scholarly journals The Interferon Resistance of Transmitted HIV-1 is a Consequence of Enhanced Replicative Fitness

2021 ◽  
Author(s):  
Elena Sugrue ◽  
Arthur Wickenhagen ◽  
Nardus Mollentze ◽  
Muhamad Afiq Aziz ◽  
Vattipally B Sreenu ◽  
...  
Keyword(s):  
Growth Rates ◽  
Specific Resistance ◽  
Underlying Mechanism ◽  
Successful Transmission ◽  
Replicative Fitness ◽  
Expression Screening ◽  
Induced Defences ◽  
Interferon Resistance ◽  
Hiv 1

HIV-1 transmission via sexual exposure is a relatively inefficient process. When successful transmission does occur, newly infected individuals are colonized by either a single or a very small number of establishing virion(s). These transmitted founder (TF) viruses are more interferon (IFN) resistant than chronic control (CC) viruses present 6 months after transmission. To identify the specific molecular defences that make CC viruses more susceptible to the IFN-induced ′antiviral state′ than TF viruses, we established a pair of fluorescent GFP-IRES-Nef TF and CC viruses and used arrayed interferon-stimulated gene (ISG) expression screening. The relatively uniform ISG resistance of transmitted HIV-1 directed us to investigate the underlying mechanism. Our subsequent in silico simulations, modelling, and in vitro characterisation of a model TF/CC pair (closely matched in replicative fitness), revealed that small differences in replicative growth rates can explain the broad IFN resistance displayed by transmitted HIV-1. We propose that the apparent IFN resistance of transmitted HIV-1 is a consequence of enhanced replicative fitness, as opposed to specific resistance to individual IFN-induced defences.

scholarly journals In vitro replicative fitness of early Transmitted founder HIV-1 variants and sensitivity to Interferon alpha

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Manickam Ashokkumar ◽  
Aanand Sonawane ◽  
Maike Sperk ◽  
Srikanth P. Tripathy ◽  
Ujjwal Neogi ◽  
...  
Keyword(s):  
Interferon Alpha ◽  
Replicative Fitness ◽  
Hiv 1

scholarly journals Epitope Mapping of Ibalizumab, a Humanized Anti-CD4 Monoclonal Antibody with Anti-HIV-1 Activity in Infected Patients

2010 ◽  
Vol 84 (14) ◽  
pp. 6935-6942 ◽  
Author(s):  
Ruijiang Song ◽  
David Franco ◽  
Chia-Ying Kao ◽  
Faye Yu ◽  
Yaoxing Huang ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Viral Entry ◽  
Underlying Mechanism ◽  
Mhc Ii ◽  
Humanized Monoclonal Antibody ◽  
Class Ii Mhc ◽  
Unique Specificity ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT Ibalizumab is a humanized monoclonal antibody that binds human CD4, the primary receptor for human immunodeficiency virus type 1 (HIV-1). With its unique specificity for domain 2 of CD4, this antibody potently and broadly blocks HIV-1 infection in vitro by inhibiting a postbinding step required for viral entry but without interfering with major histocompatibility complex class II (MHC-II)-mediated immune function. In clinical trials, ibalizumab has demonstrated anti-HIV-1 activity in patients without causing immunosuppression. Thus, a characterization of the ibalizumab epitope was conducted in an attempt to gain insight into the underlying mechanism of its antiviral activity as well as its safety profile. By studying mouse/human chimeric CD4 molecules and site-directed point mutants of CD4, amino acids L96, P121, P122, and Q163 in domain 2 were found to be important for ibalizumab binding, with E77 and S79 in domain 1 also contributing. All these residues appear to cluster on the interface between domains 1 and 2 of human CD4 on a surface opposite the site where gp120 and the MHC-II molecule bind on domain 1. Separately, the epitope of M-T441, a weakly neutralizing mouse monoclonal antibody that competes with ibalizumab, was localized entirely within domain 2 on residues 123 to 125 and 138 to 140. The results reported herein not only provide an appreciation for why ibalizumab has not had significant adverse immunological consequences in infected patients to date but also raise possible steric hindrance mechanisms by which this antibody blocks HIV-1 entry into a CD4-positive cell.

scholarly journals HIV-1LAI Nef blocks the development of hematopoietic stem/progenitor cells into myeloid-erythroid lineage cells

