CCR5 Is the Major Coreceptor Used by HIV-1 Subtype C Isolates from Patients with Active Tuberculosis

Abstract

Tuberculosis (TB) is the major opportunistic infection of HIV-infected patients in developing countries and is associated with activation of the immune system and increased HIV-1 expression. The aim of this study was to explore the biological properties of HIV-1 isolates from patients with active TB. Ten HIV-1 subtype C isolates were analyzed for biological phenotypes, using MT-2 cells, and for coreceptor usage, using coreceptor-transfected cell lines. All isolates were nonsyncytium inducing (NSI) in the MT-2 assay and replicated in CCR5-expressing cells. None of the isolates used CXCR4 or any of the minor coreceptors (CCR1, CCR2b, or CCR3) efficiently. Analysis of the V3 region showed that all isolates contained the GPGQ motif characteristic of subtype C and also had a sequence profile typical of NSI viruses. These data indicate that despite their advanced disease state, patients with TB harbor viruses that use the CCR5 coreceptor. It is possible that activation of monocytes and macrophages during TB infection results in the expansion of macrophage-tropic isolates that preferentially use CCR5.

Expansion of CCR5+ CD4+ T-lymphocytes in the course of active pulmonary tuberculosis

“…With the background that chemokine receptors play a major role in HIV infection, the very fact that the lung lymphocyte population is normally comprised of memory T-cells expressing the chemokine receptors CCR5 and CCR3, and that in pulmonary TB the population of CCR5z CD4z activated T-cells expands in the lower respiratory tract, may render the lung a preferential target for the spread of the NSI macrophage-tropic viral variants, as alveolar and tissue lung macrophages may continuously transmit virus to susceptible antigen-specific CD4zT-lymphocytes [3][4]. Consistently with this notion, NSI macrophage-tropic viral variants have been found in TB patients [10], where the infection of CCR5z CD4z T-cells is likely to lead to the deletion of M. tuberculosis-specific Th1 cells crucial for the anti-TB immune response [26], as vaginal CD4z T-lymphocytes expressing high levels of CCR5 are rapidly eliminated in the course of simian immunodeficiency infection [27]. The recent observation that the immunosuppressive drug rapamycin can downregulate CCR5 expression and inhibit R5 HIV entry into CD4 T-cells and macrophages [28] may open the way to new strategies to prevent the deletion of M. tuberculosisspecific lung memory T-cells.…”

“…M. tuberculosis infection increases cell expression of CCR5 both in vitro and in vivo, thereby enhancing susceptibility of cells of the monocyte/macrophage lineage to HIV infection [8]. An increase of both CCR5 and CXCR4 expression in peripheral CD4z T-lymphocytes from active TB patients has been described [9], and CCR5 has also been identified as the main co-receptor for nonsyncytium inducing (NSI) HIV-1 subtype-C isolates from patients with active TB [10].…”

Regional Clustering of Shared Neutralization Determinants on Primary Isolates of Clade C Human Immunodeficiency Virus Type 1 from South Africa

“…All clade C isolates from Africa had an R5 phenotype except for Du179, which was R5X4 and induced syncytium formation in MT-2 cells. Coreceptor usage of clade C isolates from South Africa was assessed in U87.CD4 cells transfected to express either CCR5 or CXCR4 as described (57). The coreceptor usage of the remaining isolates was reported previously (9,64).…”

“…Viruses were isolated by peripheral blood mononuclear cell (PBMC) coculture as described (53,57). All primary isolates were of a low passage number (three passages or fewer) in PBMC exclusively.…”

Novel subtype C human immunodeficiency virus type 1 envelopes cloned directly from plasma: coreceptor usage and neutralization phenotypes

“…Infection was detected by p24 immunostaining 48 h post-inoculation and the number of infectious foci were counted (Aasa-Chapman et al, 2006a). Table 1 shows that the cloned viruses were CCR5-tropic, as is typical of subtype C viruses regardless of the stage of infection (Abebe et al, 1999;Bjorndal et al, 1999;Cecilia et al, 2000;Cilliers et al, 2003;Li et al, 2006a;Morris et al, 2001;Zhang et al, 2006), although one virus (C344) was R5/X4 dual-tropic. The CCR5-tropism of the viruses reported here matched the V3-loop based algorithm, which stipulates that a high-positive charge of V3 and basic residues at positions 306, 321 and/or 322 is required for CXCR4 tropism (Cardozo et al, 2007;Xiao et al, 1998).…”