Identification of interdependent variables that influence coreceptor switch in R5 SHIVSF162P3N-infected macaques

ABSTRACTThe phase III RV144 human immunodeficiency virus (HIV) vaccine trial conducted in Thailand remains the only study to show efficacy in decreasing the HIV acquisition risk. In Thailand, circulating recombinant forms of HIV clade A/E (CRF01_AE) predominate; in such viruses,envoriginates from clade E (HIV-E). We constructed a simian-human immunodeficiency virus (SHIV) chimera carryingenvisolated from an RV144 placebo recipient in the SHIV-1157ipd3N4 backbone. The latter contains long terminal repeats (LTRs) with duplicated NF-κB sites, thus resembling HIV LTRs. We devised a novel strategy to adapt the parental infectious molecular clone (IMC), R5 SHIV-E1, to rhesus macaques: the simultaneous depletion of B and CD8+cells followed by the intramuscular inoculation of proviral DNA and repeated administrations of cell-free virus. High-level viremia and CD4+T-cell depletion ensued. Passage 3 virus unexpectedly caused acute, irreversible CD4+T-cell loss; the partially adapted SHIV had become dual tropic. Virus and IMCs with exclusive R5 tropism were reisolated from earlier passages, combined, and used to complete adaptation through additional macaques. The final isolate, SHIV-E1p5, remained solely R5 tropic. It had a tier 2 neutralization phenotype, was mucosally transmissible, and was pathogenic. Deep sequencing revealed 99% Env amino acid sequence conservation; X4-only and dual-tropic strains had evolved independently from an early branch of parental SHIV-E1. To conclude, our primate model data reveal that SHIV-E1p5 recapitulates important aspects of HIV transmission and pathobiology in humans.IMPORTANCEUnderstanding the protective principles that lead to a safe, effective vaccine against HIV in nonhuman primate (NHP) models requires test viruses that allow the evaluation of anti-HIV envelope responses. Reduced HIV acquisition risk in RV144 has been linked to nonneutralizing IgG antibodies with a range of effector activities. Definitive experiments to decipher the mechanisms of the partial protection observed in RV144 require passive-immunization studies in NHPs with a relevant test virus. We have generated such a virus by insertingenvfrom an RV144 placebo recipient into a SHIV backbone with HIV-like LTRs. The final SHIV-E1p5 isolate, grown in rhesus monkey peripheral blood mononuclear cells, was mucosally transmissible and pathogenic. Earlier SHIV-E passages showed a coreceptor switch, again mimicking HIV biology in humans. Thus, our series of SHIV-E strains mirrors HIV transmission and disease progression in humans. SHIV-E1p5 represents a biologically relevant tool to assess prevention strategies.

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

Journal of Virology ◽

10.1128/jvi.01865-09 ◽

2009 ◽

Vol 84 (1) ◽

pp. 340-351 ◽

Cited By ~ 16

Author(s):

Wuze Ren ◽

Silvana Tasca ◽

Ke Zhuang ◽

Agegnehu Gettie ◽

James Blanchard ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Rhesus Macaques ◽

Cell Loss ◽

Common Mechanism ◽

Anatomic Site ◽

Immunodeficiency Virus ◽

Coreceptor Switch ◽

Mechanistic Basis ◽

Virus Emergence

ABSTRACT We previously reported coreceptor switch in rhesus macaques inoculated intravenously with R5 simian-human immunodeficiency virus SF162P3N (SHIVSF162P3N). Whether R5-to-X4 virus evolution occurs in mucosally infected animals and in which anatomic site the switch occurs, however, were not addressed. We herein report a change in coreceptor preference in macaques infected intrarectally with SHIVSF162P3N. The switch occurred in infected animals with high levels of virus replication and undetectable antiviral antibody response and required sequence changes in the V3 loop of the gp120 envelope protein. X4 virus emergence was associated with an accelerated drop in peripheral CD4+ T-cell count but followed rather than preceded the onset of CD4+ T-cell loss. The conditions, genotypic requirements, and patterns of coreceptor switch in intrarectally infected animals were thus remarkably consistent with those found in macaques infected intravenously. They also overlapped with those reported for humans, suggestive of a common mechanism for coreceptor switch in the two hosts. Furthermore, two independent R5-to-X4 evolutionary pathways were identified in one infected animal, giving rise to dual-tropic and X4 viruses which differed in switch kinetics and tissue localization. The dual-tropic switch event predominated early, and the virus established infection in multiple tissues sites. In contrast, the switch to X4 virus occurred later, initiating and expanding mainly in peripheral lymph nodes. These findings help define R5 SHIVSF162P3N infection of rhesus macaques as a model to study the mechanistic basis, dynamics, and sites of HIV-1 coreceptor switch.