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Wei Zou ◽  
Juanjuan Xing ◽  
Shijie Zou ◽  
Mei Jiang ◽  
Xinping Chen ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Progenitor Cells ◽  
Cell Loss ◽  
Underlying Mechanism ◽  
Humanized Mice ◽  
Hematopoietic Stem ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Human Immunodeficiency Virus 1

Abstract Background A variety of hematopoietic abnormalities are commonly seen in human immunodeficiency virus-1 (HIV-1) infected individuals despite antiviral therapy, but the underlying mechanism remains elusive. Nef plays an important role in HIV-1 induced T cell loss and disease progression, but it is not known whether Nef participates in other hematopoietic abnormalities associated with infection. Results In the current study we investigated the influence of HIV-1LAI Nef (LAI Nef) on the development of hematopoietic stem/progenitor cells (HSPCs) into myeloid-erythroid lineage cells, and found that nef expression in HSPCs blocked their differentiation both in vitro and in humanized mice reconstituted with nef-expressing HSPCs. Conclusions Our novel findings demonstrate LAI Nef compromised the development of myeloid-erythroid lineage cells, and therapeutics targeting Nef would be promising in correcting HIV-1 associated hematopoietic abnormalities.

scholarly journals Relative Replicative Fitness of Zidovudine-Resistant Human Immunodeficiency Virus Type 1 Isolates In Vitro

1998 ◽  
Vol 72 (5) ◽  
pp. 3773-3778 ◽  
Author(s):  
P. Richard Harrigan ◽  
Stuart Bloor ◽  
Brendan A. Larder
Keyword(s):  
Selection Pressure ◽  
Wild Type Virus ◽  
Drug Selection ◽  
Type Virus ◽  
Wild Type ◽  
Replicative Fitness ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Replication of mixtures of two or more human immunodeficiency virus type 1 (HIV-1) variants would be expected to result in the eventual selection of the fittest virus due to Darwinian competition among the variants. The relative proportions of known HIV-1 variants (which may differ only by a single nucleotide from a standard “wild-type” virus, HIV-1HXB2) in mixed viral cultures were quantified by analysis of automated sequence signals of reverse transcriptase PCR products. With this method, the relative levels of replicative fitness of several zidovudine (3′-azidothymidine)-resistant HIV-1HXB2 variants were estimated under controlled in vitro conditions by measuring the rate of change in the proportions of viral variants as they replicated in cell cultures both in the presence and in the absence of drug selection pressure. These variants were engineered to contain commonly observed zidovudine resistance mutations in the HIV-1 reverse transcriptase (M41L, K70R, T215Y, and M41L+T215Y). In the absence of zidovudine, all variants tested displayed reduced replicative fitness compared to wild-type HIV-1HXB2. The order of relative fitness was wild type > K70R ≫ T215Y = M41L+T215Y > M41L. Mixed cultures in the presence of zidovudine showed a dose-dependent selection pressure against the wild-type virus which varied according to the resistance profile of each virus. The information gathered from this approach provides insight into competition among multiple HIV-1 variants, which likely occurs in vivo with drug selection pressure, and may be applicable in more complex mathematical models for predicting the emergence of HIV-1 variants after the initiation of antiretroviral therapy.

scholarly journals CD8+ T-Cell Mediated Control of HIV-1 in a Unique Cohort With Low Viral Loads

2021 ◽  
Vol 12 ◽  
Author(s):  
Amber D. Jones ◽  
Svetlana Khakhina ◽  
Tara Jaison ◽  
Erin Santos ◽  
Stephen Smith ◽  
...  
Keyword(s):  
Viral Load ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Undetectable Viral Load ◽  
Underlying Mechanism ◽  
T Cell Response ◽  
Dependent Manner ◽  
Viral Loads ◽  
Hiv 1

