Defining total-body AIDS-virus burden with implications for curative strategies

Estes, Jacob D.; Kityo, Cissy; Ssali, Francis; Swainson, Louise; Makamdop, Krystelle Nganou; Prete, Gregory Q. Del; Deeks, Steven G.; Luciw, Paul A.; Chipman, Jeffrey G.; Beilman, Gregory J.; Hoskuldsson, Torfi; Khoruts, Alexander; Anderson, Jodi; Deléage, Claire; Jasurda, Jacob; Schmidt, Thomas E.; Hafertepe, Michael; Callisto, Samuel P.; Pearson, Hope; Reimann, Thomas; Schuster, Jared; Schoephoerster, Jordan; Southern, Peter J.; Perkey, Katherine; Liu, Shang; Wietgrefe, Stephen W.; Fletcher, Courtney V.; Lifson, Jeffrey D.; Douek, Daniel C.; McCune, Joseph M.; Haase, Ashley T.; Schacker, Timothy W.

doi:10.1038/nm.4411

Cited by 345 publications

(388 citation statements)

References 42 publications

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“…Given the central importance of lymphoid tissues as a source of the HIV reservoir during HIV/simian immunodeficiency virus (SIV) infection (3–6), we investigated the frequency of expression of CD32 + CD4 + T cells, subset distribution, and phenotype in tonsil samples from ART-treated HIV-infected individuals from the Philadelphia cohort (Fig. 3 and fig.…”

Section: Resultsmentioning

confidence: 99%

CD32 is expressed on cells with transcriptionally active HIV but does not enrich for HIV DNA in resting T cells

et al. 2018

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The persistence of HIV reservoirs, including latently infected, resting CD4+ T cells, is the major obstacle to cure HIV infection. CD32a expression was recently reported to m ark CD4+ T cells harboring a replication-competent HIV reservoir during antiretroviral therapy (ART) suppression. We aimed to determine whether CD32 expression marks HIV latently or transcriptionally active infected CD4+ T cells. Using peripheral blood and lymphoid tissue of ART-treated HIV+ or SIV+ subjects, we found that most of the circulating memory CD32+ CD4+ T cells expressed markers of activation, including CD69, HLA-DR, CD25, CD38, and Ki67, and bore a TH2 phenotype as defined by CXCR3, CCR4, and CCR6. CD32 expression did not selectively enrich for HIV- or SIV-infected CD4+ T cells in peripheral blood or lymphoid tissue; isolated CD32+ resting CD4+ T cells accounted for less than 3% of the total H IV DNA in CD4+ T cells. Cell-associated HIV DNA and RNA loads in CD4+ T cells positively correlated with the frequency of CD32+ CD69+ CD4+ T cells but not with CD32 expression on resting CD4+ T cells. Using RNA fluorescence in situ hybridization, CD32 coexpression with HIV RNA or p24 was detected after in vitro HIV infection (peripheral blood mononuclear cell and tissue) and in vivo within lymph node tissue from HIV-infected individuals. Together, these results indicate that CD32 is not a marker of resting CD4+ T cells or of enriched HIV DNA-positive cells after ART; rather, CD32 is predominately expressed on a subset of activated CD4+ T cells enriched for transcriptionally active HIV after long-term ART.

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Section: Resultsmentioning

confidence: 99%

CD32 is expressed on cells with transcriptionally active HIV but does not enrich for HIV DNA in resting T cells

et al. 2018

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“…Second, as antibody glycosylation is programmed in an antigen‐specific manner, detailed experiments to gauge the impact each anti‐HIV specific antibody glycosylation on HIV persistence will be needed. Third, our data were obtained from blood; given the enrichment of the HIV reservoir in tissues, it will be needed to analyze the role of circulating glycans in maintaining HIV persistence in tissues. Lastly, our data describe cross‐sectional samples from chronically infected adults; thereby there is a need to also analyze longitudinal changes, acute infection, and both pediatric and older aged cohorts in the future.…”

Section: Discussionmentioning

confidence: 99%

“…Third, our data were obtained from blood; given the enrichment of the HIV reservoir in tissues, 72,73 it will be needed to analyze the role of circulating glycans in maintaining HIV persistence in tissues. Lastly, our data describe cross-sectional samples from chronically infected adults; thereby there is a need to also analyze longitudinal changes, acute infection, and both pediatric and older aged cohorts in the future.…”

Section: Levels Of Circulating Anti-inflammatory Glycans Associate Wimentioning

confidence: 99%

Frontline Science: Plasma and immunoglobulin G galactosylation associate with HIV persistence during antiretroviral therapy

