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

Abstract

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.

Tropism-independent protection of macaques against vaginal transmission of three SHIVs by the HIV-1 fusion inhibitor T-1249

“…Only CMPD-167 inhibited SHIV-162P3 replication in PBMCs, whereas SHIV-KU1 and SHIV-89.6P were sensitive only to AMD3465 (Table 1). This data pattern is consistent with previous reports (12)(13)(14). SHIV-89.6P therefore behaves in PBMCs as if it were an X4 virus (12).…”

“…This data pattern is consistent with previous reports (12)(13)(14). SHIV-89.6P therefore behaves in PBMCs as if it were an X4 virus (12). However, SHIV-89.6P can use either CCR5 or CXCR4 to enter indicator cell lines, and some dual-tropic viruses that use only CXCR4 to enter T cells can also use CCR5 for replication in macrophages (17,18).…”

“…We used three different challenge viruses, SHIV-162P3, SHIV-89.6P, and SHIV-KU1, allowing us to make some assessment of the breadth of activity of T-1249 against divergent strains and, more significantly, to determine whether a single inhibitor could protect against viruses that use different coreceptors for infection. Thus, although SHIV-162P3 enters cells only via CCR5, SHIV-89.6P can use both CCR5 and CXCR4, and SHIV-KU1 employs only CXCR4 (12)(13)(14). Although most naturally transmitted HIV-1 strains use only CCR5, a small but significant fraction of new infections does involve viruses that also or instead enter cells via CXCR4 (15,16).…”

Induction of Disease by a Molecularly Cloned Highly Pathogenic Simian Immunodeficiency Virus/Human Immunodeficiency Virus Chimera Is Multigenic

“…5B). The latter result is in agreement with a previous report showing that CCR5 is the coreceptor used by SIV mac239 for infection of macaque PBMC (26). SHIV DH12R-CL-7 also appears to be exclusively T cell tropic since it was unable to establish spreading infections in alveolar macrophage (13).…”

Stable reduction of CCR5 by RNAi through hematopoietic stem cell transplant in non-human primates

“…In addition, although CCR5 has been reported as the primary coreceptor for SIVmac 239 infection, SIVmac 239 has also been reported to use other coreceptors with lower efficiency (25). The use of other coreceptors may contribute to SIV production in EGFPϩ cells.…”