Changes in the V3 region of gp120 contribute to unusually broad coreceptor usage of an HIV-1 isolate from a CCR5 Δ32 heterozygote

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Virology (Impact Factor: 3.32). 06/2007; 362(1):163-78. DOI: 10.1016/j.virol.2006.11.025
Source: PubMed


Heterozygosity for the CCR5 Delta32 allele is associated with delayed progression to AIDS in human immunodeficiency virus type 1 (HIV-1) infection. Here we describe an unusual HIV-1 isolate from the blood of an asymptomatic individual who was heterozygous for the CCR5 Delta32 allele and had reduced levels of CCR5 expression. The primary virus used CCR5, CXCR4, and an unusually broad range of alternative coreceptors to enter transfected cells. However, only CXCR4 and CCR5 were used to enter primary T cells and monocyte-derived macrophages, respectively. Full-length Env clones had an unusually long V1/V2 region and rare amino acid variants in the V3 and C4 regions. Mutagenesis studies and structural models suggested that Y308, D321, and to a lesser extent K442 and E444, contribute to the broad coreceptor usage of these Envs, whereas I317 is likely to be a compensatory change. Furthermore, database analysis suggests that covariation can occur at positions 308/317 and 308/321 in vivo. Y308 and D321 reduced dependence on the extracellular loop 2 (ECL2) region of CCR5, while these residues along with Y330, K442, and E444 enhanced dependence on the CCR5 N-terminus compared to clade B consensus residues at these positions. These results suggest that expanded coreceptor usage of HIV-1 can occur in some individuals without rapid progression to AIDS as a consequence of changes in the V3 region that reduce dependence on the ECL2 region of CCR5 by enhancing interactions with conserved structural elements in G-protein-coupled receptors.

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Available from: Geoffrey H. Holm, Oct 08, 2014
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    • "The percent inhibition was calculated by subtracting this number from 100. Data were fitted with a non-linear function, and fifty-and ninety-percent inhibitory concentrations (IC 50 and IC 90 , respectively) were calculated by least squares regression analysis of inhibition curves (Gorry et al., 2007, 2002; Gray et al., 2005). "
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    • "HIV-1 viral variants can in general use either the CCR5 or CXCR4 co-receptor for entry into human cells (Gorry & Ancuta, 2011). They may also at times use a variety of other chemokine receptors for entry (Gorry et al; 2007). The normal function of chemokine receptors is to bind chemokines that target immune cells to areas of inflammation within the human body. "

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    • "It is not surprising that Tat has many connections given its central role as transactivator in promoting viral transcription and its effect on disease progression by interacting with neighboring cells after being released to the intercellular medium [27]. Gp120 also has many interactions due to its essential function in facilitating cell entry in different cell types [28] and Gp120 shedding of the virus [29]. Gp120 shows a similar distribution as Tat and is found in infected cells as well as in the intercellular space. "
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