Different Mutational Pathways to CXCR4 Coreceptor Switch of CCR5-Using Simian-Human Immunodeficiency Virus

Abstract

We report here a second case of coreceptor switch in R5 simian-human immunodeficiency virus SF162P3N (SHIV SF162P3N )-infected macaque CA28, supporting the use of this experimental system to examine factors that drive the change in coreceptor preference in vivo. Virus recovered from CA28 plasma (SHIV CA28NP ) used both CCR5 and CXCR4 for entry, but the virus recovered from lymph node (SHIV CA28NL ) used CXCR4 almost exclusively. Sequence and functional analyses showed that mutations in the V3 loop that conferred CXCR4 usage in macaque CA28 differed from those described in the previously reported case, demonstrating divergent mutational pathways for change in the coreceptor preference of the R5 SHIV SF162P3N isolate in vivo.

Different Tempo and Anatomic Location of Dual-Tropic and X4 Virus Emergence in a Model of R5 Simian-Human Immunodeficiency Virus Infection

“…Consistent with observations made in the i.v. infected macaques (28,29), emergence of the X4 and dual-R viruses in DG08 was associated with accelerated peripheral CD4 ϩ T-cell loss but appeared after and not before the onset of CD4 ϩ T-cell decline at 12 wpi.…”

“…infected macaques were found to be highly sensitive to neutralization with soluble CD4 (CD4-IgG2) (28,29). To determine whether viruses recovered from i.r.…”

“…Similar observations were made when tissue localization of X4 variants in DG08 and in the other i.v. infected macaque CA28 at the time of necropsy was analyzed (29), showing lymph node compartmentalization of X4 viruses (Table 2). These data from three switch macaques, coupled with the finding that X4 signature sequence was first detected in the inguinal lymph node of DG08, support lymph nodes as niches where the chances for X4 virus evolution as well as expansion are the greatest.…”

“…In this regard, we recently reported coreceptor switch in two of nine rhesus macaques (RM) inoculated intravenously with simian-human immunodeficiency virus SF162P3N (SHIV SF162P3N ) that bears an HIV-1 CCR5-tropic Env (28,29). In order to establish a reproducible model for coreceptor switch, however, it was crucial to document additional switching events.…”

Generation of the Pathogenic R5-Tropic Simian/Human Immunodeficiency Virus SHIV AD8 by Serial Passaging in Rhesus Macaques

“…9a and c). Interestingly, coreceptor switching has been previously reported to occur during RP infections of macaques inoculated with a different R5-tropic SHIV, SHIV SF162P3 (18,19,47). In one of the SHIV SF162P3 coreceptor-switching events, the insertion of two positively charged amino acids (HR) immediately upstream of the V3 loop GPGR crown (Fig.…”