Inhibition of apoptosis in human immunodeficiency virus-infected cells enhances virus production and facilitates persistent infection.

ABSTRACT Antiviral therapy induces a rapid drop in human immunodeficiency virus type 1 viremia, but the decline of virus levels decelerates over time. Mathematical modeling demonstrates that the source of residual virus production might be a single compartment of latently infected cells with an extended distribution of activation rates.

Download Full-text

Reinfection results in accumulation of unintegrated viral DNA in cytopathic and persistent human immunodeficiency virus type 1 infection of CEM cells.

Journal of Experimental Medicine ◽

10.1084/jem.172.4.1035 ◽

1990 ◽

Vol 172 (4) ◽

pp. 1035-1042 ◽

Cited By ~ 67

Author(s):

C D Pauza ◽

J E Galindo ◽

D D Richman

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Virus Production ◽

Neutralizing Antibody ◽

Viral Dna ◽

Immunodeficiency Virus ◽

Infected Cells ◽

Hiv 1

High levels of unintegrated viral DNA accumulate during human immunodeficiency virus type 1 (HIV-1) infection of CEM T cells. Reinfection of already infected cells is required to attain these levels and reinfection also promotes the development of HIV-induced cytopathology. Rates of virus production, however, are independent of the accumulation of unintegrated viral DNA. Neutralizing antibody added soon after infection reduced viral DNA levels without appreciably affecting the production of cell-free viral p24 antigen or reverse transcriptase activity. Only 50 pM AZT were required to reduce the accumulation of unintegrated viral DNA by 50% in contrast to the 25 nM required to inhibit virus production by 50%. Cytopathology, as measured by number of syncytia in infected cell cultures, was correlated with highly elevated levels of unintegrated viral DNA. The minimal levels of unintegrated viral DNA present constitutively in the persistently infected HCEM cell line were consonant with the absence of cytopathic effects in these cells. These data demonstrate that inhibiting the reinfection of already infected cells modulates cytopathic HIV-1 infection to a form that is persistent and noncytopathic.

Download Full-text

Effect of Latent Human Immunodeficiency Virus Infection on Cell Surface Phenotype

Journal of Virology ◽

10.1128/jvi.76.4.1673-1681.2002 ◽

2002 ◽

Vol 76 (4) ◽

pp. 1673-1681 ◽

Cited By ~ 21

Author(s):

David G. Brooks ◽

Jerome A. Zack

Keyword(s):

Human Immunodeficiency Virus ◽

Highly Active Antiretroviral Therapy ◽

Virus Production ◽

Cellular Interactions ◽

Cellular Activation ◽

Highly Active ◽

Immunodeficiency Virus ◽

Latently Infected ◽

Infected Cells

ABSTRACT Highly active antiretroviral therapy has succeeded in many cases in suppressing virus production in patients infected with human immunodeficiency virus (HIV); however, once treatment is discontinued, virus replication is rekindled. One reservoir capable of harboring HIV in a latent state and igniting renewed infection once therapy is terminated is a resting T cell. Due to the sparsity of T cells latently infected with HIV in vivo, it has been difficult to study viral and cellular interactions during latency. The SCID-hu (Thy/Liv) mouse model of HIV latency, however, provides high percentages of latently infected cells, allowing a detailed analysis of phenotype. Herein we show that latently infected cells appear phenotypically normal. Following cellular stimulation, the virus completes its life cycle and induces phenotypic changes, such as CD4 and major histocompatibility complex class I down-regulation, in the infected cell. In addition, HIV expression following activation did not correlate with expression of the cellular activation marker CD25. The apparently normal phenotype and lack of HIV expression in latently infected cells could prevent recognition by the immune response and contribute to the long-lived nature of this reservoir.

Download Full-text

Antimyristoylation of the gag proteins in the human immunodeficiency virus-infected cells with N-myristoyl glycinal diethylacetal resulted in inhibition of virus production

Biochemical and Biophysical Research Communications ◽

10.1016/0006-291x(89)92722-8 ◽

1989 ◽

Vol 165 (3) ◽

pp. 1145-1154 ◽

Cited By ~ 25

Author(s):

Akira Tashiro ◽

Shozo Shoji ◽

Yukiho Kubota

Keyword(s):

Human Immunodeficiency Virus ◽

Virus Production ◽

Gag Proteins ◽

Immunodeficiency Virus ◽

Infected Cells

Download Full-text

The effect of in vitro human immunodeficiency virus infection on dendritic-cell differentiation and function

Blood ◽

10.1182/blood.v88.11.4215.4215 ◽

1996 ◽

Vol 88 (11) ◽

pp. 4215-4228 ◽

Cited By ~ 43

Author(s):

B Canque ◽

M Rosenzwajg ◽

S Camus ◽

M Yagello ◽

ML Bonnet ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Virus Production ◽

