Internalization of the human immunodeficiency virus does not require the cytoplasmic domain of CD4

Abstract

Binding of the human immunodeficiency virus (HIV) to infectable host cells, such as B and T lymphocytes, monocytes and colorectal cells, is mediated by a high-affinity interaction between the gp120 component of the viral envelope glycoprotein and the CD4 receptor. Upon binding, it is thought that the second component of the envelope, gp41, mediates fusion between the viral envelope and host cell membranes. However, the early steps of HIV infection have not yet been thoroughly elucidated. Viral entry was first reported to be mediated by pH-dependent receptor-mediated endocytosis; subsequent studies have shown entry to be pH-independent. Although direct fusion of virus to plasma membranes of infected cells has been observed by electron microscopy, it is still formally possible that the infectious path of the virus involves receptor-mediated endocytosis. To gain a better understanding of receptor function in viral entry, we have analysed the ability of several altered or truncated forms of CD4 to serve as effective viral receptors. Our results indicate that domains beyond the HIV-binding region of CD4 are not required for viral infection. Some of the altered forms of CD4 that serve as effective HIV receptors are severely impaired in their ability to be endocytosed. These experiments therefore support the notion that viral fusion to the plasma membrane is sufficient for infection.

Analysis of the human immunodeficiency virus type 1 envelope protein interaction with the CD4 host cell receptor

“…When alkaline phosphatase is anchored in the same manner it forms tetramers (Hawrylak & Stinson, 1988). The intracellular domain of CD4 is not necessary for HIV entry, since cells transfected with CD4 without the cytoplasmic domain support HIV infection and cells expressing a CD4-CD8 chimera which contains the D1D2 region of CD4 and the hinge, transmembrane and cytoplasmic domains of human CD8 were susceptible to HIV-1 infection (at very low efficiency) (Bedinger et al, 1988). After the completion of this study, Langedijk e t al.…”

Wnt and TGF-β signaling are required for the induction of an in vitro model of primitive streak formation using embryonic stem cells

“…The foxa2 targeting construct (Fig. 6A, which is published as supporting information on the PNAS web site) contains a truncated version of the human CD4 cDNA that lacks most of the intracellular signaling domain (16). GFP-Bry ES cells were electroporated with the foxa2 targeting vector, and appropriately targeted clones were identified by Southern blot analysis (Fig.…”

Resolving the Sites of HIV Entry: Dynamin Networks Hold the Key

“…Like certain enveloped viruses such as Herpes Simplex virus-1 and Sendai virus, HIV entry was shown to be independent of pH and/or presence of lysosomal enzymes thus suggesting that virus entry into endolysosomal compartments was not required [19][20][21][22][23][24][25][26][27][28][29][30][31]. Studies with CD4 truncation mutations supported this view as mutations that tethered CD4 at the membrane did not impede HIV entry [20,22,23]. Furthermore, HIV Env on the surface of infected cells could induce "fusion from without" with CD4 molecules present on target cells at neutral pH [32] and finally HIV was shown to overcome post-entry block of the actin cortex which can act as a barrier to viruses entering by direct fusion rather than endocytosis [33,34].…”