite treatment, in a latent form that does not actively express HIV-1 gene products. One approach to eliminate these cells, colloquially termed the "shock-and-kill" strategy, focuses on the use of latency-reversing agents that induce active viral gene expression in latently infected cells, followed by immune-mediated killing. Panobinostat, a histone deacetylase inhibitor, demonstrated potent activities in reversing HIV-1 latency in a recent pilot clinical trial and reduced HIV-1 DNA levels in a subset of patients. Interestingly, we found that innate immune factors, such as natural killer cells, plasmacytoid dendritic cells, and the expression patterns of interferon-stimulated genes, were most closely linked to a decline in the HIV-1 DNA level during treatment with panobinostat. These data suggest that innate immune activity may play an important role in reducing the residual reservoir of HIV-1-infected cells.A lthough for a long time regarded as an elusive goal, the development of clinical interventions that lead to a long-term, drug-free remission of HIV-1 infection is increasingly being recognized as a more and more realistic objective (1-4). This is in part related to the identification of patients with a sterilizing or functional cure of HIV-1 infection, who provide living evidence that, ...

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Section: Resultsmentioning

confidence: 89%

Innate Immune Activity Correlates with CD4 T Cell-Associated HIV-1 DNA Decline during Latency-Reversing Treatment with Panobinostat

Olesen

Viganó

Rasmussen

et al. 2015

J Virol

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“…Both FACS and tCD4 cell isolation kits provided tCD4 cells with good purities (medians of 99.8% and 96.1%, respectively). In this comparison, 10 CA HIV-1 DNA and RNA levels adjusted for tCD4 cell purity were highly correlated for the two cell purification methods (CA HIV-1 DNA, r ϭ 0.867; CA HIV-1 RNA, r ϭ 0.770; P Ͻ 0.001) ( Fig. 3A and B; see Fig.…”

Section: Volunteersmentioning

confidence: 99%

“…Prior work showed that CA HIV-1 DNA and RNA remain detectable in most chronically infected individuals despite suppressive ART (7,8). Although the association of CA HIV-1 DNA and RNA levels with the size of the latent HIV-1 reservoir has been called into question (9), recent studies suggest that CA HIV-1 DNA and RNA levels may predict the time to virological rebound after ART cessation and thus may serve as clinically relevant biomarkers (10,11).…”

mentioning

confidence: 99%

Novel Assays for Measurement of Total Cell-Associated HIV-1 DNA and RNA

et al. 2016

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c Although a number of PCR-based quantitative assays for measuring HIV-1 persistence during suppressive antiretroviral therapy (ART) have been reported, a simple, sensitive, reproducible method is needed for application to large clinical trials. We developed novel quantitative PCR assays for cell-associated (CA) HIV-1 DNA and RNA, targeting a highly conserved region in HIV-1 pol, with sensitivities of 3 to 5 copies/1 million cells. We evaluated the performance characteristics of the assays using peripheral blood mononuclear cells (PBMCs) from 5 viremic patients and 20 patients receiving effective ART. Total and resting CD4 ؉ T cells were isolated from a subset of patients and tested for comparison with PBMCs. The estimated standard deviations including interassay variability and intra-assay variability of the assays were modest, i.e., 0.15 and 0.10 log 10 copies/10 6 PBMCs, respectively, for CA HIV-1 DNA and 0.40 and 0.19 log 10 copies/10 6 PBMCs for CA HIV-1 RNA. Testing of longitudinally obtained PBMC samples showed little variation for either viremic patients (median fold differences of 0.80 and 0.88 for CA HIV-1 DNA and RNA, respectively) or virologically suppressed patients (median fold differences of 1.14 and 0.97, respectively). CA HIV-1 DNA and RNA levels were strongly correlated (r ‫؍‬ 0.77 to 1; P ‫؍‬ 0.0001 to 0.037) for assays performed using PBMCs from different sources (phlebotomy versus leukapheresis) or using total or resting CD4 ؉ T cells purified by either bead selection or flow cytometric sorting. Their sensitivity, reproducibility, and broad applicability to small numbers of mononuclear cells make these assays useful for observational and interventional studies that examine longitudinal changes in the numbers of HIV-1-infected cells and their levels of transcription.

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“…The time to viral rebound correlates with total viremia during acute infection and with size of latent HIV reservoir at the time of ART discontinuation [67]. This supports that reducing the size of the reservoir may extend the viral free lifespan or time to viral rebound (aka "functional cure"), even if HIV reservoir depleting strategies fail to be complete.…”

Section: Challenges In Hiv Cure: the Hiv Latent Reservoirmentioning

confidence: 54%

Can We Repurpose FDA-Approved Alefacept to Diminish the HIV Reservoir?

Zaidi¹,

Meng²

2016

Immunother Open Acc

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Current anti-retroviral treatment (ART) for HIV is effective in maintaining HIV at undetectable levels. However, cessation of ART results in immediate and brisk rebound of viremia to high levels. This rebound is driven by an HIV reservoir mainly enriched in memory CD4 + T cells. In order to provide any form of functional HIV Cure, elimination of this viral reservoir has become the focus of current HIV cure strategies. Alefacept was initially developed for the treatment of chronic plaque psoriasis. Alefacept is a chimeric fusion protein consisting of the CD2-binding portion of human leukocyte function antigen-3 (LFA3) linked to the Fc region of human IgG1 (LFA3-Fc). Alefacept was designed to inhibit memory T cell activation that contributes to the chronic autoimmune disease psoriasis by blocking the CD2 coreceptor. However, it was found to deplete memory T cells that express high levels of CD2 via NK cellmediated antibody dependent cell cytotoxicity (ADCC) in vivo. Phase II and phase III clinical trials of alefacept with psoriasis patients demonstrated promising results and an excellent safety profile. Subsequently, alefacept has been successfully repurposed for other memory T cell-mediated autoimmune diseases including skin diseases other than psoriasis, organ transplantation and type I diabetes (T1D). Herein, we review our specific strategy to repurpose the FDA approved biologic alefacept to decrease and hopefully someday eliminate the HIV reservoir, for which CD2 hi memory CD4 + T cells are a significant contributor.

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HIV-1 DNA predicts disease progression and post-treatment virological control

Cited by 266 publications

References 38 publications

Innate Immune Activity Correlates with CD4 T Cell-Associated HIV-1 DNA Decline during Latency-Reversing Treatment with Panobinostat

Innate Immune Activity Correlates with CD4 T Cell-Associated HIV-1 DNA Decline during Latency-Reversing Treatment with Panobinostat

Novel Assays for Measurement of Total Cell-Associated HIV-1 DNA and RNA

Can We Repurpose FDA-Approved Alefacept to Diminish the HIV Reservoir?

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