Loss of CD4 membrane expression and CD4 mRNA during acute human immunodeficiency virus replication.

Salmon, Patrick; Olivier, René; Riviere, I; Brisson, I Edith; Gluckman, Jean-Claude; Kiény, Marie-Paule; Montagnier, Luc; Klatzmann, David

doi:10.1084/jem.168.6.1953

Cited by 70 publications

(50 citation statements)

References 44 publications

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“…These T cells constitute a minority of CD4 ϩ T cells (5,22), and therefore, the 50% depletion of the cells observed in our experiments did not translate into a significant depletion of the total numbers of CD4 ϩ T lymphocytes. We found that depletion of CD4 ϩ CCR5 ϩ cells was accompanied not only by downregulation of CD4, observed earlier in other systems (26,45), but also by downregulation of CCR5. Coreceptor downregulation was reported earlier for CXCR4 (14,57,59) and has recently been reported for CCR5 (8,59) also.…”

Section: Discussionsupporting

confidence: 81%

Differential Pathogenesis of Primary CCR5-Using Human Immunodeficiency Virus Type 1 Isolates in Ex Vivo Human Lymphoid Tissue

Karlsson

Grivel

Chen

et al. 2005

J Virol

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In the course of human immunodeficiency virus (HIV) disease, CCR5-utilizing HIV type 1 (HIV-1) variants (R5), which typically transmit infection and dominate its early stages, persist in approximately half of the infected individuals (nonswitch virus patients), while in the other half (switch virus patients), viruses using CXCR4 (X4 or R5X4) emerge, leading to rapid disease progression. Here, we used a system of ex vivo tonsillar tissue to compare the pathogeneses of sequential primary R5 HIV-1 isolates from patients in these two categories. The absolute replicative capacities of HIV-1 isolates seemed to be controlled by tissue factors. In contrast, the replication level hierarchy among sequential isolates and the levels of CCR5 ؉ CD4 ؉ T-cell depletion caused by the R5 isolates seemed to be controlled by viral factors. R5 viruses isolated from nonswitch virus patients depleted more target cells than R5 viruses isolated from switch virus patients. The high depletion of CCR5؉ cells by HIV-1 isolates from nonswitch virus patients may explain the steady decline of CD4 ؉ T cells in patients with continuous dominance of R5 HIV-1. The level of R5 pathogenicity, as measured in ex vivo lymphoid tissue, may have a predictive value reflecting whether, in an infected individual, X4 HIV-1 will eventually dominate.

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Section: Discussionsupporting

confidence: 81%

Differential Pathogenesis of Primary CCR5-Using Human Immunodeficiency Virus Type 1 Isolates in Ex Vivo Human Lymphoid Tissue

Karlsson

Grivel

Chen

et al. 2005

J Virol

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“…This finding is similar to the situation for cells chronically infected by avian retroviruses (13,14) and reflects an important cellular adaptation to infection that facilitates establishment of virus persistence. HIV-1-infected cells are known to have decreased numbers of surface CD4 receptors (38)(39)(40)(41) and similar observations have been made for HCEM cells (not shown) . Reduced receptor levels appear to be a key alteration in this cell line that decreases reinfection rates .…”

Section: Discussionsupporting

confidence: 66%

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

Pauza

Galindo

1990

The Journal of Experimental Medicine

105

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SummaryHigh 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.Depletion of CD4 T lymphocytes is an important feature of the natural history of HIV-1 infection (1, 2). Reduced numbers in this cell population predict disease progression (1-3) and are likely to contribute to immunodeficiency (4) . HIV-1 infection in vitro is rytopathic for T lymphocytes (5-7) and T lymphoid cell lines (8,9). This cytopathology occurs by the formation of syncytia when infected and uninfected CD4+ cells are admixed (8, 9) and direct cell killing by a mechanism independent of cell fusion (10) . Based on the cytopathic effects of HIV-1 infection of T cells in vitro, this mechanism was proposed to be a crucial feature of viral pathogenesis in AIDS (6,5,11, 12) . In this study, we have examined the role of reinfection and viral DNA accumulation in cytopathic and persistent HIV-1 infection of the CEM cell line.Host-pathogen interactions leading to cytopathology have been characterized extensively in avian retrovirus models. The accumulation of high levels of unintegrated viral DNA is a recognized feature of rytopathic infection by these retroviruses (13, 14) and was also shown to be an important marker of pathogenesis in the case of feline leukemia virus infection of cats (15) and equine infectious anemia virus infection of horses (16).Unintegrated viral DNA is generated by reverse transcription of infecting viral RNA . A linear viral DNA molecule 1035 flanked at both ends by long terminal repeat (LTR)t sequences (17) is generally found to be the most abundant form of unintegrated viral DNA . Intramolecular recombination between the LTR sequences then generates a circular molecule with one LTR that is of intermediate abundance . A circular DNA form with two LTR seems to arise via direct ligation of the ends of a linear molecule and is the least abundant species . Importantly, these DNA species are pro...

