Rapid biphasic decay of intact and defective HIV DNA reservoir during acute treated HIV disease.

Despite antiretroviral therapy (ART), HIV persists in latently-infected cells (the HIV reservoir) which decay slowly over time. Here, leveraging >500 longitudinal samples from 67 people living with HIV (PLWH) treated during acute infection, we developed a mathematical model to predict reservoir decay from peripheral CD4 + T cells. Nonlinear generalized additive models demonstrated rapid biphasic decay of intact DNA (week 0-5: t ~ 2.

Rapid Biphasic Decay of Intact and Defective HIV DNA Reservoir During Acute Treated HIV Disease.

Despite antiretroviral therapy (ART), HIV persists in latently-infected cells ("the reservoir") which decay slowly over time. Here, leveraging >500 longitudinal samples from 67 people with HIV (PWH) treated during acute infection, we developed a novel mathematical model to predict reservoir decay from peripheral CD4+ T cells. Nonlinear generalized additive models demonstrated rapid biphasic decay of intact DNA (week 0-5: t~2.

Varied Patterns of Decay of Intact Human Immunodeficiency Virus Type 1 Proviruses Over 2 Decades of Antiretroviral Therapy.

Fourteen people with human immunodeficiency virus type 1 had longitudinal measurements of intact, defective, and total proviral DNA over the course of two decades of antiretroviral therapy. Three patterns of intact proviral DNA decay were revealed: (1) biphasic decline with markedly slower second-phase decline, (2) initial decline that transitions to a zero-slope plateau, and (3) initial decline followed by later increases in intact proviral DNA. Defective proviral DNA levels were essentially stable.

Single center, open label dose escalating trial evaluating once weekly oral ixazomib in ART-suppressed, HIV positive adults and effects on HIV reservoir size in vivo.

Background: Achieving a functional or sterilizing cure for HIV will require identification of therapeutic interventions that reduce HIV reservoir size in infected individuals. Proteasome inhibitors, such as ixazomib, impact multiple aspects of HIV biology including latency, transcription initiation, viral replication, and infected cell killing through the HIV protease - Casp8p41 pathway, resulting in latency reversal and reduced measures of HIV reservoir size ex vivo.

Methods: We conducted a phase 1b/2a dose escalating, open label trial of weekly oral ixazomib for 24 weeks in antiretroviral (ART)-suppressed, HIV positive adults (NCT02946047).

Shared Mechanisms Govern HIV Transcriptional Suppression in Circulating CD103 and Gut CD4 T Cells.

Latent HIV infection is the main barrier to cure, and most HIV-infected cells reside in the gut, where distinct but unknown mechanisms may promote viral latency. Transforming growth factor β (TGF-β), which induces the expression of CD103 on tissue-resident memory T cells, has been implicated in HIV latency. Using CD103 as a surrogate marker to identify cells that have undergone TGF-β signaling, we compared the HIV RNA/DNA contents and cellular transcriptomes of CD103 and CD103 CD4 T cells from the blood and rectum of HIV-negative (HIV) and antiretroviral therapy (ART)-suppressed HIV-positive (HIV) individuals.

Nonstructured Treatment Interruptions Are Associated With Higher Human Immunodeficiency Virus Reservoir Size Measured by Intact Proviral DNA Assay in People Who Inject Drugs.

The latent reservoir for human immunodeficiency virus type 1 (HIV-1) in CD4+ T cells is a major barrier to cure. HIV-1-infected persons who inject drugs (PWID) often struggle to maintain suppression of viremia and experience nonstructured treatment interruptions (NTIs). The effects of injecting drugs or NTIs on the reservoir are unclear.

Differential decay of intact and defective proviral DNA in HIV-1-infected individuals on suppressive antiretroviral therapy.

BACKGROUNDThe relative stabilities of the intact and defective HIV genomes over time during effective antiretroviral therapy (ART) have not been fully characterized.METHODSWe used the intact proviral DNA assay (IPDA) to estimate the rate of change of intact and defective proviruses in HIV-infected adults on ART. We used linear spline models with a knot at seven years and a random intercept and slope up to the knot.

Elite suppressors have low frequencies of intact HIV-1 proviral DNA.

: Elite controllers or suppressors control viral replication without antiretroviral therapy. We used the intact proviral DNA assay to approximate the size of the inducible latent reservoir in elite suppressors and found that, while the median frequency of both total and intact proviral DNA was markedly lower than the frequencies seen in chronic progressors on antiretroviral therapy there was no significant difference in the ratio of intact to total proviral DNA between elite suppressors and chronic progressors.