Human Endogenous Retrovirus Expression Is Inversely Associated with Chronic Immune Activation in HIV-1 Infection

ABSTRACTThe matrix (MA) domain of HIV-1 mediates proper Gag localization and membrane binding via interaction with a plasma-membrane (PM)-specific acidic phospholipid, phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2]. HIV-1 MA also interacts with RNA, which prevents Gag from binding to membranes containing phosphatidylserine, a prevalent cellular acidic phospholipid. These results suggest that the MA-bound RNA promotes PM-specific localization of HIV-1 Gag by blocking nonspecific interactions with cellular membranes that do not contain PI(4,5)P2. To examine whether PI(4,5)P2dependence and RNA-mediated inhibition collectively determine MA phenotypes across a broad range of retroviruses and elucidate the significance of their interrelationships, we compared a panel of Gag-leucine zipper constructs (GagLZ) containing MA of different retroviruses. We found thatin vitromembrane binding of GagLZ via HIV-1 MA and Rous sarcoma virus (RSV) MA is both PI(4,5)P2dependent and susceptible to RNA-mediated inhibition. The PM-specific localization and virus-like particle (VLP) release of these GagLZ proteins are severely impaired by overexpression of a PI(4,5)P2-depleting enzyme, polyphosphoinositide 5-phosphatase IV (5ptaseIV). In contrast, membrane binding of GagLZ constructs that contain human T-lymphotropic virus type 1 (HTLV-1) MA, murine leukemia virus (MLV) MA, and human endogenous retrovirus K (HERV-K) MA is PI(4,5)P2independent and not blocked by RNA. The PM localization and VLP release of these GagLZ chimeras were much less sensitive to 5ptaseIV expression. Notably, single amino acid substitutions that confer a large basic patch rendered HTLV-1 MA susceptible to the RNA-mediated block, suggesting that RNA readily blocks MA containing a large basic patch, such as HIV-1 and RSV MA. Further analyses of these MA mutants suggest a possibility that HIV-1 and RSV MA acquired PI(4,5)P2dependence to alleviate the membrane binding block imposed by RNA.IMPORTANCEMA basic residues in the HIV-1 structural protein Gag interact with phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2] and RNA. RNA inhibits HIV-1 MA binding to non-PI(4,5)P2acidic lipids. This inhibition may promote PM specificity of Gag membrane binding, an early essential step in virus assembly. However, whether and how relationships between these interactions have developed among retroviruses are poorly understood. In this study, by comparing diverse retroviral MA domains, we elucidated a strong correlation among PI(4,5)P2dependence, susceptibility to RNA-mediated inhibition, and cellular behaviors of Gag. Mutagenesis analyses suggest that a large basic patch on MA is sufficient to confer susceptibility to RNA-mediated inhibition but not for PI(4,5)P2-dependent membrane binding. Our findings highlight RNA’s role as a general blocker of large basic patches and suggest a possibility that some retroviruses, including HIV-1, have evolved to bind PI(4,5)P2, while others have adopted smaller basic patches on their MA domains, to overcome the RNA-mediated restriction of membrane binding.

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Disruption of the HPA axis through down-regulation of glucocorticoid receptor expression in T cells of HIV-1-infected patients as a mechanism of chronic immune activation

Brain Behavior and Immunity ◽

10.1016/j.bbi.2010.07.138 ◽

2010 ◽

Vol 24 ◽

pp. S42

Author(s):

J.M. Milush ◽

V.A. York ◽

M. Acree ◽

M.E. Kemeny ◽

D.F. Nixon ◽

...

Keyword(s):

T Cells ◽

Glucocorticoid Receptor ◽

Hpa Axis ◽

Immune Activation ◽

Receptor Expression ◽

Chronic Immune Activation ◽

Down Regulation ◽

Hiv 1

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HIV-1 Interacts with Human Endogenous Retrovirus K (HML-2) Envelopes Derived from Human Primary Lymphocytes

Journal of Virology ◽

10.1128/jvi.00669-14 ◽

2014 ◽

Vol 88 (11) ◽

pp. 6213-6223 ◽

Cited By ~ 29

Author(s):

D. Brinzevich ◽

G. R. Young ◽

R. Sebra ◽

J. Ayllon ◽

S. M. Maio ◽

...

Keyword(s):

Endogenous Retrovirus ◽

Human Endogenous Retrovirus ◽

Hiv 1

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Mutational Definition of Functional Domains within the Rev Homolog Encoded by Human Endogenous Retrovirus K

Journal of Virology ◽

10.1128/jvi.74.20.9353-9361.2000 ◽

2000 ◽

Vol 74 (20) ◽

pp. 9353-9361 ◽

Cited By ~ 10

Author(s):

Hal P. Bogerd ◽

Heather L. Wiegand ◽

Jin Yang ◽

Bryan R. Cullen

Keyword(s):