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“…Once inside the cell, the genetic material of the virus directs rapid and sustained downregulation of CD4 (26,62), a phenomenon that promotes viral spread by preventing superinfection, enabling the release of progeny virions, and interfering with the host immune response (3,6,34,53). The ability of HIV-1 to downregulate CD4 depends on two accessory proteins encoded in the viral genome, Nef and Vpu (32,38,45,61).…”

mentioning

confidence: 99%

Transmembrane Domain Determinants of CD4 Downregulation by HIV-1 Vpu

Magadán

Bonifacino

2012

J Virol

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The transmembrane domains (TMDs) of integral membrane proteins do not merely function as membrane anchors but play active roles in many important biological processes. The downregulation of the CD4 coreceptor by the Vpu protein of HIV-1 is a prime example of a process that is dependent on specific properties of TMDs. Here we report the identification of Trp22 in the Vpu TMD and Gly415 in the CD4 TMD as critical determinants of Vpu-induced targeting of CD4 to endoplasmic reticulum (ER)-associated degradation (ERAD). The two residues participate in different aspects of ERAD targeting. Vpu Trp22 is required to prevent assembly of Vpu into an inactive, oligomeric form and to promote CD4 polyubiquitination and subsequent recruitment of the VCP-UFD1L-NPL4 dislocase complex. In the presence of a Vpu Trp22 mutant, CD4 remains integrally associated with the ER membrane, suggesting that dislocation from the ER into the cytosol is impaired. CD4 Gly415, on the other hand, contributes to CD4-Vpu interactions. We also identify two residues, Val20 and Ser23, in the Vpu TMD that mediate retention of Vpu and, by extension, CD4 in the ER. These findings highlight the exploitation of several TMD-mediated mechanisms by HIV-1 Vpu in order to downregulate CD4 and thus promote viral pathogenesis. Human immunodeficiency virus type 1 (HIV-1) targets helper T cells and macrophages/monocytes through interaction of the viral envelope glycoprotein (Env) with a combination of the CD4 and CCR5/CXCR4 cell surface receptors (59). Once inside the cell, the genetic material of the virus directs rapid and sustained downregulation of CD4 (26, 62), a phenomenon that promotes viral spread by preventing superinfection, enabling the release of progeny virions, and interfering with the host immune response (3,6,34,53). The ability of HIV-1 to downregulate CD4 depends on two accessory proteins encoded in the viral genome, Nef and Vpu (32,38,45,61). Nef is a myristoylated protein that attaches to the cytosolic leaflet of the plasma membrane, where it functions to link the cytosolic tail of CD4 to the clathrinassociated adaptor protein 2 (AP-2) complex (1,12,16,17,19,24,39). These interactions lead to rapid internalization of cell surface CD4 by a clathrin-dependent pathway (14,16,30,60). Nef exerts a second function in endosomes, namely, the targeting of internalized CD4 to the multivesicular body pathway for eventual degradation in lysosomes (20).Vpu is a type III integral membrane protein that, in contrast to Nef, acts on newly synthesized CD4, causing its retention in the endoplasmic reticulum (ER) (42) and subsequent delivery to the ER-associated degradation (ERAD) pathway (7,42,63,79). The mechanism of CD4 downregulation by Vpu involves a physical interaction of the cytosolic domains of both proteins (11, 47). A phosphoserine (pS)-based motif, DpSGxxpS, in the cytosolic domain of Vpu then acts as a binding site for the ␤-TrCP1/2 component of the SCF ␤-TrCP1/2 E3 ubiquitin (Ub)-ligase complex (15,25,48), which in turn mediates lysine-and serine/threon...

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Loss of CD4 membrane expression and CD4 mRNA during acute human immunodeficiency virus replication.

Cited by 70 publications

References 44 publications

Differential Pathogenesis of Primary CCR5-Using Human Immunodeficiency Virus Type 1 Isolates in Ex Vivo Human Lymphoid Tissue

Differential Pathogenesis of Primary CCR5-Using Human Immunodeficiency Virus Type 1 Isolates in Ex Vivo Human Lymphoid Tissue

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

Transmembrane Domain Determinants of CD4 Downregulation by HIV-1 Vpu

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