Isolation of CD4-Independent Primary Human Immunodeficiency Virus Type 1 Isolates That Are Syncytium Inducing and Acutely Cytopathic for CD8
            <sup>+</sup>
            Lymphocytes

Zerhouni, Bouchra; Nelson, Julie A.; Saha, Kunal

doi:10.1128/jvi.78.12.6707.2004

Cited by 24 publications

(36 citation statements)

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“…1B). As reported before (37), in addition to efficient replication in CD4 ϩ cells (Fig. 1A), the parental 93US143 isolate was also able to replicate in CD8 ϩ cells, albeit to a much lower level than its replication in CD4 ϩ cells (Fig.…”

Section: Infection Of Primary Cd4supporting

confidence: 56%

“…93US143-T8, the HIV-1 isolate used in this study, came from the bulk viruses of a newborn patient, 93US143 (obtained from Merlin Robb through the AIDS Research and Reagents Program, National Institutes of Health [NIH]). The CD4-independent 93US143-T8 strain was isolated from the viral quasispecies of this newborn by stringent selection of infected CD8 ϩ lymphocytes in short-term culture as described recently (37). The X4 laboratory isolate IIIB, the R5 virus JR-FL, and the parental 93US143 isolate were used as controls for these experiments.…”

Section: Methodsmentioning

confidence: 99%

“…Purified CD4 ϩ and CD8 ϩ cells, as well as CD4 ϩ CXCR4 ϩ MT-2 and CEM T-cell lines, were used for infection and inhibition studies (34,37). For infection of primary CD4 ϩ and CD8 ϩ lymphocytes, cells from four different healthy donors were used in separate experiments.…”

Section: Methodsmentioning

confidence: 99%

“…We have recently isolated CD4-independent variants from the quasispecies of several HIV-1-infected patients using a highly stringent selection method. Although these isolates can infect independently of CD4, most of these viruses have still maintained an unchanged ability to infect CD4 ϩ cells by using the CD4 receptor like regular HIV-1 strains (37). Here, we used AMD3100 to study the role of CXCR4 in the infection of CD4 ϩ and CD8 ϩ cells by 93US143-T8, a primary CD4-independent HIV-1 variant originally isolated from an infected infant (37).…”

mentioning

confidence: 99%

“…Although these isolates can infect independently of CD4, most of these viruses have still maintained an unchanged ability to infect CD4 ϩ cells by using the CD4 receptor like regular HIV-1 strains (37). Here, we used AMD3100 to study the role of CXCR4 in the infection of CD4 ϩ and CD8 ϩ cells by 93US143-T8, a primary CD4-independent HIV-1 variant originally isolated from an infected infant (37). We found that while treatment with AMD3100 strongly inhibits infection of CD8 ϩ cells, it has no effect on infection of CD4 ϩ cells.…”

mentioning

confidence: 99%

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CXCR4-Dependent Infection of CD8 ⁺ , but Not CD4 ⁺ , Lymphocytes by a Primary Human Immunodeficiency Virus Type 1 Isolate

Zerhouni

Nelson

Saha

2004

J Virol

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We recently isolated from an infant an X4-syncytium-inducing (SI) human immunodeficiency virus type 1 (HIV-1) variant (92US143-T8) that was able to infect CD8؉ lymphocytes independently of CD4. Although it was CD4 independent, the 92US143-T8 isolate also maintained the ability to infect CD4 ؉ cells. In the present study, we investigated the role of CXCR4 in the infection of CD4؉ and CD8 ؉ cells by this primary isolate. The expression of CXCR4 was down modulated in CD8؉ lymphocytes after infection with the 93US143-T8 isolate. Infection of CD8؉ lymphocytes by the 93US143-T8 isolate was prevented by treatment with AMD3100, a specific antagonist for CXCR4, indicating CXCR4-dependent infection. Interestingly, AMD3100 treatment had no inhibitory role in the infection of purified CD4؉ lymphocytes by the same isolate. Furthermore, AMD3100 treatment failed to prevent infection of known CD4 ؉ CXCR4 ؉ T-cell lines (MT-2 and CEM) by the 93US143-T8 isolate. In fact, virus replication in the CD4؉ cells was often enhanced in the presence of AMD3100. Viruses produced from the infected CD4؉ cells in the presence of AMD3100 maintained an unchanged envelope genotype and an SI phenotype. For the first time, these results provide evidence of CXCR4-dependent infection of CD8 ؉ lymphocytes by a primary HIV-1 isolate. This study also shows a different mode of infection for the CD4 ؉ and CD8 ؉ lymphocytes by the same HIV-1 variant. Finally, our findings suggest that a more careful evaluation is necessary before the random use of AMD3100 as a new entry inhibitor in patients harboring SI HIV-1 strains.Although a large number of chemokine receptors that can play critical roles as coreceptors for human immunodeficiency virus (HIV) entry have been identified, primary HIV type 1 (HIV-1) isolates generally use either CXCR4 (X4 strains) or CCR5 (R5 strains) as a coreceptor for infection of CD4 ϩ cells (13). X4 viruses generally appear late in HIV-1 disease, and their appearance is frequently associated with rapid progression to AIDS. However, many HIV-1 isolates that use CXCR4 are also capable of using CCR5 and thus are called dual tropic (R5X4) (6,16,26). X4 and R5X4 viruses are able to infect a larger proportion of the immune cells because, unlike CCR5, the CXCR4 molecules are abundantly expressed on most primary T cells, including the resting T lymphocytes (7). Furthermore, X4 and R5X4 isolates frequently form syncytia in CD4 ϩ cells in vitro, and it is believed that these viruses are primarily responsible for the profound loss of CD4 ϩ cells in the late stages of HIV-1 disease (17). AMD3100, a bicyclam compound, is a specific antagonist for CXCR4 that has emerged as a potent inhibitor of infection by X4 and R5X4 strains (11,15,21,22,28,38). Strong selection pressure against the more pathogenic X4 strains has prompted the suggestion that AMD3100 might be used even in asymptomatic HIV-1-infected patients to prevent the emergence of the more pathogenic X4 viruses (11, 15). We have recently isolated CD4-independent variants from the quasispecie...