Nuclear Export ◽

Biological Activities ◽

Endogenous Retrovirus ◽

Viral Rna ◽

Human Endogenous Retrovirus ◽

Nuclear Rna ◽

Rna Export ◽

Nuclear Rna Export ◽

Hiv 1 ◽

Rev Protein

ABSTRACT Nuclear export of the incompletely spliced mRNAs encoded by several complex retroviruses, including human immunodeficiency virus type 1 (HIV-1), is dependent on a virally encoded adapter protein, termed Rev in HIV-1, that directly binds both to a cis-acting viral RNA target site and to the cellular Crm1 export factor. Human endogenous retrovirus K, a family of ancient endogenous retroviruses that is not related to the exogenous retrovirus HIV-1, was recently shown to also encode a Crm1-dependent nuclear RNA export factor, termed K-Rev. Although HIV-1 Rev and K-Rev display little sequence identity, they share the ability not only to bind to Crm1 and to RNA but also to form homomultimers and shuttle between nucleus and cytoplasm. We have used mutational analysis to identify sequences in the 105-amino-acid K-Rev protein required for each of these distinct biological activities. While mutations in K-Rev that inactivate any one of these properties also blocked K-Rev-dependent nuclear RNA export, several K-Rev mutants were comparable to wild type when assayed for any of these individual activities yet nevertheless defective for RNA export. Although several nonfunctional K-Rev mutants acted as dominant negative inhibitors of K-Rev-, but not HIV-1 Rev-, dependent RNA export, these were not defined by their inability to bind to Crm1, as is seen with HIV-1 Rev. In total, this analysis suggests a functional architecture for K-Rev that is similar to, but distinct from, that described for HIV-1 Rev and raises the possibility that viral RNA export mediated by the ∼25 million-year-old K-Rev protein may require an additional cellular cofactor that is not required for HIV-1 Rev function.

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Determination of Sequences Required for Human Endogenous Retrovirus K Transduction and Its Recognition by Foreign Retroviral Virions

Journal of Virology ◽

10.1128/jvi.02731-15 ◽

2015 ◽

Vol 90 (6) ◽

pp. 3243-3246

Author(s):

Otto Erlwein ◽

Nathan P. Sweeney ◽

Raffaele de Leon ◽

Gillian Wills ◽

Mark J. Robinson ◽

...

Keyword(s):

Gene Therapy ◽

Murine Leukemia Virus ◽

Leukemia Virus ◽

Endogenous Retrovirus ◽

Human Endogenous Retrovirus ◽

Gene Therapy Vectors ◽

Working Together ◽

Hiv 1 ◽

Murine Leukemia

Sequences necessary for transduction of human endogenous retrovirus (HERV)-Kcon, a consensus of the HERV-K(HML-2) family, were analyzed and found to reside in the leader/gagregion. They act in an orientation-dependent way and consist of at least two sites working together. Having defined these sequences, we exploited this information to produce a simple system to investigate to what extent virions of HERV-Kcon, murine leukemia virus, and HIV-1 have the ability to transduce each other's genomes, leading to potential contamination of gene therapy vectors.

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Antibody to Human Endogenous Retrovirus Peptide in Urine of Human Immunodeficiency Virus Type 1-Positive Patients

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.6.6.783-786.1999 ◽

1999 ◽

Vol 6 (6) ◽

pp. 783-786 ◽

Cited By ~ 15

Author(s):

Roy W. Stevens ◽

Aldona L. Baltch ◽

Raymond P. Smith ◽

Bruce J. McCreedy ◽

Phyllis B. Michelsen ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Endogenous Retrovirus ◽

Clinical State ◽

Human Endogenous Retrovirus ◽

Related Peptide ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Human endogenous retrovirus (HERV)-like sequences are normal inherited elements that constitute several hundredths of the human genome. The expression of genes located within these elements can occur as a consequence of several different events, including persistent inflammation or genotoxic events. Antibodies to endogenous retroviral gene products have been found in a number of infectious, chronic, and malignant diseases, suggesting a role in disease initiation and progression. We studied human immunodeficiency virus type 1 (HIV-1)-infected patients for evidence of urine antibody to a HERV peptide and investigated correlates with clinical and laboratory parameters. Forty-three HIV-1-infected patients in documented asymptomatic, symptomatic, or AIDS stages of disease and 21 age- and gender-matched, uninfected controls were tested for antibody to HERV-related peptide 4.1. Urine specimens were examined in a blinded fashion with the Calypte Biomedical Corp. experimental enzyme immunoassay for antibody to peptide 4.1. Results were compared with demographic data, medical history, clinical state of disease, and results of other laboratory tests. Thirty-six percent of the asymptomatic (Centers for Disease Control and Prevention [CDC] category A) and 81.3% of both the symptomatic (CDC category B) and AIDS (CDC category C) patients were positive for antibody to HERV-related peptide 4.1. None of the controls were positive. In this study, antibodies to HERV-related peptide 4.1 were found more frequently in patients with advanced stages (categories B and C) of HIV-1 disease than in those patients with an earlier stage (category A) of HIV disease. In HIV patients, severe immunosuppression, defined as having had at least one opportunistic infection, correlated with the expression of antibody to a HERV-related peptide.

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