The CCR5 and CXCR4 Coreceptors Are Both Used by Human Immunodeficiency Virus Type 1 Primary Isolates from Subtype C

Abstract

Human immunodeficiency virus type 1 (HIV-1) subtype C viruses with different coreceptor usage profiles were isolated from 29 South African patients with advanced AIDS. All 24 R5 isolates were inhibited by the CCR5-specific agents, PRO 140 and RANTES, while the two X4 viruses and the three R5X4 viruses were sensitive to the CXCR4-specific inhibitor, AMD3100. The five X4 or R5X4 viruses were all able to replicate in peripheral blood mononuclear cells that did not express CCR5. When tested using coreceptor-transfected cell lines, one R5 virus was also able to use CXCR6, and another R5X4 virus could use CCR3, BOB/GPR15, and CXCR6. The R5X4 and X4 viruses contained more-diverse V3 loop sequences, with a higher overall positive charge, than the R5 viruses. Hence, some HIV-1 subtype C viruses are able to use CCR5, CXCR4, or both CXCR4 and CCR5 for entry, and they are sensitive to specific inhibitors of entry via these coreceptors. These observations are relevant to understanding the rapid spread of HIV-1 subtype C in the developing world and to the design of intervention and treatment strategies.

Mycobacterium tuberculosis-Induced CXCR4 and Chemokine Expression Leads to Preferential X4 HIV-1 Replication in Human Macrophages

“…The observation that a large proportion of HIV-1 derived from the lung during TB has CD14 in its envelope supports the conclusion that AM are the major source of viral replication. Interaction of gp120 with CXCR4 is probably due to electrostatic interactions between the positively charged coreceptor binding site of the V3 loop in gp120 and the negatively charged extracellular domains of CXCR4 (45,46). All CD14-captured viruses had V3 loops with higher positive charge than the loops of input or CD26-captured viruses.…”

Differential Expression of Rac-1, Cxcr4 and CCR5 on CD4 T-Cells at Different Stages of HIV-1 Disease Relate To Its Progression in Therapy Naive Individuals

“…On the other hand, in advanced stage of the disease with CD4 count <250 cells/μl, the number of CCR5 positive Treg were significantly lower when compared to HIV-1 individuals in early stage of disease (p=0.0022). With previous reports in non-subtype C infections, the depletion of CCR5 expressing memory cells in acute infection may drive viral evolution towards CXCR4 [28,29], and recent reports showing about 30% of CXCR4-utilising viruses in untreated and treated HIV-1 subtype C infected adults from South Africa, Malawi, and Zimbabwe, suggesting a shift in viral properties [30][31][32]. This change in CCR5 expression might be responsible for increase in the frequency of Treg cells in the advanced stages of the disease.…”

Structural Descriptors of gp120 V3 Loop for the Prediction of HIV-1 Coreceptor Usage

“…Indicator performs prediction based on an SVM using a binary sequence encoding, which uses a bit-vector to indicate the presence or absence of a specific amino acid at a specific V3 loop sequence position. We evaluated the two structural descriptors and the two sequence-based predictors on data compiled from the Los Alamos HIV Sequence Database and several publications [14,[34][35][36][37]. The evaluation is performed on a dataset containing 514 mutually distinct V3 sequences (SEQ indels,514 ) and a smaller subset, containing 432 sequences without indels (SEQ noindels,432 ).…”

“…From the HIV Sequence Database at Los Alamos National Laboratory and several publications [14,[34][35][36][37], we obtained 1,100 clonal samples with annotated coreceptor phenotype from 332 patients. To reduce the risk of positively biased results, we removed all duplicate V3 sequences (i.e., sequences with 100% sequence identity to another sequence in the dataset), resulting in 514 mutually distinct sequences.…”