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Immunologic Biomarkers, Morbidity, and Mortality in Treated HIV Infection

Rosuvastatin slows progression of subclinical atherosclerosis in patients with treated HIV infection

Antiretroviral therapy for the prevention of HIV-1 transmission

HIV Transmission Risk Persists During the First 6 Months of Antiretroviral Therapy

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Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomised controlled trial

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Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis

Outcomes of HIV-associated Hodgkin lymphoma in the era of antiretroviral therapy

CD4+ and CD8+ T-cell kinetics in aviremic HIV-infected patients developing Hodgkin or non-Hodgkin lymphoma

CD8 T-Cell Expansion and Inflammation Linked to CMV Coinfection in ART-treated HIV Infection

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Ongoing HIV Replication Replenishes Viral Reservoirs During Therapy

Incidence and progression of coronary artery calcium in HIV-infected and HIV-uninfected men

Transient elastography for the detection of hepatic fibrosis in HIV-monoinfected adults with elevated aminotransferases on antiretroviral therapy

Association of immune-activation and senescence markers with non-AIDS-defining comorbidities in HIV-suppressed patients

Effects of randomized rosuvastatin compared with placebo on bone and body composition among HIV-infected adults

Levels of intracellular HIV-DNA in patients with suppressive antiretroviral therapy

Cancer Risk and Use of Protease Inhibitor or Nonnucleoside Reverse Transcriptase Inhibitor–Based Combination Antiretroviral Therapy The D:A:D Study

Time trends for risk of severe age-related diseases in individuals with and without HIV infection in Denmark: a nationwide population-based cohort study

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The effect of cumulating exposure to abacavir on the risk of cardiovascular disease events in patients from the Swiss HIV Cohort Study

Course and Clinical Significance of CD8+ T-Cell Counts in a Large Cohort of HIV-Infected Individuals

Impact of low-level viremia on clinical and virological outcomes in treated HIV-1-infected patients

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Influence of the Timing of Antiretroviral Therapy on the Potential for Normalization of Immune Status in Human Immunodeficiency Virus 1–Infected Individuals

Cross-sectional Comparison of the Prevalence of Age-Associated Comorbidities and Their Risk Factors Between HIV-Infected and Uninfected Individuals: The AGEhIV Cohort Study

CD4/CD8 ratio normalisation and non-AIDS-related events in individuals with HIV who achieve viral load suppression with antiretroviral therapy: an observational cohort study

Baseline HIV-1 resistance, virological outcomes, and emergent resistance in the SECOND-LINE trial: an exploratory analysis

Effects of statin therapy on coronary artery plaque volume and high-risk plaque morphology in HIV-infected patients with subclinical atherosclerosis: a randomised, double-blind, placebo-controlled trial

Low Bone Mineral Density in Patients With Well-Suppressed HIV Infection: Association With Body Weight, Smoking, and Prior Advanced HIV Disease

Early versus delayed initiation of highly active antiretroviral therapy for HIV-positive adults with newly diagnosed pulmonary tuberculosis (TB-HAART): a prospective, international, randomised, placebo-controlled trial

A chronic kidney disease risk score to determine tenofovir safety in a prospective cohort of HIV-positive male veterans

Single-agent tenofovir versus combination emtricitabine plus tenofovir for pre-exposure prophylaxis for HIV-1 acquisition: an update of data from a randomised, double-blind, phase 3 trial

Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1

Ongoing HIV Replication Replenishes Viral Reservoirs During Therapy
Published by François RAFFI

Updated: 24 February, 2016

Lorenzo-Redondo R et al. Nature. 2016 Feb 4;530(7588):51-6.

A better understanding of how HIV persists in the body is essential for developing strategies to eliminate viral reservoirs—a prerequisite to achieving a cure for HIV infection. Current ART regimens quickly suppress HIV to levels undetectable in the blood in most patients, but cannot eliminate persistent viral reservoirs in the tissues. There is debate whether these reservoirs are maintained because latently infected cells are long-lived, because low-level HIV replication persists or for both reasons.

This study, funded by the National Institutes of Health, addresses this question,
Sequenced viral DNA from lymph-node and blood cells were collected from 3 HIV-infected patients before and during the first 6 months of ART. In these patients, the virus evolved over time, indicating ongoing replication, but did not accumulate mutations conferring drug resistance. Cells in the lymph node tissue can still produce new virus and infect new target cells. Previous work had suggested that antiretroviral drug concentrations are lower in lymphoid tissue than in blood, and that HIV can hide in sanctuaries that drugs do not penetrate well. In this study, from these temporally and compartmentally structured sequence data, researchers demonstrated that continued HIV replication in lymphoid tissue sanctuaries, where drug concentrations are not fully suppressive, can persist to replenish the viral reservoir and traffic to blood or lymphoid tissue in patients on ART who have achieved undetectable blood levels of HIV.
These results, which reconstruct the dynamics of HIV-1 spread within the body, imply that in patients with no detectable viral RNA in plasma, the virus reservoir is constantly replenished by low-level virus replication in lymphoid tissue. Distinguishing between low amounts of viral replication and pools of latently infected cells that may persist and reactivate HIV-1 infection is methodologically difficult.

Furthermore, the virus does not inevitably develop resistance to antiretroviral drugs because the lower concentration of drugs in the sanctuary sites is not sufficient to confer a competitive advantage upon drug-resistant strains. The investigators constructed a mathematical model to explain how the virus evolves during ART without the emergence of highly drug-resistant strains. According to their calculations, drug-sensitive HIV strains tend to dominate over drug-resistant strains when the effective drug concentration is low. At intermediate drug concentrations, drug-resistant strains start to dominate, and at high concentrations, HIV cannot grow.
These findings explain the failure of treatment intensification to fully suppress de novo infection and highlight issues surrounding the barriers to delivering antiretroviral drugs at clinically effective concentrations in the infectious viral reservoir (the lymphoid tissue compartment).

This study provides a new perspective on the persistence of HIV-1 in the body, showing a different type of "sanctuary," harboring cells with low levels of HIV replication that move into the blood. These results also reveal how dynamic and spatial processes act together to permit HIV-1 to persist within the infected host and avoid development of resistance despite antiretroviral therapy.

Achieving optimal cellular pharmacokinetics and spatial distribution of antiretroviral drugs in lymphoid tissue to fully suppress viral replication and preserve immune function would be a prerequisite to the elimination of the viral reservoir and ultimately a step towards a cure for HIV-1 infection.