A unique population of HIV-1 infected individuals can control infection without antiretroviral therapy. These individuals fall into a myriad of categories based on the degree of control (low or undetectable viral load), the durability of control over time and the underlying mechanism (i.e., possession of protective HLA alleles or the absence of critical cell surface receptors). In this study, we examine a cohort of HIV-1 infected individuals with a documented history of sustained low viral loads in the absence of therapy. Through in vitro analyses of cells from these individuals, we have determined that infected individuals with naturally low viral loads are capable of controlling spreading infection in vitro in a CD8+ T-cell dependent manner. This control is lost when viral load is suppressed by antiretroviral therapy and correlates with a clinical CD4:CD8 ratio of <1. Our results support the conclusion that HIV-1 controllers with low, but detectable viral loads may be controlling the virus due to an effective CD8+ T-cell response. Understanding the mechanisms of control in these subjects may provide valuable understanding that could be applied to induce a functional cure in standard progressors.

scholarly journals Publisher Correction: In vitro replicative fitness of early Transmitted founder HIV-1 variants and sensitivity to Interferon alpha

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Manickam Ashokkumar ◽  
Aanand Sonawane ◽  
Maike Sperk ◽  
Srikanth P. Tripathy ◽  
Ujjwal Neogi ◽  
...  
Keyword(s):  
Interferon Alpha ◽  
Replicative Fitness ◽  
Hiv 1

scholarly journals HIV-1 establishes a sanctuary site in the testis by permeating the BTB through changes in cytoskeletal organization

Endocrinology ◽  
2021 ◽  
Author(s):  
Siwen Wu ◽  
Ines Frank ◽  
Nina Derby ◽  
Elena Martinelli ◽  
C Yan Cheng
Keyword(s):  
Sertoli Cell ◽  
Sertoli Cells ◽  
Underlying Mechanism ◽  
Antiretroviral Drugs ◽  
Permeability Barrier ◽  
Tat Protein ◽  
Vitro Model ◽  
Hiv 1

Abstract Studies suggest that HIV-1 invades the testis through permeation of the blood-testis barrier (BTB). The selectivity of the BTB to antiretroviral drugs makes this site a sanctuary for the virus. Little is known about how HIV-1 crosses the BTB and invades the testis. Herein, we used two approaches to examine the underlying mechanism(s) by which HIV-1 permeates the BTB and gains entry into the seminiferous epithelium. First, we examined if recombinant Tat protein was capable of perturbing the BTB and making the barrier leaky, using the primary rat Sertoli cell in vitro model that mimics the BTB in vivo. Second, we used HIV-1 infected Sup-T1 cells to investigate the activity of HIV-1 infection on co-cultured Sertoli cells. Using both approaches, we found that the Sertoli cell tight junction (TJ)-permeability barrier was considerably perturbed and that HIV-1 effectively permeates the BTB by inducing actin-, microtubule-, vimentin- and septin-based cytoskeletal changes in Sertoli cells. These studies suggest that HIV-1 directly perturbs BTB function, potentially through the activity of the Tat protein.

DEVELOPMENT OF APPROACHES FOR DETECTION OF GENOME-INTEGRATED PROVIRAL DNA OF THE HUMAN IMMUNODEFICIENCY VIRUS (HIV-1) IN ULTRA LOW CONCENTRATIONS USING THE CRISPR/CAS SYSTEM

2020 ◽  
Author(s):  
M.A. Tyumentseva ◽  
◽  
A.I. Tyumentsev ◽  
V.G. Akimkin ◽  
◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Health Monitoring ◽  
Biological Samples ◽  
Proviral Dna ◽  
Guide Rnas ◽  
Ribonucleoprotein Complexes ◽  
Low Concentrations ◽  
Immunodeficiency Virus ◽  
Hiv 1

For the effective functioning of supervisory and health monitoring services, it is necessary to introduce modern molecular technologies into their practice. Therefore, the task of developing new effective methods for detecting pathogen, for example HIV, based on CRISPR/CAS genome editing systems, remains urgent. In the present work, guide RNAs and specific oligonucleotides were developed for preliminary amplification of highly conserved regions of the HIV-1 genome. The developed guide RNAs make it possible to detect single copies of HIV-1 proviral DNA in vitro as part of CRISPR/CAS ribonucleoprotein complexes in biological samples after preliminary amplification.

In vitro binding activity between HCK SH3 domain and HIV-1 Nef protein

2011 ◽  
Vol 31 (3) ◽  
pp. 262-265
Author(s):  
Xiao-lin QIN ◽  
Chao-qi LIU ◽  
Dong-ming REN ◽  
Yong-qin ZHOU
Keyword(s):  
Sh3 Domain ◽  
Binding Activity ◽  
Hiv 1
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