scholarly journals Recovery of Replication-Competent Residual HIV-1 from Plasma of a Patient Receiving Prolonged, Suppressive Highly Active Antiretroviral Therapy

2010 ◽  
Vol 84 (16) ◽  
pp. 8348-8352 ◽  
Author(s):  
Gautam K. Sahu ◽  
Juan C. Sarria ◽  
Miles W. Cloyd
Keyword(s):  
Antiretroviral Therapy ◽  
Highly Active Antiretroviral Therapy ◽  
Host Cells ◽  
Drug Resistant ◽  
Residual Viremia ◽  
Viral Genomes ◽  
Highly Active ◽  
Hiv 1 ◽  
Adherence To Therapy

ABSTRACT The clinical significance of persistent residual viremia in patients on prolonged highly active antiretroviral therapy (HAART) is not clear. Moreover, it remains to be demonstrated whether residual viremia consists of viruses capable of spreading infection in vivo upon termination of therapy. Using residual viral RNAs (vRNAs) isolated from a HAART-treated patient's plasma, we cloned full-length viral genomes and found that most of them could produce infectious, replication-competent HIVs when transfected into TZM-bl cells, suggesting that residual viruses produced in the absence of therapy can initiate fresh cycles of infection and spread in host cells. The data further indicate that residual viremia may pose a major concern with regard to the emergence of drug-resistant HIVs during periods of low adherence to therapy.

scholarly journals Mesenchymal Stromal Cells: a Possible Reservoir for HIV-1?

2022 ◽  
Author(s):  
K. Kallmeyer ◽  
M. A. Ryder ◽  
M. S. Pepper
Keyword(s):  
Antiretroviral Therapy ◽  
Highly Active Antiretroviral Therapy ◽  
The Body ◽  
Differentiation Potential ◽  
Proliferation Capacity ◽  
Highly Active ◽  
Latent Hiv ◽  
Hiv 1

AbstractThe introduction of antiretroviral therapy (ART) and highly active antiretroviral therapy (HAART) has transformed human immunodeficiency virus (HIV)-1 into a chronic, well-managed disease. However, these therapies do not eliminate all infected cells from the body despite suppressing viral load. Viral rebound is largely due to the presence of cellular reservoirs which support long-term persistence of HIV-1. A thorough understanding of the HIV-1 reservoir will facilitate the development of new strategies leading to its detection, reduction, and elimination, ultimately leading to curative therapies for HIV-1. Although immune cells derived from lymphoid and myeloid progenitors have been thoroughly studied as HIV-1 reservoirs, few studies have examined whether mesenchymal stromal/stem cells (MSCs) can assume this function. In this review, we evaluate published studies which have assessed whether MSCs contribute to the HIV-1 reservoir. MSCs have been found to express the receptors and co-receptors required for HIV-1 entry, albeit at levels of expression and receptor localisation that vary considerably between studies. Exposure to HIV-1 and HIV-1 proteins alters MSC properties in vitro, including their proliferation capacity and differentiation potential. However, in vitro and in vivo experiments investigating whether MSCs can become infected with and harbour latent integrated proviral DNA are lacking. In conclusion, MSCs appear to have the potential to contribute to the HIV-1 reservoir. However, further studies are needed using techniques such as those used to prove that cluster of differentiation (CD)4+ T cells constitute an HIV-1 reservoir before a reservoir function can definitively be ascribed to MSCs. Graphical abstract MSCs may contribute to HIV-1 persistence in vivo in the vasculature, adipose tissue, and bone marrow by being a reservoir for latent HIV-1. To harbour latent HIV-1, MSCs must express HIV-1 entry markers, and show evidence of productive or latent HIV-1 infection. The effect of HIV-1 or HIV-1 proteins on MSC properties may also be indicative of HIV-1 infection.

scholarly journals Evidence that Low-Level Viremias during Effective Highly Active Antiretroviral Therapy Result from Two Processes: Expression of Archival Virus and Replication of Virus

