Human Immunodeficiency Virus Type 1 Coreceptor Preferences Determine Target T-Cell Depletion and Cellular Tropism in Human Lymphoid Tissue

Abstract

The present study sought to determine how usage of coreceptors by human immunodeficiency virus type 1 dictates cell tropism and depletion of CD4 ؉ T cells in human lymphoid tissues cultured ex vivo. We found that coreceptor preferences control the marked, preferential depletion of coreceptor-expressing CD4 ؉ lymphocytes. In addition, there was a strong, but not absolute, preference shown by CXCR4-using strains for lymphocytes and by CCR5-using strains for macrophages.The hallmark of human immunodeficiency virus type 1 (HIV-1) disease is the progressive depletion of CD4 ϩ lymphocytes. Different strains of HIV vary with respect to their target cell range and cytopathic potential. The molecular basis for differential cell tropism and virulence remained obscure until the discovery of select chemokine receptors that act as essential cofactors for cellular entry by HIV-1 (1). We previously reported that HIV-1 envelope glycoprotein (gp120) determinants controlling a preference for CXCR4 resulted in marked depletion of CD4 ϩ T cells in human lymphoid histocultures, while those specifying a preference for CCR5 resulted in only mild depletion of such cells. These results suggested that either X4 viruses are intrinsically more cytopathic than R5 viruses or viruses with different coreceptor specificities target quantitatively distinct CD4 ϩ T-cell pools. Our earlier study established that R5 HIV-1 variants exclusively deplete CCR5-expressing CD4 ϩ lymphocytes, while X4 HIV-1 variants preferentially deplete CXCR4-expressing cells (5). However, the diverse HIV-1 isolates used in this work differed from each other by many parameters other than coreceptor usage that could influence cytopathicity.The present study sought to establish a specific causative relationship among coreceptor usage, tropism, and CD4 ϩ Tcell depletion in mature lymphoid tissue. Human tonsil histocultures were inoculated with pairs of recombinant strains of HIV-1 that differ exclusively in small regions of gp120 that control coreceptor preference. Three pairs of viruses based on an isogenic (NL4-3) viral backbone were studied: (i) NL4-3 (X4) and 49-5 (R5), virus chimeras that differ only in the gp120 V3 loop region that specifies strict reciprocal tropism for CXCR4 and CCR5, respectively (9, 12, 13); (ii) 134 (X4) and 126 (R5), site-directed mutants that differ in a single V3 amino acid residue that likewise dictates preference for CXCR4 or CCR5, respectively (3, 12); and 123 (X4) and USV3 (R5), chimeras that contain V3 loop segments derived from primary X4 and R5 viral isolates (references 3 and 12 and unpublished data).T-cell depletion and viral replication were measured 12 to 15 days following inoculation as described previously (4). Consistent with our earlier report (9), NL4-3 (X4) severely depleted these cultures of CD4 ϩ T cells, while the paired virus 49-5 (R5) depleted these cells only mildly (Fig. 1A). Recombinant strain 134 (X4) also severely depleted these cells, while its paired strain, 126 (R5), which differs by a single amino acid within the ...

CD4+ T‐cell depletion in HIV infection: mechanisms of immunological failure

“…One of the more critical discoveries in the investigation of AIDS pathogenesis was the demonstration that HIV entry (and therefore, the targeting of the infection) is dependent not only on expression of a primary receptor, CD4, but also on expression of co‐receptors. These co‐receptors, which were shown to be chemokine receptors, typically CCR5 or CXCR4, are differentially expressed on CD4 + T cells . CXCR4 is highly expressed on the vast majority of peripheral T cells and can indeed mediate a generalized infection and destruction of all CD4 + T cells in infections with viruses using CXCR4 as co‐receptor, as demonstrated by the profound generalized CD4 + T‐cell destruction and acute onset of AIDS in NHPs infected with a CXCR4‐using SHIV .…”

“…First, HIV replication was shown to be continuous and high throughout the course of infection, despite the slow progression to end‐stage disease . Second, because of the use of CCR5 as a viral co‐receptor (CCR5 tropism), infecting strains preferentially infect memory CD4 + T cells (particularly the more differentiated effector memory subset) and these preferentially targeted cells, which comprise the majority of CD4 + T cells in extra‐lymphoid effector sites such as the intestinal mucosa, are rapidly and profoundly depleted during acute HIV infection, long before the onset of AIDS . Third, the level of immune activation in HIV‐infected subjects predicts disease progression as well or better than the levels of virus replication .…”

Extracellular vesicles generated by placental tissues ex vivo: A transport system for immune mediators and growth factors

“…Following the pioneer works of Hoffman et al, we developed cultures of ex vivo tissues maintained on collagen sponges at the medium/air interface to study HIV pathogenesis in human lymphoid, cervico‐vaginal, and recto‐sigmoid tissues, and to investigate the physiology of atherosclerotic plaques ex vivo. A comparable culture method was used to study cytomegalovirus infection .…”

Human Immunodeficiency Virus Immune Cell Receptors, Coreceptors, and Cofactors: Implications for Prevention and Treatment

“…67 Specifically, CXCR4 is expressed on 88.5% of CD4 + T cells in resting tissues, whereas CCR5 is expressed on 10.4% of cells. 68 Thus, HIV infection inhibition via CCR5 targeting will be discussed in more detail below. Due to the concurrence of viral subtypes that have different cellular tropism, the inhibition of CXCR4 alone may not be sufficient to decrease viral load.…”