Chemokines and HIV–1 second receptors

We explore the impact of a host genetic factor on heterosexual HIV epidemics by using a deterministic mathematical model. A protective allele unequally distributed across populations is exemplified in our models by the 32-bp deletion in the host-cell chemokine receptor CCR5, CCR5⌬32. Individuals homozygous for CCR5⌬32 are protected against HIV infection whereas those heterozygous for CCR5⌬32 have lower pre-AIDS viral loads and delayed progression to AIDS. CCR5⌬32 may limit HIV spread by decreasing the probability of both risk of infection and infectiousness. In this work, we characterize epidemic HIV within three dynamic subpopulations: CCR5͞CCR5 (homozygous, wild type), CCR5͞CCR5⌬32 (heterozygous), and CCR5⌬32͞CCR5⌬32 (homozygous, mutant). Our results indicate that prevalence of HIV͞ AIDS is greater in populations lacking the CCR5⌬32 alleles (homozygous wild types only) as compared with populations that include people heterozygous or homozygous for CCR5⌬32. Also, we show that HIV can provide selective pressure for CCR5⌬32, increasing the frequency of this allele.

Section: Html) (For Brevitymentioning

confidence: 99%

Section: Html) (For Brevitymentioning

confidence: 99%

The coreceptor mutation CCR5Δ32 influences the dynamics of HIV epidemics and is selected for by HIV

Sullivan

Wigginton

Kirschner

2001

“…Human immunodeficiency virus type 1 (HIV-1) infects T cells through CD4 and chemokine coreceptors (1), but infection of quiescent cells is aborted during reverse transcription, producing an unintegrated partial viral genome with a short half life (2)(3)(4). Most T cells in vivo are quiescent and therefore not permissive for efficient infection by HIV-1, so the 2 ϫ 10 9 permissive T cells in an infected individual that are destroyed daily by the virus (5, 6) need to be replaced by activated T cells to sustain a productive infection.…”

mentioning

confidence: 99%

Tat protein induces self-perpetuating permissivity for productive HIV-1 infection

Ueda

Shi

et al. 1997

106

We report that human immunodeficiency virus type 1 (HIV-1) has evolved a self-perpetuating mechanism to actively generate cells permissive for productive and cytopathic infection. Only activated T cells can be productively infected, which leads to their rapid depletion (2 ؋ 10 9 ͞day in an infected individual). Establishment of productive HIV-1 infection therefore requires continual activations from the large pool of quiescent T cells. Tat protein, which is secreted by infected cells, activated uninfected quiescent T cells in vitro and in vivo. These Tat-activated uninfected cells became highly permissive for productive HIV-1 infection. Activation of primary T cells by Tat protein involved integrin receptors and was associated with activation of mitogen-activated protein kinases, including ERK1 and JNK kinase. Accordingly, these primary T cells progressed from G 0 to the late G 1 phase of the cell cycle.

“…The three ␤-chemokines initially selected for study were chosen because they suppress the replication of NSI strains of HIV-1 (33) by binding to CC chemokine receptor 5 (CCR5), the ␤-chemokine receptor that has been shown to be critical for the acquisition of HIV-1 infection (34)(35)(36). To determine whether the numbers of ␤-chemokines produced by CD40L-stimulated macrophages were sufficient to inhibit the replication of a virus that uses CCR5 as a coreceptor, purified CD4 ϩ T cells were stimulated with PHA and IL-2 and infected with the NSI Immunology: Kornbluth et al Proc.…”

Section: T Cell Soluble Factors Ifn-␥ and Gm-csf Fail To Inducementioning

confidence: 99%

“…Instead, SDF-1, an ␣-chemokine that is the ligand for CXCR4, is capable of blocking the infection of CD4 ϩ T cells by many SI strains (34)(35)(36). To evaluate the effects of CD40L-stimulated MDM supernatants against an SI strain of HIV-1, these supernatants were added to CD4 ϩ T cells exposed to HIV-1 LAI .…”

Section: T Cell Soluble Factors Ifn-␥ and Gm-csf Fail To Inducementioning

confidence: 99%

CD40 ligand (CD154) stimulation of macrophages to produce HIV-1-suppressive β-chemokines

Kornbluth

Kee

Richman

1998

117

ABSTRACT␤-chemokines play an important role in the development of immunologic reactions. Macrophages are major ␤-chemokine-producing cells during T-cell directed, delayed-type hypersensitivity reactions in tissues, and have been reported to be important producers of ␤-chemokines in the lymph nodes of HIV-1-infected individuals. However, the physiological signals responsible for inducing macrophages to produce ␤-chemokines have not been established. Two soluble T cell products, interferon-␥ and granulocyte-macrophage colony stimulating factor, were added to cultured macrophages, but failed to stimulate the production of macrophage inf lammatory protein-1␣ and -1␤; regulated upon activation, normal T cell expressed and secreted (RANTES); or monocyte chemoattractant protein-1. Instead, direct cell-cell contact between macrophages and cells engineered to express CD40L (also known as CD154) resulted in the production of large amounts of macrophage inf lammatory protein-1␣ and -1␤, and RANTES (all ligands for CCR5), and monocyte chemoattractant protein-1 (a ligand for CCR2). Supernatants from CD40L-stimulated macrophages protected CD4 ؉ T cells from infection by a nonsyncytium-inducing strain of HIV-1 (which uses CCR5 as a coreceptor). These results have implications for granulomatous diseases, and conditions such as atherosclerosis and multiple sclerosis, where CD40L-bearing cells have been found in the macrophage-rich lesions where ␤-chemokines are being produced. Overall, these findings define a pathway linking the specific recognition of antigen by T cells to the production of ␤-chemokines by macrophages. This pathway may play a role in anti-HIV-1 immunity and the development of immunologic reactions or lesions.