Polymerase Chain Reaction Analysis ◽

Viral Dna ◽

Human Cord Blood ◽

Necrosis Factor Alpha ◽

Dendritic Cell Differentiation ◽

Immunodeficiency Virus ◽

Infected Cells

Abstract CD1a+ dendritic cells (DC) differentiate from a major population of nonadherent CD13(hi)lin-cells that appear when human cord blood CD34+ hematopoietic progenitor cells are cultured with stem-cell factor, granulocyte/macrophage (MA) colony-stimulating factor, and tumor necrosis factor-alpha (TNF-alpha) for 5 days. CD13hilin- cells, which also comprise MA and granulocyte precursors, are CD4+ and can thus be targets of human immunodeficiency virus (HIV). Low replication was noted when these day 5 cells were infected with lymphotropic HIV-1LA1 (p24: < or = 4 ng/mL on day 8 postinfection [PI]), while high virus production occurred with MA-tropic HIV-1Ba-L, HIV-1Ada, or HIV-1-m-n. (p24: 50 to > or = 1,000 ng/mL). Strong cytopathicity (CPE) was then observed in nonadherent cells as in adherent MA. However, FACS analysis on day 7 PI showed that HIV did not affect differentiation of DC that survived CPE: apart from CD4 downmodulation related to HIV production, overall expression of CD40, CD80, and CD86 costimulatory molecules, and of HLA-DR, was unchanged relative to controls. At that time, the capacity of DC from HIV-infected cultures to stimulate the mixed leukocyte reaction was only altered less than 10-fold. Immunocytochemistry on day 7 PI showed that most HIV-infected cells were included in syncytia that were stained by anti-CD1a, anti-S100, and anti-CD14 antibodies, indicating that syncytia consisted of DC and cells of the MA lineage. Polymerase chain reaction analysis of FACS- sorted CD1a+ cells confirmed that they harbored then HIV DNA. Viral DNA was also detected in CD1a+ DC from noninfected cultures that had been exposed to HIV only after sorting. Therefore, we examined whether in infected cultures DC precursors were infected at the onset or if virus spread later from other infected cells to differentiated DC. This was answered by showing that, 24 hours postexposure to HIV, viral DNA was preferentially detected in day 5 sorted CD13hilin-versus CD13hilin- cells, and that it was found in the CD1a+ progeny of CD13(hi)lin-cells 48 hours later. In addition, HIV replication did not affect myeloid clonogenic progenitors in day 0 to day 7 PI cultures, although viral DNA was detected in colony-forming unit-granulocyte/macrophage (CFU-GM)/CFU-M colonies derived from day 3 and 7 PI cultures. Thus, precursors of DC and their progeny are susceptible to HIV in vitro, but, apart from CPE, the effect of virus production on DC differentiation or function is limited.

Download Full-text

Kinetics of Antiviral Activity by Human Immunodeficiency Virus Type 1-Specific Cytotoxic T Lymphocytes (CTL) and Rapid Selection of CTL Escape Virus In Vitro

Journal of Virology ◽

10.1128/jvi.72.8.6851-6857.1998 ◽

1998 ◽

Vol 72 (8) ◽

pp. 6851-6857 ◽

Cited By ~ 59

Author(s):

C. A. Van Baalen ◽

M. Schutten ◽

R. C. Huisman ◽

P. H. M. Boers ◽

R. A. Gruters ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Antiviral Activity ◽

Virus Production ◽

Virus Release ◽

Immunodeficiency Virus ◽

Infected Cells ◽

Kinetics Of ◽

Hiv 1 ◽

Selection Of

ABSTRACT The antiviral activity of a CD8+ cytotoxic T-lymphocyte (CTL) clone (TCC108) directed against a newly identified HLA-B14-restricted epitope, human immunodeficiency virus type 1 (HIV-1) Rev(67-75) SAEPVPLQL, was analyzed with respect to its kinetics of target cell lysis and inhibition of HIV-1 production. Addition of TCC108 cells or CD8+ reverse transcriptase-specific CTLs to HLA-matched CD4+ T cells at different times after infection with HIV-1 IIIB showed that infected cells became susceptible to CTL-mediated lysis before peak virus production but after the onset of progeny virus release. When either of these CTLs were added to part of the infected cells immediately after infection, p55 expression and virus production were significantly suppressed. These data support a model in which CTLs, apart from exerting cytolytic activity which may prevent continued virus release, can interfere with viral protein expression during the eclipse phase via noncytolytic mechanisms. TCC108-mediated inhibition of virus replication in peripheral blood mononuclear cells caused rapid selection of a virus with a mutation (69E→K) in the Rev(67-75) CTL epitope which abolished recognition by TCC108 cells. Taken together, these data suggest that both cytolytic and noncytolytic antiviral mechanisms of CTLs can be specifically targeted to HIV-1-infected cells.

