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Immunologic Biomarkers, Morbidity, and Mortality in Treated HIV Infection

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Ongoing HIV Replication Replenishes Viral Reservoirs During Therapy

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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.