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Persistent HIV-1 replication maintains the tissue reservoir during therapy
 
 
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"Our 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."
 
"Our results 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. From these temporally and compartmentally structured sequence data, we conclude that continued virus production from infected cells in lymphoid tissue sanctuary sites, where drug concentrations are not fully suppressive, can continue to replenish the viral reservoir and traffic to blood or lymphoid tissue18. We further show that 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. Our 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 state-of-the-art sequencing approach, innovative time-calibrated phyloanatomic tree construction, and a novel model of compartmentalized intra-host population dynamics provide a new perspective on the persistence of HIV-1 in the body. 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."
 
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Ongoing HIV Replication Replenishes Viral Reservoirs During Therapy

 
NIH, For Immediate Release: Wednesday, Jan. 27, 2016
NIH-Funded Study Provides Insights Into HIV Evolution and Persistence
http://www.niaid.nih.gov/news/newsreleases/2016/Pages/HIVreplicationReplenishesViralReservoirs.aspx
 
WHAT:
In HIV-infected patients undergoing antiretroviral therapy (ART), ongoing HIV replication in lymphoid tissues such as the lymph nodes helps maintain stores, or reservoirs, of the virus, a new study funded by the National Institutes of Health suggests. 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. Scientists have debated whether these reservoirs are maintained because latently infected cells are long-lived, because low-level HIV replication persists or for both reasons.
 
To help address this question, Northwestern University's Steven Wolinsky, M.D., and colleagues sequenced viral DNA from lymph-node and blood cells collected from three HIV-infected patients before and during the first six months of ART. In these patients, the virus evolved over time, indicating ongoing replication, but did not accumulate mutations conferring drug resistance. 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, researchers demonstrated that continued HIV replication in lymphoid tissue sanctuaries refills viral reservoirs in patients on ART who have achieved undetectable blood levels of HIV.
 
Next, 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 observations suggest the importance of devising strategies to deliver clinically effective drug concentrations throughout the lymphoid tissue compartment, the investigators note.
 
Future studies using drugs that better penetrate the entire lymphoid tissue compartment should provide a more complete picture of how viral reservoirs are maintained and help pave a promising path to a cure, according to the authors.
 
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https://www.washingtonpost.com/news/to-your-health/wp/2016/01/27/study-hiv-can-hide-and-grow-in-sanctuaries-in-body-after-its-undetectable-in-blood/
 
The researchers found that cells in the  lymph node tissue can still produce new virus and infect new target cells.
 
The groundbreaking idea of reservoirs of HIV made headlines in July 2014 when a Mississippi girl born with HIV, who was believed to be cured after early treatment, tested positive for the virus after stopping therapy. In her case, doctors think the infection reemerged from a viral reservoir containing cells in a resting state that were not proliferating.
 
The latest study appears to show a different type of "sanctuary," as the researchers called it, harboring cells with low levels of HIV replication that move into the blood. Researchers used a mathematical model to track the amount of virus and the amount of infected cells as they grew and circulated through the body. This suggests that virus growth could occur in a place where drug concentrations are very low.
 
"These findings are important as it is critical for the field of HIV cure research to know whether new infectious cycles are indeed continuing in patients on seemingly effective treatment," Deborah Persaud, a professor of infectious diseases at Johns Hopkins University School of Medicine, told The Washington Post.
 
ARTICLE:
R Lorenzo-Redondo et al. Persistent HIV-1 replication maintains the tissue reservoir during therapy. Nature DOI: 10.1038/nature16933 (2016).
 
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Persistent HIV-1 replication maintains the tissue reservoir during therapy
 
Ramon Lorenzo-Redondo1*, Helen R. Fryer2*, Trevor Bedford3, Eun-Young Kim1, John Archer4, Sergei L. Kosakovsky Pond5, Yoon-Seok Chung6, Sudhir Penugonda1, Jeffrey G. Chipman7, Courtney V. Fletcher8, Timothy W. Schacker9, Michael H. Malim10, Andrew Rambaut11, Ashley T. Haase12, Angela R. McLean2 & Steven M. Wolinsky1
 