Download Full-text

The effect of in vitro human immunodeficiency virus infection on dendritic-cell differentiation and function

Blood ◽

10.1182/blood.v88.11.4215.bloodjournal88114215 ◽

1996 ◽

Vol 88 (11) ◽

pp. 4215-4228 ◽

Cited By ~ 1

Author(s):

B Canque ◽

M Rosenzwajg ◽

S Camus ◽

M Yagello ◽

ML Bonnet ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Virus Production ◽

Polymerase Chain Reaction Analysis ◽

Viral Dna ◽

Human Cord Blood ◽

Necrosis Factor Alpha ◽

Dendritic Cell Differentiation ◽

Immunodeficiency Virus ◽

Infected Cells

CD1a+ dendritic cells (DC) differentiate from a major population of nonadherent CD13(hi)lin-cells that appear when human cord blood CD34+ hematopoietic progenitor cells are cultured with stem-cell factor, granulocyte/macrophage (MA) colony-stimulating factor, and tumor necrosis factor-alpha (TNF-alpha) for 5 days. CD13hilin- cells, which also comprise MA and granulocyte precursors, are CD4+ and can thus be targets of human immunodeficiency virus (HIV). Low replication was noted when these day 5 cells were infected with lymphotropic HIV-1LA1 (p24: < or = 4 ng/mL on day 8 postinfection [PI]), while high virus production occurred with MA-tropic HIV-1Ba-L, HIV-1Ada, or HIV-1-m-n. (p24: 50 to > or = 1,000 ng/mL). Strong cytopathicity (CPE) was then observed in nonadherent cells as in adherent MA. However, FACS analysis on day 7 PI showed that HIV did not affect differentiation of DC that survived CPE: apart from CD4 downmodulation related to HIV production, overall expression of CD40, CD80, and CD86 costimulatory molecules, and of HLA-DR, was unchanged relative to controls. At that time, the capacity of DC from HIV-infected cultures to stimulate the mixed leukocyte reaction was only altered less than 10-fold. Immunocytochemistry on day 7 PI showed that most HIV-infected cells were included in syncytia that were stained by anti-CD1a, anti-S100, and anti-CD14 antibodies, indicating that syncytia consisted of DC and cells of the MA lineage. Polymerase chain reaction analysis of FACS- sorted CD1a+ cells confirmed that they harbored then HIV DNA. Viral DNA was also detected in CD1a+ DC from noninfected cultures that had been exposed to HIV only after sorting. Therefore, we examined whether in infected cultures DC precursors were infected at the onset or if virus spread later from other infected cells to differentiated DC. This was answered by showing that, 24 hours postexposure to HIV, viral DNA was preferentially detected in day 5 sorted CD13hilin-versus CD13hilin- cells, and that it was found in the CD1a+ progeny of CD13(hi)lin-cells 48 hours later. In addition, HIV replication did not affect myeloid clonogenic progenitors in day 0 to day 7 PI cultures, although viral DNA was detected in colony-forming unit-granulocyte/macrophage (CFU-GM)/CFU-M colonies derived from day 3 and 7 PI cultures. Thus, precursors of DC and their progeny are susceptible to HIV in vitro, but, apart from CPE, the effect of virus production on DC differentiation or function is limited.

Download Full-text

Activation of a beta-galactosidase recombinant provirus: application to titration of human immunodeficiency virus (HIV) and HIV-infected cells.

Journal of Virology ◽

10.1128/jvi.64.6.2660-2668.1990 ◽

1990 ◽

Vol 64 (6) ◽

pp. 2660-2668 ◽

Cited By ~ 64

Author(s):

D Rocancourt ◽

C Bonnerot ◽

H Jouin ◽

M Emerman ◽

J F Nicolas

Keyword(s):

Human Immunodeficiency Virus ◽

Immunodeficiency Virus ◽

Infected Cells ◽

Beta Galactosidase

Download Full-text

Induction of Autophagy to Achieve a Human Immunodeficiency Virus Type 1 Cure

Cells ◽

10.3390/cells10071798 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1798

Author(s):

Grant R. Campbell ◽

Stephen A. Spector

Keyword(s):

Human Immunodeficiency Virus ◽

Antiretroviral Therapy ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Functional Cure ◽

Immunodeficiency Virus ◽

Latently Infected ◽

Infected Cells ◽

Hiv 1

Effective antiretroviral therapy has led to significant human immunodeficiency virus type 1 (HIV-1) suppression and improvement in immune function. However, the persistence of integrated proviral DNA in latently infected reservoir cells, which drive viral rebound post-interruption of antiretroviral therapy, remains the major roadblock to a cure. Therefore, the targeted elimination or permanent silencing of this latently infected reservoir is a major focus of HIV-1 research. The most studied approach in the development of a cure is the activation of HIV-1 expression to expose latently infected cells for immune clearance while inducing HIV-1 cytotoxicity—the “kick and kill” approach. However, the complex and highly heterogeneous nature of the latent reservoir, combined with the failure of clinical trials to reduce the reservoir size casts doubt on the feasibility of this approach. This concern that total elimination of HIV-1 from the body may not be possible has led to increased emphasis on a “functional cure” where the virus remains but is unable to reactivate which presents the challenge of permanently silencing transcription of HIV-1 for prolonged drug-free remission—a “block and lock” approach. In this review, we discuss the interaction of HIV-1 and autophagy, and the exploitation of autophagy to kill selectively HIV-1 latently infected cells as part of a cure strategy. The cure strategy proposed has the advantage of significantly decreasing the size of the HIV-1 reservoir that can contribute to a functional cure and when optimised has the potential to eradicate completely HIV-1.

Download Full-text