2005 ◽  
Vol 79 (15) ◽  
pp. 9625-9634 ◽  
Author(s):  
Nicole H. Tobin ◽  
Gerald H. Learn ◽  
Sarah E. Holte ◽  
Yang Wang ◽  
Ann J. Melvin ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Highly Active Antiretroviral Therapy ◽  
Drug Resistant ◽  
Plasma Virus ◽  
Highly Active ◽  
Infected Cells ◽  
Resistant Mutants ◽  
Viral Sequences ◽  
Hiv 1 ◽  
Selection Of

ABSTRACT Episodes of low-level viremia (LLV), with plasma human immunodeficiency virus type 1 (HIV-1) RNA levels ranging from 50 to 400 copies (c)/ml, occur commonly during highly active antiretroviral therapy (HAART). LLV has been associated with virologic failure of HAART in some studies, while in others LLV did not appear to affect the clinical outcome. To understand the processes leading to LLV, genetic analyses were used to determine whether plasma virions emanated from archived or from newly evolved viral genomes. Episodes of LLV (plasma HIV-1 RNA, 50 to 379 [median, 77] c/ml) were detected in 21/37 (57%) HIV-1-infected children with median plasma HIV-1 RNA levels of <50 c/ml during 79 patient years of HAART. Viral sequences were derived by direct sequencing of PCR products from 21 plasma specimens diluted to end point. In phylogenetic analysis, LLV viral sequences grouped with virus from early in the course of infection in 8/11 subjects. Six specimens had multiple identical viral sequences, suggesting origin from clonally expanded infected cells. LLV plasma virus evolved over time, indicating viral replication, in 3/11 subjects. Two of these had frequent LLV, including the selection of drug-resistant mutants. In summary, plasma virus from episodes of LLV during effective HAART appeared to originate from two distinct processes, (i) clonal outgrowth from long-lived HIV-1-infected cells, presumably following activation and proliferation of these cells, and (ii) ongoing viral replication that included the selection of new drug-resistant mutants. These observations provide a plausible explanation for the divergent clinical outcomes previously associated with LLV.

Drug-resistant mutants of HIV-1 in patients exhibiting increasing CD4 cell count despite virological failure of highly active antiretroviral therapy

AIDS ◽  
2001 ◽  
Vol 15 (17) ◽  
pp. 2325-2327 ◽  
Author(s):  
Andrea Antinori ◽  
Giuseppina Liuzzi ◽  
Antonella Cingolani ◽  
Ada Bertoli ◽  
Simona Di Giambenedetto ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Cell Count ◽  
Virological Failure ◽  
Highly Active Antiretroviral Therapy ◽  
Drug Resistant ◽  
Cd4 Cell Count ◽  
Highly Active ◽  
Resistant Mutants ◽  
Cd4 Cell ◽  
Hiv 1

scholarly journals Evidence for Human Immunodeficiency Virus Type 1 Replication In Vivo in CD14+ Monocytes and Its Potential Role as a Source of Virus in Patients on Highly Active Antiretroviral Therapy

