Coreceptor usage of BOB/GPR15 and Bonzo/STRL33 by primary isolates of human immunodeficiency virus type 1.

The chemokine receptors CCR5 and CXCR4 function as the principal coreceptors for human immunodeficiency virus type 1 (HIV-1). Coreceptor function has also been demonstrated for a variety of related receptors in vitro. The relative contributions of CCR5, CXCR4, and other putative coreceptors to HIV-1 disease in vivo have yet to be defined. In this study, we used sequential primary isolates and recombinant strains of HIV-1 to demonstrate that CXCR4-using (X4) viruses emerging in association with disease progression are highly pathogenic in ex vivo lymphoid tissues compared to CXCR4-independent viruses. Furthermore, synthetic receptor antagonists that specifically block CXCR4-mediated entry dramatically suppressed the depletion of CD4 ؉ T cells by recombinant and clinically derived X4 HIV-1 isolates. Moreover, in vitro specificity for the additional coreceptors CCR3, CCR8, BOB, and Bonzo did not augment cytopathicity or diminish sensitivity toward CXCR4 antagonists in lymphoid tissues. These data provide strong evidence to support the concept that adaptation to CXCR4 specificity in vivo accelerates HIV-1 disease progression. Thus, therapeutic intervention targeting the interaction of HIV-1 gp120 with CXCR4 may be highly valuable for suppressing the pathogenic effects of late-stage viruses.

Section: Discussionmentioning

confidence: 99%

Viral Entry through CXCR4 Is a Pathogenic Factor and Therapeutic Target in Human Immunodeficiency Virus Type 1 Disease

Schramm

Penn

Speck

et al. 2000

“…These patterns of coreceptor usage correspond to the phenotypes previously defined by the MT-2 assay; here, syncytium-inducing (SI) viruses use CXCR4, while non-syncytium-inducing (NSI) viruses use CCR5 (3). Some isolates from AIDS patients can also use other chemokine receptors as coreceptors in receptor-transfected cell lines, including CCR1, CCR2b, CCR3, BOB (GPR15), and CXCR6 (Bonzo/STRL33) (14,18,39,45,61,63; G. Alkhatib, F. Liao, E. A. Berger, J. M. Farber, and K. W. Peden, Letter, Nature 388:238, 1997). Rarely, however, are such alternative coreceptors used in primary cells (45,64).…”

mentioning

confidence: 99%

The CCR5 and CXCR4 Coreceptors Are Both Used by Human Immunodeficiency Virus Type 1 Primary Isolates from Subtype C

Cilliers¹,

Nhlapo²,

Coetzer³

et al. 2003

171

149

Human immunodeficiency virus type 1 (HIV-1) subtype C viruses with different coreceptor usage profiles were isolated from 29 South African patients with advanced AIDS. All 24 R5 isolates were inhibited by the CCR5-specific agents, PRO 140 and RANTES, while the two X4 viruses and the three R5X4 viruses were sensitive to the CXCR4-specific inhibitor, AMD3100. The five X4 or R5X4 viruses were all able to replicate in peripheral blood mononuclear cells that did not express CCR5. When tested using coreceptor-transfected cell lines, one R5 virus was also able to use CXCR6, and another R5X4 virus could use CCR3, BOB/GPR15, and CXCR6. The R5X4 and X4 viruses contained more-diverse V3 loop sequences, with a higher overall positive charge, than the R5 viruses. Hence, some HIV-1 subtype C viruses are able to use CCR5, CXCR4, or both CXCR4 and CCR5 for entry, and they are sensitive to specific inhibitors of entry via these coreceptors. These observations are relevant to understanding the rapid spread of HIV-1 subtype C in the developing world and to the design of intervention and treatment strategies.

“…The major coreceptor for the macrophage-tropic, nonsyncytium-inducing (NSI) viruses, now designated R5 isolates, was found to be CCR5 (2,20,22,27,28). A plethora of other coreceptors has also been described to function for HIV-1 entry, especially for SI viruses, at least in the context of coreceptor-transfected cells in vitro (5,19,20,22,27,31,32,38,40,50,60,62,84,85,92,93,96,102,104,105,116).…”

mentioning

confidence: 99%

“…The broad tropism of SI viruses in coreceptor-transfected cell lines is well known (5,19,20,22,27,31,32,38,40,50,60,62,84,85,92,93,96,104,105,116). However, the growth of HIV-1, HIV-2, and SHIV isolates in GHOST-CD4 cells transfected with other coreceptors was only rarely comparable to the replication of the same viruses in CCR5-or CXCR4-expressing cells.…”

mentioning

confidence: 99%

Use of Inhibitors To Evaluate Coreceptor Usage by Simian and Simian/Human Immunodeficiency Viruses and Human Immunodeficiency Virus Type 2 in Primary Cells

Zhang

Lou

Lal

et al. 2000

153

134

We have used coreceptor-targeted inhibitors to investigate which coreceptors are used by human immunodeficiency virus type 1 (HIV-1), simian immunodeficiency viruses (SIV), and human immunodeficiency virus type 2 (HIV-2) to enter peripheral blood mononuclear cells (PBMC). The inhibitors are TAK-779, which is specific for CCR5 and CCR2, aminooxypentane-RANTES, which blocks entry via CCR5 and CCR3, and AMD3100, which targets CXCR4. We found that for all the HIV-1 isolates and all but one of the HIV-2 isolates tested, the only relevant coreceptors were CCR5 and CXCR4. However, one HIV-2 isolate replicated in human PBMC even in the presence of TAK-779 and AMD3100, suggesting that it might use an undefined, alternative coreceptor that is expressed in the cells of some individuals. SIV mac 239 and SIV mac 251 (from macaques) were also able to use an alternative coreceptor to enter PBMC from some, but not all, human and macaque donors. The replication in human PBMC of SIV rcm (from a red-capped mangabey), a virus which uses CCR2 but not CCR5 for entry, was blocked by TAK-779, suggesting that CCR2 is indeed the paramount coreceptor for this virus in primary cells.