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Section: Infection Of Primary Cd4supporting

confidence: 56%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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CXCR4-Dependent Infection of CD8 ⁺ , but Not CD4 ⁺ , Lymphocytes by a Primary Human Immunodeficiency Virus Type 1 Isolate

Zerhouni

Nelson

Saha

2004

J Virol

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Homology models of the HIV‐1 attachment inhibitor BMS‐626529 bound to gp120 suggest a unique mechanism of action

et al. 2014

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HIV-1 gp120 undergoes multiple conformational changes both before and after binding to the host CD4 receptor. BMS-626529 is an attachment inhibitor (AI) in clinical development (administered as prodrug BMS-663068) that binds to HIV-1 gp120. To investigate the mechanism of action of this new class of antiretroviral compounds, we constructed homology models of unliganded HIV-1 gp120 (UNLIG), a pre-CD4 binding-intermediate conformation (pCD4), a CD4 bound-intermediate conformation (bCD4), and a CD4/co-receptor-bound gp120 (LIG) from a series of partial structures. We also describe a simple pathway illustrating the transition between these four states. Guided by the positions of BMS-626529 resistance substitutions and structure–activity relationship data for the AI series, putative binding sites for BMS-626529 were identified, supported by biochemical and biophysical data. BMS-626529 was docked into the UNLIG model and molecular dynamics simulations were used to demonstrate the thermodynamic stability of the different gp120 UNLIG/BMS-626529 models. We propose that BMS-626529 binds to the UNLIG conformation of gp120 within the structurally conserved outer domain, under the antiparallel β20–β21 sheet, and adjacent to the CD4 binding loop. Through this binding mode, BMS-626529 can inhibit both CD4-induced and CD4-independent formation of the “open state” four-stranded gp120 bridging sheet, and the subsequent formation and exposure of the chemokine co-receptor binding site. This unique mechanism of action prevents the initial interaction of HIV-1 with the host CD4+ T cell, and subsequent HIV-1 binding and entry. Our findings clarify the novel mechanism of BMS-626529, supporting its ongoing clinical development. Proteins 2015; 83:331–350. © 2014 Wiley Periodicals, Inc.

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Human Immunodeficiency Virus Type 1 Cellular Entry and Exit in the T Lymphocytic and Monocytic Compartments

Aiamkitsumrit

Sullivan

Nonnemacher

et al. 2015

Advances in Virus Research

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Isolation of CD4-Independent Primary Human Immunodeficiency Virus Type 1 Isolates That Are Syncytium Inducing and Acutely Cytopathic for CD8 ⁺ Lymphocytes

Cited by 24 publications

References 0 publications

CXCR4-Dependent Infection of CD8 ⁺ , but Not CD4 ⁺ , Lymphocytes by a Primary Human Immunodeficiency Virus Type 1 Isolate

CXCR4-Dependent Infection of CD8 ⁺ , but Not CD4 ⁺ , Lymphocytes by a Primary Human Immunodeficiency Virus Type 1 Isolate

Homology models of the HIV‐1 attachment inhibitor BMS‐626529 bound to gp120 suggest a unique mechanism of action

Human Immunodeficiency Virus Type 1 Cellular Entry and Exit in the T Lymphocytic and Monocytic Compartments

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Isolation of CD4-Independent Primary Human Immunodeficiency Virus Type 1 Isolates That Are Syncytium Inducing and Acutely Cytopathic for CD8 + Lymphocytes

Cited by 24 publications

References 0 publications

CXCR4-Dependent Infection of CD8 + , but Not CD4 + , Lymphocytes by a Primary Human Immunodeficiency Virus Type 1 Isolate

CXCR4-Dependent Infection of CD8 + , but Not CD4 + , Lymphocytes by a Primary Human Immunodeficiency Virus Type 1 Isolate

Homology models of the HIV‐1 attachment inhibitor BMS‐626529 bound to gp120 suggest a unique mechanism of action

Human Immunodeficiency Virus Type 1 Cellular Entry and Exit in the T Lymphocytic and Monocytic Compartments

Contact Info

Product

Resources

About

Isolation of CD4-Independent Primary Human Immunodeficiency Virus Type 1 Isolates That Are Syncytium Inducing and Acutely Cytopathic for CD8 ⁺ Lymphocytes

CXCR4-Dependent Infection of CD8 ⁺ , but Not CD4 ⁺ , Lymphocytes by a Primary Human Immunodeficiency Virus Type 1 Isolate

CXCR4-Dependent Infection of CD8 ⁺ , but Not CD4 ⁺ , Lymphocytes by a Primary Human Immunodeficiency Virus Type 1 Isolate