Binding of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp120 to both CD4 and one of several chemokine receptors (coreceptors) permits entry of virus into target cells. Infection of tissues may establish latent viral reservoirs as well as cause direct pathologic effects that manifest as clinical disease such as HIV-associated dementia. We sought to identify the critical coreceptors recognized by HIV-1 tissue-derived strains as well as to correlate these coreceptor preferences with site of infection and dementia diagnosis. To reconstitute coreceptor use, we cloned HIV-1 envelope V3 sequences encoding the primary determinants of coreceptor specificity from 13 brain-derived and 6 colon-derived viruses into an isogenic (NL4-3) viral background. All V3 recombinants utilized the chemokine receptor CCR5 uniformly and efficiently as a coreceptor but not CXCR4, BOB/GPR15, or Bonzo/STRL33. Other receptors such as CCR3, CCR8, and US28 were inefficiently and variably used as coreceptors by various envelopes. CCR5 without CD4 present did not allow for detectable infection by any of the tested recombinants. In contrast to the pathogenic switch in coreceptor specificity frequently observed in comparisons of blood-derived viruses early after HIV-1 seroconversion and after onset of AIDS, the characteristics of these V3 recombinants suggest that CCR5 is a primary coreceptor for brain- and colon-derived viruses regardless of tissue source or diagnosis of dementia. Therefore, tissue infection may not depend significantly on viral envelope quasispeciation to broaden coreceptor range but rather selects for CCR5 use throughout disease progression.
Leflunomide's anti-HIV activity and clinical profile make it an attractive candidate for further study of its effects. Since HIV RNA levels are an effective predictor of AIDS-free survival, leflunomide's partial suppression of HIV RNA may be valuable in certain patients.
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 ...
In the early 2000s, novel humanized mouse models based on the transplantation of human hematopoietic stem and progenitor cells (HSPCs) into immunocompromised mice were introduced (hu mice). The human HSPCs gave rise to a lymphoid system of human origin. The HIV research community has greatly benefitted from these hu mice. Since human immunodeficiency virus (HIV) type 1 infection results in a high-titer disseminated HIV infection, hu mice have been of great value for all types of HIV research from pathogenesis to novel therapies. Since the first description of this new generation of hu mice, great efforts have been expended to improve humanization by creating other immunodeficient mouse models or supplementing mice with human transgenes to improve human engraftment. Many labs have their own customized hu mouse models, making comparisons quite difficult. Here, we discuss the different hu mouse models in the context of specific research questions in order to define which characteristics should be considered when determining which hu mouse model is appropriate for the question posed. We strongly believe that researchers must first define their research question and then determine whether a hu mouse model exists, allowing the research question to be studied.
To evaluate the feasibility of using transgenic rabbits expressing CCR5 and CD4 as a small-animal model of human immunodeficiency virus type 1 (HIV) disease, we examined whether the expression of the human chemokine receptor (CCR5) and human CD4 would render a rabbit cell line (SIRC) permissive to HIV replication. Histologically, SIRC cells expressing CD4 and CCR5 formed multinucleated cells (syncytia) upon exposure to BaL, a macrophagetropic strain of HIV that uses CCR5 for cell entry. Intracellular viral capsid p24 staining showed abundant viral gene expression in BaL-infected SIRC cells expressing CD4 and CCR5. In contrast, neither SIRC cells expressing CD4 alone nor murine 3T3 cells expressing CCR5 and CD4 exhibited significant expression of p24. These stably transfected rabbit cells were also highly permissive for the production of virions upon infection by two other CCR5-dependent strains (JR-CSF and YU-2) but not by a CXCR4-dependent strain (NL4-3). The functional integrity of these virions was demonstrated by the successful infection of human peripheral blood mononuclear cells (PBMC) with viral stocks prepared from these transfected rabbit cells. Furthermore, primary rabbit PBMC were found to be permissive for production of infectious virions after circumventing the cellular entry step. These results suggest that a transgenic rabbit model for the study of HIV disease may be feasible.
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