Vadrevu

Trbojević‐Akmačić

Kossenkov

et al. 2018

Journal of Leukocyte Biology

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Global antibody glycosylation is dynamic and plays critical roles in shaping different immunological outcomes and direct antibody functionality during HIV infection. However, the relevance of global antibody or plasma glycosylation patterns to HIV persistence after antiretroviral therapy (ART) has not been characterized. First, we compared glycomes of total plasma and isolated immunoglobulin G (IgG) from HIV+ ART-suppressed, HIV+ viremic, and HIV-negative individuals. Second, in ART-suppressed individuals, we examined the associations between glycomes and (1) levels of cell-associated HIV DNA and RNA in PBMCs and isolated CD4+ T cells, (2) CD4 count and CD4%, and (3) expression of CD4+ T-cell activation markers. HIV infection is associated with persistent alterations in the IgG glycome including decreased levels of disialylated glycans, which is associated with a lower anti-inflammatory activity, and increased levels of fucosylated glycans, which is associated with lower antibody-dependent cell-mediated cytotoxicity (ADCC). We also show that levels of certain mono- and digalactosylated nonfucosylated glycomic traits (A2G1, A2G2, and A2BG2), which have been reported to be associated with higher ADCC and higher anti-inflammatory activities, exhibit significant negative correlations with levels of cell-associated total HIV DNA and HIV RNA in ART-suppressed individuals. Finally, levels of certain circulating anti-inflammatory glycans are associated with higher levels of CD4 T cells and lower levels of T-cell activation. Our findings represent the first proof-of-concept evidence that glycomic alterations, known to be associated with differential states of inflammation and ADCC activities, are also associated with levels of HIV persistence in the setting of ART suppression.

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“…The inability to detect minority viral variants as well as latently infected cells using current assays 31,32 highlights the challenge associated with testing our hypothesis experimentally. Current assays can rarely detect variants below a frequency of ~1% 33 , implying that, given the prevalent estimates of the latent reservoir size of 10 5 –10 8 cells 4,34 , variants present in as many as 10 3 latently infected cells may go undetected and be responsible for therapy failure. Indeed, in many individuals who failed rapidly in the trials above 17 , resistance could not be detected pre-treatment.…”

Section: Introductionmentioning

confidence: 99%

Pre-existing resistant proviruses can compromise maintenance of remission by VRC01 in chronic HIV-1 infection

Saha

Dixit

2020

Preprint

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16Broadly neutralizing antibodies (bNAbs) of HIV-1 hold promise of eliciting long-term HIV-1 17 remission. Surprisingly, the bNAb VRC01, when administered concomitantly with the cessation 18 of successful antiretroviral therapy (ART), failed rapidly in chronic HIV-1 patients. We 19 hypothesized that the failure was due to VRC01-resistant strains that were formed before ART 20 initiation, survived ART in latently infected cells, and were reactivated during VRC01 therapy. 21 Current assay limitations preclude testing this hypothesis experimentally. We developed a 22 mathematical model based on the hypothesis and challenged it with available clinical data. The 23 model integrated within-host HIV-1 evolution, stochastic latency reactivation and viral dynamics 24 with multiple dose VRC01 pharmacokinetics. With a virtual patient population, model predictions 25 quantitatively captured data from two independent clinical trials. Accordingly, we attributed 26 VRC01 failure to single-mutant VRC01-resistant proviruses in the latent reservoir triggering viral 27 recrudescence, particularly during trough VRC01 levels. Accounting for pre-existing resistance 28 may help bNAb therapies maximize HIV-1 remission. 29 30 Antiretroviral therapy (ART) for HIV-1 infection rapidly suppresses viremia to 32 undetectable levels and curtails disease progression but is unable to eradicate the virus. 1 33 Discontinuation of ART, even long after viremic control is established, typically leads to rapid 34 viral rebound, often within days to weeks of discontinuation, and to progressive disease. 2 The 35 rebound is caused by a reservoir of latently infected cells 3 that is formed soon after infection 4 . The 36 reservoir is sustained by cell proliferation 5,6 , which can continue even when ART has stopped new 37 infections, allowing the reservoir to exist long-term 7 . The reservoir can get reactivated 38 stochastically and reignite infection once ART is stopped 8,9 . ART must therefore be administered 39 lifelong. In a remarkable breakthrough, the VISCONTI study showed that when ART is 40 administered early in infection, some individuals can maintain viremic control for many years after 41 the cessation of ART 10 . This study has raised hopes of a functional cure, or long-term remission, 42 of HIV-1, where the viremic control once established by ART can be maintained without lifelong 43 treatment 11 . The success of ART in inducing post-treatment control, however, is small: only ~5-44 15% of the patients treated achieve lasting post-treatment control 12 . Enormous efforts are 45 underway to improve this success rate 11 . 46 One strategy that holds promise is to administer broadly neutralizing antibodies (bNAbs) 47 of HIV-1 for a short period post-ART, i.e., during an analytical treatment interruption (ATI) 13,14 . 48 bNAbs target diverse viral genomic variants 15,16 , and are expected to suppress viremia arising from 49 the reactivation of latently infected cells 17,18 . Simultaneously, they may engage the host immune 50 system 19 , ...

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Defining total-body AIDS-virus burden with implications for curative strategies

Cited by 345 publications

References 42 publications

CD32 is expressed on cells with transcriptionally active HIV but does not enrich for HIV DNA in resting T cells

CD32 is expressed on cells with transcriptionally active HIV but does not enrich for HIV DNA in resting T cells

Frontline Science: Plasma and immunoglobulin G galactosylation associate with HIV persistence during antiretroviral therapy

Pre-existing resistant proviruses can compromise maintenance of remission by VRC01 in chronic HIV-1 infection

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