Intrinsic Obstacles to Human Immunodeficiency Virus Type 1 Coreceptor Switching

Abstract

The natural evolution of human immunodeficiency virus type 1 infection often includes a switch in coreceptor preference late in infection from CCR5 to CXCR4, a change associated with expanded target cell range and worsened clinical prognosis. Why coreceptor switching takes so long is puzzling, since it requires as few as one to two mutations. Here we report three obstacles that impede the CCR5-to-CXCR4 switch. Coreceptor switch variants were selected by target cell replacement in vitro. Most switch variants showed diminished replication compared to their parental R5 isolate. Transitional intermediates were more sensitive to both CCR5 and CXCR4 inhibitors than either the parental R5 virus or the final R5X4 (or rare X4) variant. The small number of mutations in viruses selected for CXCR4 use were distinctly nonrandom, with a dominance of charged amino acid substitutions encoded by G-to-A transitions, changes in N-linked glycosylation sites, and isolate-specific mutation patterns. Diminished replication fitness, less-efficient coreceptor use, and unique mutational pathways may explain the long delay from primary infection until the emergence of CXCR4-using viruses.The entry of human immunodeficiency virus type 1 (HIV-1) into target cells requires binding of the viral envelope glycoprotein gp120 to CD4 and one of two chemokine receptors, CCR5 or CXCR4 (1,9,15,17,19). Although other chemokine receptors have been identified as potential entry factors, only CCR5 and CXCR4 appear to be important for infection by clinical isolates of HIV-1 (53, 54). This observation is reflected in the current nomenclature for HIV-1 coreceptor use (E. A. Berger, R. W. Doms, E. M. Fenyo, B. T. Korber, D. R. Littman, J. P. Moore, Q. J. Sattentau, H. Schuitemaker, J. Sodroski, and R. A. Weiss, Letter, Nature 391:240, 1998): R5 for viruses that use only CCR5, X4 for viruses that use only CXCR4, and R5X4 for viruses that can use both receptors. R5 virus isolates are equivalent to macrophage-tropic, non-syncytium-inducing (NSI) viruses, and R5X4 or X4 isolates are T-cell-tropic, syncytium-inducing viruses (43,44,47), with only a few interesting exceptions (51, 52). R5 HIV-1 accounts for the vast majority of primary infections regardless of the route of transmission (12,43). During the evolution of virus populations (quasispecies) within an infected individual, coreceptor switching from R5 to X4 is common in clade B HIV-1 infection (12, 43) and less common in clade C infection (29,40). The R5-to-X4 coreceptor switch is a harbinger of accelerated clinical disease progression and typically occurs after 8 to 10 years of infection (6, 11). The issue of coreceptor switching has become relevant to drug resistance as coreceptor inhibitors enter clinical trials (18,37,48,49). Coreceptor switching is one route to resistance to these compounds (37, 49).Coreceptor use maps to the variable V3 and V2 loops of gp120, and the R5-to-X4 switch is often accompanied by an increase in charged residues in the V3 loop (7,8,20,25,27,42,46). As few as one or two amino...

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“…2, lane 5). N-terminal sequencing of both ϳ120 kDa bands resulted in the sequence EKLWVTVYYGVPVWK, which corresponds with 100% accuracy to the known N-terminal sequence of gp120 BaL (22).…”

Fitness Epistasis and Constraints on Adaptation in a Human Immunodeficiency Virus Type 1 Protein Region

“…V3 determines which coreceptor is used by the virus (Hwang et al 1991) through its sequence variation (Dittmar et al 1997;Speck et al 1997;Cormier and Dragic 2002), although have shown that the contiguous first and second variable regions (V1/V2) and the second conserved region (C2), which separates V1/V2 from V3, may also be involved. Pastore et al (2004) used selection experiments to identify the amino acid changes putatively involved in coreceptor switching. They selected for CXCR4 use in CCR5-adapted HIV-1 strains by passaging (serially transferring) virus through cell cultures containing progressively increasing proportions of CXCR4-expressing cells.…”

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

“…It is generally believed that relatively late appearance of X4 virus variants is driven by evolution of virus population during the course of disease [42]. This assumption is in conflict with viral property of rapid turnover of about 10 10 to 10 12 virions every two days combined with the high mutation rate of HIV [42][43][44][45][46][47][48][49][50]. This should result in emergence of X4 variants fairly early during infection, especially because, in some cases, only two mutations are thought to be necessary for co-receptor switch.…”