Abstract
 
Lymphoid tissue is a key reservoir established by HIV-1 during acute infection. It is a site associated with viral production, storage of viral particles in immune complexes, and viral persistence. Although combinations of antiretroviral drugs usually suppress viral replication and reduce viral RNA to undetectable levels in blood, it is unclear whether treatment fully suppresses viral replication in lymphoid tissue reservoirs. Here we show that virus evolution and trafficking between tissue compartments continues in patients with undetectable levels of virus in their bloodstream. We present a spatial and dynamic model of persistent viral replication and spread that indicates why the development of drug resistance is not a foregone conclusion under conditions in which drug concentrations are insufficient to completely block virus replication. These data provide new insights into the evolutionary and infection dynamics of the virus population within the host, revealing that HIV-1 can continue to replicate and replenish the viral reservoir despite potent antiretroviral therapy.
 
Introduction

 
Combinations of antiretroviral drugs routinely impair HIV-1 production and replication to levels that are undetectable in the blood within weeks of starting treatment1. None of the current treatments, however, is capable of eradicating the virus from a long-lived reservoir in resting memory CD4+ T cells and other cell types that potentially protect the virus from antiretroviral drugs or immune surveillance2, 3, 4, 5. Intermittent virus production from reactivation of a small proportion of latently infected CD4+ T cells (rather than low levels of ongoing replication) is thought to drive viral rebound detected in blood of treated patients with well-suppressed infection6, 7, 8. Ongoing replication is considered unlikely because neither viral genetic divergence over time, nor the emergence of drug resistance mutations have been convincingly documented9, 10. As earlier studies only examined viral sequences derived from the blood of patients who continued to suppress viral replication in that anatomic compartment11, the conclusions are not necessarily generalizable to other compartments in the body, particularly to lymphoid tissue where the frequency of infection per cell is mostly higher12 and the intracellular drug concentrations are much lower than in blood13. Under low drug concentrations, the virus may continue to replicate and evolve in 'sanctuary sites' within the reservoir of cells in lymphoid tissue, and remain undetectable in the bloodstream for a time depending on viral population migration dynamics between the two compartments. Here we use a multi-pronged strategy of deep-sequencing, time-calibrated phylogenetic analysis, and mathematical modelling to characterize the distinct temporal structure and divergence of compartmentally sampled viral sequences. We discover ongoing replication in lymphoid tissue sanctuary sites of patients despite undetectable blood levels of virus. Our sampling approach differs fundamentally from those of previous studies14, 15, 16, which do not address evolutionary dynamics within lymphoid tissue, and better suits investigation of the dynamic nature of the viral reservoir during treatment with potent antiretroviral drugs.
 
Our 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. A small number of HIV-1 sequences isolated at consecutive time points that persisted without evidence of genetic change might result from long-lived central memory cells, a fraction of which may have reverted to a resting state, or latently infected transitional memory cells that persist by clonal expansion (driven by homeostatic proliferation) or survival of long-lived infected CD4+ T cells that contain replication-competent virus8, 15, 22, 31, 32, 33, 34. Two of the subjects (1774 and 1679) showed that some haplotypes persist as a single tree branch through time (Fig. 1d and f), consistent with proliferation of HIV-1-infected cells or long-term cell survival33, 34. Regardless of the different mechanisms for self-renewal/persistence by which some of these quite similar latent or defective viral lineages may have persisted, these quiescent viruses differ from others that have evolved and trafficked between compartments. The temporally and compartmentally sampled data show that viral lineages continue to diverge in well-suppressed patients and help to explain the persistence of infectious viral reservoirs with little reduction of the virus pool35. The dynamic nature of the viral population in lymphoid tissue sanctuaries—where infected cells can still produce new viruses, infect new target cells, and replenish the pool—undermines previous estimates of the time necessary to purge the reservoir of latently infected cells and achieve virus eradication3.
 
CONCLUSION
 
Our results 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. From these temporally and compartmentally structured sequence data, we conclude that continued virus production from infected cells in lymphoid tissue sanctuary sites, where drug concentrations are not fully suppressive, can continue to replenish the viral reservoir and traffic to blood or lymphoid tissue18. We further show that 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. Our 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 state-of-the-art sequencing approach, innovative time-calibrated phyloanatomic tree construction, and a novel model of compartmentalized intra-host population dynamics provide a new perspective on the persistence of HIV-1 in the body. 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.

 
 
 
 
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