2002 ◽  
Vol 76 (2) ◽  
pp. 707-716 ◽  
Author(s):  
Tuofu Zhu ◽  
David Muthui ◽  
Sarah Holte ◽  
David Nickle ◽  
Feng Feng ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Antiretroviral Therapy ◽  
Human Immunodeficiency Virus Type ◽  
Highly Active Antiretroviral Therapy ◽  
Highly Active ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT In vitro studies show that human immunodeficiency virus type 1 (HIV-1) does not replicate in freshly isolated monocytes unless monocytes differentiate to monocyte-derived macrophages. Similarly, HIV-1 may replicate in macrophages in vivo, whereas it is unclear whether blood monocytes are permissive to productive infection with HIV-1. We investigated HIV-1 replication in CD14+ monocytes and resting and activated CD4+ T cells by measuring the levels of cell-associated viral DNA and mRNA and the genetic evolution of HIV-1 in seven acutely infected patients whose plasma viremia had been <100 copies/ml for 803 to 1,544 days during highly active antiretroviral therapy (HAART). HIV-1 DNA was detected in CD14+ monocytes as well as in activated and resting CD4+ T cells throughout the course of study. While significant variation in the decay slopes of HIV-1 DNA was seen among individual patients, viral decay in CD14+ monocytes was on average slower than that in activated and resting CD4+ T cells. Measurements of HIV-1 sequence evolution and the concentrations of unspliced and multiply spliced mRNA provided evidence of ongoing HIV-1 replication, more pronounced in CD14+ monocytes than in resting CD4+ T cells. Phylogenetic analyses of HIV-1 sequences indicated that after prolonged HAART, viral populations related or identical to those found only in CD14+ monocytes were seen in plasma from three of the seven patients. In the other four patients, HIV-1 sequences in plasma and the three cell populations were identical. CD14+ monocytes appear to be one of the potential in vivo sources of HIV-1 in patients receiving HAART.

scholarly journals A Simian Immunodeficiency Virus-Infected Macaque Model To Study Viral Reservoirs That Persist during Highly Active Antiretroviral Therapy

2009 ◽  
Vol 83 (18) ◽  
pp. 9247-9257 ◽  
Author(s):  
Jason B. Dinoso ◽  
S. Alireza Rabi ◽  
Joel N. Blankson ◽  
Lucio Gama ◽  
Joseph L. Mankowski ◽  
...  
Keyword(s):  
Animal Model ◽  
T Cells ◽  
Antiretroviral Therapy ◽  
Highly Active Antiretroviral Therapy ◽  
Antiretroviral Drugs ◽  
Residual Viremia ◽  
Viral Reservoirs ◽  
Highly Active ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The treatment of human immunodeficiency virus type 1 (HIV-1) infection with highly active antiretroviral therapy (HAART), a combination of three or more antiretroviral drugs, suppresses viremia below the clinical limit of detection (50 HIV-1 RNA copies/ml), but latently infected resting CD4+ T cells serve as lifelong reservoirs, and low-level viremia can be detected with special assays. Recent studies have provided evidence for additional reservoirs that contribute to residual viremia but are not present in circulating cells. Identification of all the sources of residual viremia in humans may be difficult. These discoveries highlight the need for a tractable model system to identify additional viral reservoirs that could represent barriers to eradication. In this study, simian immunodeficiency virus (SIV)-infected pig-tailed macaques (Macaca nemestrina) were treated with four antiretroviral drugs to develop an animal model for viral suppression during effective HAART. Treatment led to a biphasic decay in viremia and a significant rise in levels of circulating CD4+ T cells. At terminal infection time points, the frequency of circulating resting CD4+ T cells harboring replication-competent virus was reduced to a low steady-state level similar to that observed for HIV-infected patients on HAART. The frequencies of resting CD4+ T cells harboring replication-competent virus in the pooled head lymph nodes, gut lymph nodes, spleen, and peripheral blood were reduced relative to those for untreated SIV-infected animals. These observations closely parallel findings for HIV-infected humans on suppressive HAART and demonstrate the value of this animal model to identify and characterize viral reservoirs persisting in the setting of suppressive antiretroviral drugs.

scholarly journals Antigen-driven CD4+ T cell and HIV-1 dynamics: Residual viral replication under highly active antiretroviral therapy

1999 ◽  
Vol 96 (26) ◽  
pp. 15167-15172 ◽  
Author(s):  
N. M. Ferguson ◽  
F. deWolf ◽  
A. C. Ghani ◽  
C. Fraser ◽  
C. A. Donnelly ◽  
...  
Keyword(s):  
T Cell ◽  
Antiretroviral Therapy ◽  
Viral Replication ◽  
Highly Active Antiretroviral Therapy ◽  
Cd4 T Cell ◽  
Highly Active ◽  
Hiv 1
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