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Conserved Changes in Envelope Function during Human Immunodeficiency Virus Type 1 Coreceptor Switching

Journal of Virology ◽

10.1128/jvi.02792-06 ◽

2007 ◽

Vol 81 (15) ◽

pp. 8165-8179 ◽

Cited By ~ 18

Author(s):

Cristina Pastore ◽

Rebecca Nedellec ◽

Alejandra Ramos ◽

Oliver Hartley ◽

John L. Miamidian ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Envelope Function ◽

Site Directed Mutagenesis ◽

Target Cells ◽

Immunodeficiency Virus ◽

Coreceptor Switch ◽

Soluble Cd4

ABSTRACT We studied the evolution of human immunodeficiency virus type 1 (HIV-1) envelope function during the process of coreceptor switching from CCR5 to CXCR4. Site-directed mutagenesis was used to introduce most of the possible intermediate mutations in the envelope for four distinct coreceptor switch mutants, each with a unique pattern of CCR5 and CXCR4 utilization that extended from highly efficient use of both coreceptors to sole use of CXCR4. Mutated envelopes with some preservation of entry function on either CCR5- or CXCR4-expressing target cells were further characterized for their sensitivity to CCR5 or CXCR4 inhibitors, soluble CD4, and the neutralizing antibodies b12-IgG and 4E10. A subset of mutated envelopes was also studied in direct CD4 or CCR5 binding assays and in envelope-mediated fusion reactions. Coreceptor switch intermediates displayed increased sensitivity to CCR5 inhibitors (except for a few envelopes with mutations in V2 or C2) that correlated with a loss in CCR5 binding. As use of CXCR4 improved, infection mediated by the mutated envelopes became more resistant to soluble CD4 inhibition and direct binding to CD4 increased. These changes were accompanied by increasing resistance to the CXCR4 inhibitor AMD3100. Sensitivity to neutralizing antibody was more variable, although infection of CXCR4-expressing targets was generally more sensitive to neutralization by both b12-IgG and 4E10 than infection of CCR5-expressing target cells. These changes in envelope function were uniform in all four series of envelope mutations and thus were independent of the final use of CCR5 and CXCR4. Decreased CCR5 and increased CD4 binding appear to be common features of coreceptor switch intermediates.

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Absence of Coreceptor Switch with Disease Progression in Human Immunodeficiency Virus Infections in India

Virology ◽

10.1006/viro.2000.0297 ◽

2000 ◽

Vol 271 (2) ◽

pp. 253-258 ◽

Cited By ~ 89

Author(s):

D. Cecilia ◽

S.S. Kulkarni ◽

S.P. Tripathy ◽

R.R. Gangakhedkar ◽

R.S. Paranjape ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Disease Progression ◽

Virus Infections ◽

Immunodeficiency Virus ◽

Coreceptor Switch

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HIV-1 coreceptor switch during 2 years of structured treatment interruptions

European Journal of Clinical Microbiology & Infectious Diseases ◽

10.1007/s10096-013-1911-z ◽

2013 ◽

Vol 32 (12) ◽

pp. 1565-1570 ◽

Cited By ~ 2

Author(s):

S. Baroncelli ◽

C. M. Galluzzo ◽

M. Andreotti ◽

M. F. Pirillo ◽

V. Fragola ◽

...

Keyword(s):

Treatment Interruptions ◽

Coreceptor Switch ◽

Hiv 1

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Evolution of CCR5 Use before and during Coreceptor Switching

Journal of Virology ◽

10.1128/jvi.01141-08 ◽

2008 ◽

Vol 82 (23) ◽

pp. 11758-11766 ◽

Cited By ~ 28

Author(s):

Mia Coetzer ◽

Rebecca Nedellec ◽

Janelle Salkowitz ◽

Sherry McLaughlin ◽

Yi Liu ◽

...

Keyword(s):

Envelope Gene ◽

Virus Population ◽

Ccr5 Expression ◽

Immunodeficiency Virus ◽

Coreceptor Switch ◽

Transmitted Sequence ◽

Rapid Divergence ◽

Selective Forces ◽

Hiv 1

ABSTRACT The envelope gene (env) of human immunodeficiency virus type 1 (HIV-1) undergoes rapid divergence from the transmitted sequence and increasing diversification during the prolonged course of chronic infection in humans. In about half of infected individuals or more, env evolution leads to expansion of the use of entry coreceptor from CCR5 alone to CCR5 and CXCR4. The stochastic nature of this coreceptor switch is not well explained by host selective forces that should be relatively constant between infected individuals. Moreover, differences in the incidence of coreceptor switching among different HIV-1 subtypes suggest that properties of the evolving virus population drive the switch. We evaluated the functional properties of sequential env clones from a patient with evidence of coreceptor switching at 5.67 years of infection. We found an abrupt decline in the ability of viruses to use CCR5 for entry at this time, manifested by a 1- to 2-log increase in susceptibility to CCR5 inhibitors and a reduced ability to infect cell lines with low CCR5 expression. There was an abnormally rapid 5.4% divergence in env sequences from 4.10 to 5.76 years of infection, with the V3 and V4/V5 regions showing the greatest divergence and evidence of positive selection. These observations suggest that a decline in the fitness of R5 virus populations may be one driving force that permits the emergence of R5X4 variants.

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